Methods and materials for inhibiting NF-kB activity

This document provides compounds that are inhibitors of NF-κB activity, as well as the methods of using such compounds for treating diseases and conditions such as cancer, inflammatory conditions, or autoimmune diseases.

1. 11. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IIIa): or a pharmaceutically acceptable salt thereof, wherein: X1 is selected from O, S, and NRN; RN is selected from H and C1-6 alkyl; X2 is selected from S(O) and S(O)2; RS is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11; each R11 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1; each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1 NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12; each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.

CLAIM OF PRIORITY
This application is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2020/061670, having an International Filing Date of Nov. 20, 2020 which claims priority to U.S. Provisional Patent Application Ser. No. 63/059,488, filed on Jul. 31, 2020, and U.S. Provisional Patent Application Ser. No. 62/938,820, filed on Nov. 21, 2019, the entire contents of which are hereby incorporated by reference.


FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
This invention was made with government support under grant numbers HL139860, HL142777, HL142663, and HL142589 awarded by National Institutes of Health (NIH). The government has certain rights in the invention.


TECHNICAL FIELD
This document relates to methods and materials for inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. For example, this document provides compounds (e.g., organic compounds) having the ability to inhibit NF-κB activity within cells, formulations containing one or more compounds having the ability to inhibit NF-κB activity within cells, methods for making one or more compounds having the ability to inhibit NF-κB activity within cells, methods for inhibiting NF-κB activity within cells, and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of NF-κB activity.
BACKGROUND
The transcription factor NF-κB is a key regulator of both the innate and adaptive immune response to various pathogens. Activated by an array of stressors, NF-κB protein complexes initiate expression of a wide array of cytokines and other inflammatory mediators. Inappropriate or excessive activation of an NF-κB regulatory pathway can lead to excessive inflammation, which may be harmful to an individual and may lead to numerous disease states. Reducing excessive inflammation, acute or chronic, may be beneficial, for example, in a number of auto-immune conditions.
SUMMARY
This document provides methods and materials for inhibiting NF-κB activity. For example, the document provides compounds (e.g., organic compounds) having the ability to inhibit NF-κB activity within cells, formulations containing one or more compounds having the ability to inhibit NF-κB activity within cells, methods for making one or more compounds having the ability to inhibit NF-κB activity within cells, methods for making formulations containing one or more compounds having the ability to inhibit NF-κB activity within cells, methods for inhibiting NF-κB activity within cells, and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of NF-κB activity. Suitable examples of conditions responsive to inhibition of NF-κB activity within cells include autoimmune conditions, such as Crohn's disease, ulcerative colitis, colitis, psoriatic arthritis, systemic lupus, erythematosis (SLE), and psoriasis.
As described herein, the methods and materials provided herein can be used to inhibit NF-κB activity within cells in vitro, in vivo, or ex vivo. In some cases, the compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition associated with activation of an NF-κB polypeptide complex within cells. In some cases, one or more compounds provided herein can be used to treat mammals (e.g., humans) having a disease, disorder, or condition that is responsive to inhibition of NF-κB activity.
In one general aspect, the present disclosure provides a method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Ia):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, Y1, Y2, R5, R6, and ring A are as described herein.
    
    


In another general aspect, the present disclosure provides a compound of Formula (Ib):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R5, R6, R7, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically available carrier.
In yet another general aspect, the present disclosure provides a method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Ic):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Id):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a compound of Formula (Ie):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, ring A, R3, R4, R5, R6, and R7 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (Ie), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (If):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, ring A, R1, R2, R3, R4, R5, and R6 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (If), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (Ig):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a method of inhibiting activation of an NF-κB pathway within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R2, R3, R4, R5, R6, R7, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a compound of Formula (IIb):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN, Hal, R2, R4, R5, R8 and R11 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN, RB, R2, R4, R5, R7 and R11 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IId):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RA, R1, R2, R4, R5, R6, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IId), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN, R2a, R2b, R4, R5, RB, R7, and R11 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIe), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN, R2a, R2b, R4, R5, RB, R7, and R11 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIf), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN, R2a, R2b, R4, R5, RB, R7, and R11 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIg), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IIIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, RS, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a compound selected from any one of the compounds of Table 3b, or a pharmaceutically acceptable salt thereof.
In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising any one of the compound of Table 3b, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIc), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIId):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIId), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, RN2, RN1, R1, R2, R3, R4, R5, R6, R7, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIe), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, R5, R6, R7, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIf), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIg-2):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIg-2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIg), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIh):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R3, R4, R5, R8 and R9 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIh), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IIIi):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, X2, R1, R2, R3, R4, R5, R6 and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IIIi), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IVa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein RN1, RN2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a compound selected from any one of the compounds of Table 4b, or a pharmaceutically acceptable salt thereof.
In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising any one of the compounds of Table 4b, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVb):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, and R5 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, and R5 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVc), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVd):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, and R5 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVd), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVe):




or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R5, R7, and R8 are as described herein.
In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVe), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R5, R7, and R8 are as described herein.
    
    


In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVf), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a compound of Formula (IVg):




or a pharmaceutically acceptable salt thereof, wherein R1, R2, ring A, RN1, and RN2 are as described herein.
In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (IVg), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In yet another general aspect, the present disclosure provides a method of treating a mammal having a disease, disorder, or condition responsive to inhibiting NF-κB activity within a cell, wherein said method comprises administering, to said mammal, any one of the compounds described herein, or a pharmaceutical composition comprising same. In some embodiments, the mammal is a human. In some embodiments, the method comprises treating a mammal having a cancer. In some embodiments, the method comprises treating a mammal having an inflammation. In some embodiments, the inflammation is an autoimmune disease.
In yet another general aspect, the present disclosure provides a method for inhibiting NF-κB activity within cells of a mammal, wherein said method comprises administering, to said mammal, any one of the compounds described herein or a pharmaceutical composition comprising same.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.



DESCRIPTION OF DRAWINGS
FIG. 1 contains line plots showing NF-κB activity of exemplified compounds. 25k THP1-NF-κB-LUC cells were dispensed into 384 well plate (per well). Cells were treated with compounds (2 μM and 0.2 μM) for 2 hours before addition of LPS (10 ng/mL) for 18 hours. Secreted luciferase activity were measured using quant-luc reagents (1 bag of luc reagent dilute to 40 mL, use 10 μL per well). Data were normalized to vehicle control and graphed. Structures of selected exemplified compounds are shown.
FIG. 2 contains heat charts showing NF-κB activity of exemplified compounds as a function of concentration. 25k THP1-NF-κB-LUC cells were dispensed into 384 well plate (per well). Cells were treated with compounds (with serial dilution) for 2 hours before addition of LPS (10 ng/ml) for 18 hours. Secreted luciferase activity were measured using quant-luc reagents (1 bag of luc reagent dilute to 40 mL, use 10 μL per well). Structures of selected exemplified compounds are shown.
FIG. 3 contains heat charts showing NF-κB activity of exemplified compounds as a function of concentration. 25k THP1-NF-κB-LUC cells were dispensed into 384 well plate (per well). Cells were treated with compounds (with serial dilution) for 2 hours before addition of Pam3CSK4 (1 g/mL) for 18 hours. Secreted luciferase activity were measured using quant-luc reagents (1 bag of luc reagent dilute to 40 mL, use 10 μL per well). Structures of selected exemplified compounds are shown.
FIG. 4 contains heat charts showing NF-κB activity of exemplified compounds as a function of concentration. 25k THP1-NF-κB-LUC cells were dispensed into 384 well plate (per well). Cells were treated with compounds (with serial dilution) for 2 hours before addition of R848 (1 μg/mL) for 18 hours. Secreted luciferase activity were measured using quant-luc reagents (1 bag of luc reagent dilute to 40 mL, use 10 μL per well). Structures of selected exemplified compounds are shown.
FIG. 5 contains a bar graph showing TNFα inhibitory activity for selected exemplified compounds. Mouse bone marrow macrophages were cultured in 96 well and differentiated before compound treatment at various concentrations for 2 hours. Cells were further treated with LPS (10 ng/mL) for 2 hours, and supernatants were collected and assayed for TNF.



DETAILED DESCRIPTION
This document provides methods and materials for inhibiting NF-κB activity. For example, the document provides compounds (e.g., organic compounds) having the ability to inhibit NF-κB activity within cells, formulations containing one or more compounds having the ability to inhibit NF-κB activity within cells, methods for making one or more compounds having the ability to inhibit NF-κB activity within cells, methods for making formulations containing one or more compounds having the ability to inhibit NF-κB activity within cells, methods for inhibiting NF-κB activity within cells, and methods for treating mammals (e.g., humans) having a condition responsive to inhibition of NF-κB activity. Suitable examples of conditions responsive to inhibition of NF-κB activity within cells include autoimmune conditions, such as Crohn's disease, ulcerative colitis, colitis, psoriatic arthritis, systemic lupus, erythematosis (SLE), and psoriasis.
Methods of Treatment Using One or More Inhibitors of NF-κB Activity
In some cases, this document provides methods for inhibiting NF-κB activity within a cell by contacting the cell with one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof).
In some cases, methods for inhibiting NF-κB activity within cells can be performed in vivo. For example, one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) can be administered to a mammal (e.g., a human) to inhibit NF-κB activity within cells within that mammal. In some cases, methods for inhibiting NF-κB activity within cells can be performed in vitro. For example, one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) can be added to a cell culture containing cells (e.g., human cells) to inhibit NF-κB activity within those cells. In some cases, such intervention can improve the quality of the cell while in culture or subsequently.
This document also provides methods for treating diseases, disorders, and conditions in a mammal by administering one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is responsive to inhibiting NF-κB activity within cells within the mammal. In some cases, the disease, disorder, or condition being treated can be a disease, disorder, or condition that is associated with enhanced NF-κB activity within the mammal.
Examples of diseases, disorders, and conditions that can be treated with one or more compounds provided herein include, without limitation, cancer and inflammation disorders (e.g., acute or chronic inflammation, or viral or influenza-induced inflammation such as HIV-related inflammation).
Suitable examples of disorders associated with inflammation include asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis (e.g., hypersensitivity pneumonitis and radiation pneumonitis), pneumonia, cystic fibrosis, psoriasis, arthritis, rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergy (e.g., hay fever), nephritis, conjunctivitis, encephalitis, meningitis, opthalmitis, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, diabetes, osteoarthritis, psoriatic arthritis, autoimmune diseases or conditions, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), colitis, sepsis, vasculitis, bursitis, connective tissue disease, systemic lupus erythematosis (SLE), polymyalgia rheumatica, scleroderma, Wegener's granulomatosis, temporal arteritis, vasculitis, cryoglobulinemia, multiple sclerosis, and edema.
Suitable examples of cancers include prostate cancer, pancreatic cancer, ovarian cancer, breast cancer, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a. Wilms' tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastroesophageal cancer, gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma, hepatobiliary cancer); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasmlungrectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).
In some cases, provided herein are methods for treating a cancer (e.g., any one of the cancers described herein) in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.
In some cases, provided herein are methods for treating inflammation (e.g., any one of the inflammation disorders described herein) in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.
In some cases, provided herein are methods for treating autoimmune disease (e.g., any one of the autoimmune diseases described herein) in a mammal (e.g., human) by administering one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) to a mammal in need thereof.
In some cases, one or more compounds provided herein (e.g., a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof) can be used as described herein (e.g., to inhibit NF-κB activity within cells and/or to treat a disease, disorder, or condition as described herein) as the sole active ingredient(s). For example, a composition containing a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof, can lack any other active ingredients that inhibit NF-κB activity within cells. In some cases, a composition containing a compound set forth in any one of the Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof, can lack any other active ingredients that are effective to treat a disease, disorder, or condition as described herein.
Therapeutic Compounds
As described herein, any one or more of the compounds provided herein can be used to inhibit NF-κB activity within cells and/or can be used to treat (or prevent) a disease, disorder, and condition in a mammal (e.g., a human) as described herein.
Formula (Ia)
In one general aspect, the present disclosure provides a compound of Formula (Ia):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        Y1 is selected from C(O) and S(O)2;
        Y2 is selected from C(O) and S(O)2;
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        X3 is selected from N and CR3;
        X4 is selected from N and CR4;
        provided that no more than two of X1, X2, X3, and X4 are N;
        each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R5 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1 wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, Y1 is C(O). In some embodiments, Y1 is S(O)2.
In some embodiments, Y2 is C(O). In some embodiments, Y2 is S(O)2.
In some embodiments, Y1 is C(O) and Y2 is S(O)2. In some embodiments, Y1 is C(O) and Y2 is C(O). In some embodiments, Y1 is S(O)2 and Y2 is S(O)2. In some embodiments, Y1 is S(O)2 and Y2 is C(O).
In some embodiments, X1 is N. In some embodiments, X1 is CR1. In some embodiments, X2 is N. In some embodiments, X2 is CR2. In some embodiments, X3 is N. In some embodiments, X3 is CR3. In some embodiments, X4 is N. In some embodiments, X4 is CR1. In some embodiments, one of X1, X2, X3, and X4 is N. In some embodiments, two of X1, X2, X3, and X4 are N.
In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is substituted with 1-6 substituents independently selected from RA.
In some embodiments, ring A is C6-10 aryl, substituted with 1-5 substituents independently selected from RA. In some embodiments, ring A is phenyl, optionally substituted with 1-5 substituents independently selected from RA. In some embodiments, ring A is naphthyl, optionally substituted with 1-5 substituents independently selected from RA.
In some embodiments, ring A is 5-10 membered heteroaryl, substituted with 1-6 substituents independently selected from RA. In some embodiments, ring A is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazlol-4-yl, pyrazol-5-yl, quinolin-6-yl, quinolin-7-yl, thiazolyl, 1,3,4-thiadiazolyl, and quinoxaline-6-yl, each of which is optionally substituted with 1-6 substituents independently selected from RA.
In some embodiments, ring A is selected from any one of the following moieties:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, ring A is:




In some embodiments, the compound of Formula (Ia) is selected from any one of the following compounds:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, RA is H. In some embodiments, RA is halo. In some embodiments, RA is CN. In some embodiments, RA is C1-6 alkyl. In some embodiments, RA is C1-6 alkoxy.
In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7.
In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, and ORa1. In some embodiments, at least one of R1, R2, R3, R4, and R6 is H. In some embodiments, at least one of R1, R2, R3, R4, and R6 is halo. In some embodiments, at least one of R1, R2, R3, R4, and R6 is CN. In some embodiments, at least one of R1, R2, R3, R4, and R6 is C1-6 alkyl. In some embodiments, at least one of R1, R2, R3, R4, and R6 is ORa1.
In some embodiments, R1, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; R2, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl; R3, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl; R4, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and R6, if present in the compound of Formula (Ia), is selected from H and OH. In some embodiments, R6 is OH.
In some embodiments, R7 is selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, R8 is selected from Cy1, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, R8 is selected from Cy1 and C(O)NRc1Rd1. In some embodiments, R8 is Cy1. In some embodiments, R8 is C(O)NRc1Rd1.
In some embodiments, R5 is H.
In some embodiments, R5 is Cy1.
In some embodiments, R5 is C1-6 alkyl, optionally substituted with Cy1. In some embodiments, R5 is C1-6 alkyl substituted with Cy1. I In some embodiments, R5 is C1-6 alkyl, optionally substituted with C(O)NRc1Rd1. In some embodiments, R5 is C1-6 alkyl substituted with C(O)NRc1Rd1.
In some embodiments, Cy1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1.
In some embodiments, Cy1 is C6-10 aryl, optionally substituted with RCy1. In some embodiments, RCy1 is selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl. In some embodiments, RCy1 is halo.
In some embodiments, Cy1 is C6-10 aryl, optionally substituted with halo.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, each R8 is independently selected from halo and C1-6 alkyl.
In some embodiments of Formula (Ia):

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        R7 is selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments of Formula (Ia):

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, and ORa1;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1 and C(O)NRc1Rd1;
        Cy1 is C6-10 aryl, optionally substituted with RCy1;
        RCy1 is selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        wherein each Rg is independently selected from halo and C1-6 alkyl.
    
    


In some embodiments:

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy;
        R1, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R2, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R3, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R4, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R6, if present in the compound of Formula (Ia), is selected from H and OH.
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1 and C(O)NRc1Rd1;
        Cy1 is C6-10 aryl, optionally substituted with halo;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from halo and C1-6 alkyl.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (Ia) is selected from any one of the compounds of Table 1a, Table 1d, or Table 1e, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) is selected from any one of the compounds of Table 1a, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (Ia) is selected from any one of the compounds of Table 1d, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) is selected from any one of the compounds of Table 1e, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (Ia) has Formula (Ib), or a pharmaceutically acceptable salt thereof.
Formula (Ib):
In one general aspect, the present disclosure provides a compound of Formula (Ib):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        X3 is selected from N and CR3;
        X4 is selected from N and CR4;
        provided that at least one of X1, X2, X3, and X4 is N;
        each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R5 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R7 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1.
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is N. In some embodiments, X1 is CR1. In some embodiments, X2 is N. In some embodiments, X2 is CR2. In some embodiments, X3 is N. In some embodiments, X3 is CR3. In some embodiments, X4 is N. In some embodiments, X4 is CR1. In some embodiments, one of X1, X2, X3, and X4 is N. In some embodiments, two of X1, X2, X3, and X4 are N.
In some embodiments, the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R7 and R8 are each independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, R7 and R8 are each independently selected from H, halo, and C1-6 alkyl. In some embodiments, R7 is H and R8 is halo. In some embodiments, R7 is halo and R8 is H. In some embodiments, R7 is C1-6 alkyl and R8 is halo. In some embodiments, R7 is halo and R8 is C1-6 alkyl. In some embodiments, R7 and R8 are each halo. In some embodiments, R8 is F.
In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, and ORa1. In some embodiments, at least one of R1, R2, R3, and R4 is selected from halo and C1-6 alkoxy. In some embodiments, R6 is H. In some embodiments, R6 is OH.
In some embodiments:

    
    
        each of R1, R2, R3, and R4, if present in the compound of Formula (Ib), is independently selected from H, halo, and C1-6 alkoxy; and
        R6 is selected from H and OH.
    
    


In some embodiments, R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R5 is selected from H and C1-6 alkyl.
In some embodiments, R5 is H.
In some embodiments, R5 is Cy1.
In some embodiments, R5 is C1-6 alkyl, optionally substituted with R10.
In some embodiments, R10 is selected from Cy1, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1. In some embodiments, R10 is ORa1. In some embodiments, R10 is C(O)NRc1Rd1. In some embodiments, R10 is C(O)ORa1. In some embodiments, R10 is NRc1Rd1.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
In some embodiments:

    
    
        R7 and R8 are each independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10, and
        Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
    
    


In some embodiments:

    
    
        R7 and R8 are each independently selected from H, halo, and C1-6 alkyl;
        each of R1, R2, R3, and R4, if present in the compound of Formula (Ib), is independently selected from H, halo, and C1-6 alkoxy;
        R6 is selected from H and OH;
        R5 is selected from H and C1-6 alkyl; and
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (Ib) is selected from any one of the compounds of Table 1d, or a pharmaceutically acceptable salt thereof.
In one general aspect, the present disclosure provides a compound selected from any one of the compounds of Table 1e, or a pharmaceutically acceptable salt thereof.
Formula (Ic):
In a general aspect, the present disclosure provides a compound of Formula (Ic):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB,
        each RB is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RB.
In some embodiments, each RB is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, and C(O)ORa1.
In some embodiments, at least one of R1, R2, R3, R4, and R5 is halo. In some embodiments, at least one of R1, R2, R3, R4, and R5 is ORa1. In some embodiments, at least one of R1, R2, R3, R4, and R5 is C1-6 alkoxy.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, and C1-6 alkoxy.
In some embodiments, each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RC.
In some embodiments, each RC is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, and C1-6 alkyl. In some embodiments, at least one of R6, R7, R8, R9, and R10 is halo. In some embodiments, at least one of R6, R7, R8, R9, and R10 is CN. In some embodiments, at least one of R6, R7, R8, R9, and R10 is C1-6 alkyl.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
In some embodiments:

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1,
        NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
    
    


In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, and C1-6 alkoxy; and each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, and C1-6 alkyl.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (Ic) is selected from any one of the compound of Table 1b, or a pharmaceutically acceptable salt thereof.
Formula (Id):
In one general aspect, the present disclosure provides a compound of Formula (Id)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R2, R3, and R4 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R5, R6, R7, R8, and R9 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, R1 is H. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is selected from H, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R1 is selected from H and C1-6 alkyl. In some embodiments, R1 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, each R10 is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each R10 is independently selected from OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, each of R2, R3, and R4 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is each optionally substituted with 1, 2, or 3 substituents independently selected from RB.
In some embodiments, each RB is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each RB is independently selected from OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, each of R2, R3, and R4 is independently selected from H and C1-6 alkyl. In some embodiments, R3 is H, and R2 and R4 are each C1-6 alkyl.
In some embodiments, each of R5, R6, R7, R8, and R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, and ORa1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RC.
In some embodiments, each RC is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each RC is independently selected from OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2. In some embodiments, each of R5, R6, R7, R8, and R9 is independently selected from H and halo. In some embodiments, at least one of R5, R6, R7, R8, and R9 is halo.
In some embodiments, each of Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg.
In some embodiments, each of Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
In some embodiments:

    
    
        R1 is H;
        each of R2, R3, and R4 is independently selected from H and C1-6 alkyl; and
        each of R5, R6, R7, R8, and R9 is independently selected from H and halo.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (Id) is selected from any one of the compounds of Table 1c, or a pharmaceutically acceptable salt thereof.
Formula (Ie)
In one general aspect, the present disclosure provides a compound of Formula (Ie):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        each R1, R2, R3, R4, R5, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8,
        each R8 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R7 is selected from ORa2 and NRc2Rd2;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each R8 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H and C1-6 alkyl.
In some embodiments, R7 is ORa2. In some embodiments, R7 is OH. In some embodiments, R7 is C1-6 alkoxy. In some embodiments, R7 is NRc2Rd2. In some embodiments, R7 is amino. In some embodiments, R7 is C1-6 alkylamino. In some embodiments, R7 is di(C1-6 alkyl)amino.
In some embodiments, ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA.
In some embodiments, ring A is C6-10 aryl, substituted with 1-5 substituents independently selected from RA. In some embodiments, ring A is phenyl, optionally substituted with 1-5 substituents independently selected from RA. In some embodiments, ring A is naphthyl, optionally substituted with 1-5 substituents independently selected from RA.
In some embodiments, ring A is 5-10 membered heteroaryl, substituted with 1-6 substituents independently selected from RA. In some embodiments, ring A is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazlol-4-yl, pyrazol-5-yl, quinolin-6-yl, quinolin-7-yl, thiazolyl, 1,3,4-thiadiazolyl, and quinoxaline-6-yl, each of which is optionally substituted with 1-6 substituents independently selected from RA.
In some embodiments, ring A is selected from any one of the following moieties:




In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, RA is H. In some embodiments, at least one RA is halo. In some embodiments, at least one RA is CN. In some embodiments, at least one RA is C1-6 alkyl. In some embodiments, at least one RA is C1-6 alkoxy.
In some embodiments, each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H and C1-6 alkyl. In some embodiments, Rc2 is H and Rd2 is C1-6 alkyl. In some embodiments, Rc2 and Rd2 are both H. In some embodiments, Rc2 and Rd2 are both C1-6 alkyl.
In some embodiments:

    
    
        R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1 and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments:

    
    
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, OH, C1-6 alkyl, and C1-6 alkoxy;
        ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy; and
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H and C1-6 alkyl.
    
    


In some embodiments, each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (Ie) is selected from any one of the compounds of Table If, or a pharmaceutically acceptable salt thereof.
Formula (If)
In one general aspect, the present disclosure provides a compound of Formula (If):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R1, R3, R4, R5, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
    
    


each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;

    
    
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is S.
In some embodiments, X1 is S(O).
In some embodiments, X1 is S(O)2.
In some embodiments, R1, R3, R4, R5, and R6 is independently selected from H, halo, OH, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, R1, R3, R4, R5, and R6 are each H.
In some embodiments, R2 is selected from H, C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl.
In some embodiments:

    
    
        R1, R3, R4, R5, and R6 is independently selected from H, halo, OH, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino;
        R2 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and ring A is C6-10 aryl, optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl.
    
    


In some embodiments, the compound of Formula (If) is selected from any one of the compound of Table 1g, or a pharmaceutically acceptable salt thereof.
Formula (Ig)
In one general aspect, the present disclosure provides a compound of Formula (Ig):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R2, R3, and R4 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
        each of R5, R6, R7, R8, and R9 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is selected from S(O) and S(O)2.
In some embodiments, R1 is H.
In some embodiments, each of R2, R3, and R4 is independently selected from H and C1-6 alkyl.
In some embodiments, each of R5, R6, R7, R8, and R9 is independently selected from H, halo, and C1-6 alkyl.
In some embodiments:

    
    
        X1 is S(O) or S(O)2;
        R1 is H;
        each of R2, R3, and R4 is independently selected from H and C1-6 alkyl; and
        each of R5, R6, R7, R8, and R9 is independently selected from H, C1-6 alkyl and halo.
    
    


In some embodiments, the compound of Formula (Ig) is selected from any one of the compounds of Table 1h, or a pharmaceutically acceptable salt thereof.
Formula (IIa)
In one general aspect, the present disclosure provides a compound of Formula (IIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from O and NR1;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, oxo, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R1 and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, S(O)2NRc1Rd1; and a group of formula (i):
    
    






    
    
        wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R7 and R8 is a group of formula (i);
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a -10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rb1, and C(O)NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R2 is selected from H and C1-6 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is C1-6 alkyl.
In some embodiments, R4 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R4 is H. In some embodiments, R4 is C1-6 alkyl.
In some embodiments, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R5 and R6 are each independently selected from H, halo, C1-6 alkyl, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with R9.
In some embodiments, R5 is H and R6 is C1-6 alkyl, optionally substituted with NRc1Rd1. In some embodiments, R5 is H and R6 is halo. In some embodiments, R5 is Hand R6 is S(O)2Rb1.
In some embodiments, R7 is selected from H and C1-6 alkyl (and R8 is a moiety of formula (i)). In some embodiments, R8 is selected from H and C1-6 alkyl (and R7 is a moiety of formula (i)).
In some embodiments, RN is selected from H and C1-6 alkyl. In some embodiments, RN is H. In some embodiments, RN is C1-6 alkyl.
In some embodiments, R11 is ring A.
In some embodiments, R11 is C1-6 alkyl, optionally substituted with ring A.
In some embodiments, RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, ring A is selected from any one of the following moieties:




In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each R11 is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with C(O)ORa1.
In some embodiments, each R9 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, OH, C1-6 alkoxy, carboxy, amino, C(O)NH2, C1-6 alkylamino, di(C1-6 alkyl)amino, and C1-6 haloalkoxy. In some embodiments, each R9 is independently selected from OH, C1-6 alkoxy, carboxy, C(O)NH2, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C(O)NH2, and carboxy.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rb1, and C(O)NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H and oxo;
        R4 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are independently selected from H, C1-6 alkyl, and a moiety of formula (i);
        RN is selected from H and C1-6 alkyl; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        R11 is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1 
        R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H and oxo;
        R4 is H;
        R5 and R6 are each independently selected from H, halo, C1-6 alkyl, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with R9;
        R7 and R8 are independently selected from H, C1-6 alkyl, and a moiety of formula (i);
        RN is selected from H and C1-6 alkyl; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with C(O)ORa1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2a, Table 2c, Table 2c-2, Table 2d, Table 2d-2, Table 2e, or Table 16, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2a, Table 2c, Table 2d, or Table 2e, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2a, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2c, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2d, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2e, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2c-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 2d-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIa) is selected from any one of the compounds of Table 16, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 16, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIa) has Formula (IIb), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIa) has Formula (IIc), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIa) has Formula (IId), or a pharmaceutically acceptable salt thereof.
Formula (IIb)
In one general aspect, the present disclosure provides a compound of Formula (IIb):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        Hal is a halogen, and
        R2, R4, R5, R8, RN, and R11 are as described herein for Formula (IIa).
    
    


In some embodiments:

    
    
        Hal is a halogen;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, for a -10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, R2 is H or C1-6 alkyl.
In some embodiments, R4 is H or C1-6 alkyl.
In some embodiments, R5 is H or C1-6 alkyl.
In some embodiments, R8 is H or C1-6 alkyl.
In some embodiments, R4, R5, and R8 are each H.
In some embodiments, RN is H.
In some embodiments, RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R11 is ring A. In some embodiments, R11 is C1-6 alkyl, optionally substituted with ring A.
In some embodiments, ring A is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R4.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1-10 substituents independently selected from RA.
In some embodiments, ring A is C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each RA is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R4, R5, and R8 are each H;
        RN is H; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; ring A is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
    
    


In some embodiments, RA is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIb) is selected from any one of the compounds of Table 2c or Table 2c-2, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIb) is selected from any one of the compounds of Table 2c, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIb) is selected from any one of the compounds of Table 2c-2, or a pharmaceutically acceptable salt thereof.
Formula (IIc)
In one general aspect, the present disclosure provides a compound of Formula (IIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1; and
        R2, R4, R5, R7, RN, and R11 are as described herein for Formula (IIa).
    
    


In some embodiments:

    
    
        RB is selected from halogen and S(O)2Rb1;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RY, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, RB is a halogen (e.g., C1, F, or Br). In some embodiments, RB is C1. In some embodiments, RB is S(O)2Rb1 (e.g., Rb1 is C1-6 alkyl). In some embodiments, RB is ethylsulfonyl.
In some embodiments, R2 is selected H and C1-6 alkyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R7 is selected H and C1-6 alkyl.
In some embodiments, RN is H.
In some embodiments, RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R11 is ring A. In some embodiments, R11 is C1-6 alkyl, optionally substituted with ring A.
In some embodiments, ring A is selected from C6-10 aryl and C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1-10 substituents independently selected from RA.
In some embodiments, ring A is C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments:

    
    
        R2 is selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        ring A is selected from C6-10 aryl and C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIc) is selected from any one of the compounds of Table 2d or Table 2d-2, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IIc) is selected from any one of the compounds of Table 2d, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIc) is selected from any one of the compounds of Table 2d-2, or a pharmaceutically acceptable salt thereof.
Formula (IId)
In one general aspect, the present disclosure provides a compound of Formula (IId):




or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R5, R6, R8, and RA are as described herein for Formula (IIa).
In some embodiments:

    
    
        R1 and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5, R6, and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1,
        C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, R2 is selected from H and C1-6 alkyl.
In some embodiments, R4 is H.
In some embodiments, R1 is selected from H, C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R9 is independently selected from OH, C1-6 alkoxy, carboxy, C(O)NH2, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, R5, R6, and R8 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy. In some embodiments, R5, R6, and R8 are each H.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each RA is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, halo, CN, OH, C1-6 alkoxy, carboxy, amino, C(O)NH2, C1-6 alkylamino, di(C1-6 alkyl)amino, and C1-6 haloalkoxy. In some embodiments, each RA is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, halo, and C1-6 alkoxy. In some embodiments, each RA is independently selected from H and C1-6 alkyl. In some embodiments, each RA is H.
In some embodiments:

    
    
        R2 is selected from H and C1-6 alkyl;
        R4 is H;
        R5, R6, and R8 are each H;
        R1 is selected from H, C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from OH, C1-6 alkoxy, carboxy, C(O)NH2, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino; and
        each RA is H.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IId) is selected from any one of the compounds of Table 2e, or a pharmaceutically acceptable salt thereof.
Formula (IIe)
In one general aspect, the present disclosure provides a compound of Formula (IIe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
    
    


ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;

    
    
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, RB is S(O)2Rb1.
In some embodiments, R2a and R2b are each independently selected from H and C1-6 alkyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R7 is selected H and C1-6 alkyl.
In some embodiments, RN is H.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, the compound of Formula (IIe) is selected from any one of the compounds of Table 2f, or a pharmaceutically acceptable salt thereof.
Formula (IIf)
In one general aspect, the present disclosure provides a compound of Formula (IIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, RB is a halogen.
In some embodiments, RB is S(O)2Rb1.
In some embodiments, R2a and R2b are each independently selected from H and C1-6 alkyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R7 is selected H and C1-6 alkyl.
In some embodiments, RN is H.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, the compound of Formula (IIf) is selected from any one of the compounds of Table 2g, or a pharmaceutically acceptable salt thereof.
Formula (IIg)
In one general aspect, the present disclosure provides a compound of Formula (IIg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, RB is a halogen.
In some embodiments, RB is S(O)2Rb1.
In some embodiments, R2a and R2b are each independently selected from H and C1-6 alkyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R7 is selected H and C1-6 alkyl.
In some embodiments, RN is H.
In some embodiments, ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
In some embodiments, each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA, and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, the compound of Formula (IIg) is selected from any one of the compounds of Table 2h, or a pharmaceutically acceptable salt thereof.
Formula (IIIa)
In one general aspect, the present disclosure provides a compound of Formula (IIIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from O, S, and NRN,
        RN is selected from H and C1-6 alkyl;
        X2 is selected from S, S(O), and S(O)2;
        RS is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        or any two adjacent R1, R2, R3, R4, and R5 groups, together with the carbon atoms to which they are attached, form a C6-10 aryl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments:

    
    
        X1 is selected from O, S, and NRN;
        RN is selected from H and C1-6 alkyl;
        X2 is selected from S, S(O), and S(O)2;
        RS is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is O. In some embodiments, X1 is S. In some embodiments, X1 is NRN. In some embodiments, X2 is S. In some embodiments, X2 is S(O). In some embodiments, X2 is S(O)2.
In some embodiments, X1 is O and X2 is S. In some embodiments, X1 is O and X2 is S(O). In some embodiments, X1 is O and X2 is S(O)2. In some embodiments, X1 is S and X2 is S. In some embodiments, X1 is S and X2 is S(O). In some embodiments, X1 is S and X2 is S(O)2. In some embodiments, X1 is NRN and X2 is S. In some embodiments, X1 is NRN and X2 is S(O). In some embodiments, X1 is NRN and X2 is S(O)2.
In some embodiments, the compound of Formula (IIIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11.
In some embodiments, RS is C1-6 alkyl, optionally substituted with Cy1, ORa1, C(O)Rb1, NRc1Rd1, and C(O)NRc1Rd1.
In some embodiments, RS is C1-6 alkyl, optionally substituted with Cy1, ORa1, C(O)Rb1, and C(O)NRc1Rd1. In some embodiments, RS is C1-6 alkyl. In some embodiments, RS is C1-6 alkyl, optionally substituted with Cy1. In some embodiments, RS is C1-6 alkyl, optionally substituted with ORa1. In some embodiments, RS is C1-6 alkyl, optionally substituted with C1-6 alkoxy. In some embodiments, RS is C1-6 alkyl, optionally substituted with C(O)Rb1. In some embodiments, RS is C1-6 alkyl, optionally substituted with C(O)NRc1Rd1.
In some embodiments, RS is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, RS is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, RS is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, RS is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, RS is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl. In some embodiments, RS is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl.
In some embodiments, each R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1. In some embodiments, R11 is Cy1. In some embodiments, R11 is halo. In some embodiments, R11 is C1-6 alkyl. In some embodiments, R11 is ORa1. In some embodiments, R11 is C1-6 alkoxy. In some embodiments, R11 is C(O)Rb1. In some embodiments, R11 is C(O)NRc1Rd1.
In some embodiments, each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1. In some embodiments, Cy1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from RCy1. In some embodiments, Cy1 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from RCy1. In some embodiments, each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, (O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R12. In some embodiments, RCy1 is halo. In some embodiments, RCy1 is C1-6 alkyl. In some embodiments, RCy1 is C1-6 haloalkyl. In some embodiments, RCy1 is ORa1. In some embodiments, RCy1 is C1-6 alkoxy. In some embodiments, RCy1 is C(O)Rb1. In some embodiments, RCy1 is NRc1Rd1. In some embodiments, each RCy1 is independently selected from halo, CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and S(O)2NH2.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy. In some embodiments, R8 is halo. In some embodiments, Rg is C1-6 alkyl.
In some embodiments:

    
    
        RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3, 4, or 5 substituents independently selected from R11;
        R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, NRc1Rd1, and C(O)NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, (O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy. In some aspects of these embodiments, R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1.
    
    


In some embodiments:

    
    
        RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3, 4, or 5 substituents independently selected from R11;
        R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1 NRc1Rd1, and C(O)NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and S(O)2NH2;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy. In some aspects of these embodiments, R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIIa) is selected from any one of the compounds of Table 3a, Table 3b, Table 3b-2, Table 10, or Table 11.
In some embodiments, the compound of Formula (IIIa) is selected from any one of the compounds of Table 3a or Table 3b, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIa) is selected from any one of the compounds of Table 3a, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIa) is selected from any one of the compounds of Table 3b, or a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 3b or Table 3b-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 3b, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 3b-2, or a pharmaceutically acceptable salt thereof.
Formula (IIIc)
In a general aspect, the present disclosure provides a compound of Formula (IIIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are as described herein.
    
    


In some embodiments:

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R13;
        each R13 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy.
In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIIc) is:




    
    
        or a pharmaceutically acceptable salt thereof.

Formula (IIId)

    
    


In some embodiments, the present disclosure provides a compound of Formula (IIId):




    
    
        or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are as described herein.
    
    


In some embodiments:

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R13;
        each R13 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy.
In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIId) is:




    
    
        or a pharmaceutically acceptable salt thereof.

Formula (IIIe)

    
    


In one general aspect, the present disclosure provides a compound of Formula (IIIe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each  represents a single bond or a double bond, provided that not more than two of  are double bonds;
        RN2 is absent if  between the N atom to which RN2 is attached and the C atom to which X1 is attached is a double bond; or
        RN2 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        RN1 is absent if  between the N atom to which RN1 is attached and the C atom to which NR6R7 is attached is a double bond; or
        RN1 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and RN1 together with the N atoms to which they are attached from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1 NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is selected from S(O) and S(O)2. In some embodiments, X1 is S(O). In some embodiments, X1 is S(O)2. In some embodiments, X1 is S.
In some embodiments, the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, RN1 is selected from H and C1-6 alkyl. In some embodiments, RN1 is H. In some embodiments, RN1 is C1-6 alkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R6 is H. In some embodiments, R7 is H. In some embodiments, R6 and R7 are each independently selected from H and C1-6 alkyl. In some embodiments, R6 and R7 are both H. In some embodiments, R6 is H and R7 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R6 and R7 are each independently selected from H and C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R6 is H and R7 is C6-10 aryl (e.g., phenyl, naphthyl), optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R6 is H and R7 is C3-10 cycloalkyl (e.g., cyclohexyl, cyclopropyl), optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R6 is H and R7 is 5-10 membered heteroaryl (e.g., pyridine), optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R6 is H and R7 is 4-10 membered heterocycloalkyl (e.g., piperidine, tetrahydropyran), optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R6 and RN1 together with the N atoms to which they are attached from a 5-10 membered heteroaryl, substituted with 1, 2, or 3 substituents independently selected from R10 (e.g., pyrimidine, triazine).
In some embodiments, R6 and RN1 together with the N atoms to which they are attached from a 4-10 membered heterocycloalkyl, substituted with 1, 2, or 3 substituents independently selected from R10 (e.g., hexahydropyrimidine).
In some embodiments, the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1 In some embodiments, each R10 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, each R10 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, each R10 is independently selected from H, OH, and C1-6 alkyl.
In some embodiments, RN2 is selected from H and C1-6 alkyl. In some embodiments, RN2 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, RN2 is H.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H and C1-6 alkyl. In some embodiments, R1, R2, R3, R4, and R5 are all H.
In some embodiments, R8 is C1-6 alkyl. In some embodiments, R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is selected from C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R8 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is C3-10 cycloalkyl (e.g., cyclopentyl, cyclohexyl), optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is 4-10 membered heterocycloalkyl (e.g., tetrahydrofuran), optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R8 is C1-6 alkyl, optionally substituted with ORa1. In some embodiments, R8 is C1-6 alkyl, optionally substituted with C1-6 alkoxy. In some embodiments, R8 is C1-6 alkyl, optionally substituted with NRc1Rd1.
In some embodiments, each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1 In some embodiments, each R9 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, each R9 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, each R9 is independently selected from H and C1-6 alkyl.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
In some embodiments (when R6 and RN1 together with the N atoms to which they are attached form a ring):

    
    
        X1 is selected from S(O) and S(O)2;
        each R10 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy;
        RN2 is selected from H and C1-6 alkyl;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R8 is C1-6 alkyl.
    
    


In some embodiments (when R6 and RN1 together with the N atoms to which they are attached form a ring):

    
    
        X1 is selected from S(O) and S(O)2;
        each R10 is independently selected from H, OH, and C1-6 alkyl;
        RN2 is H;
        R1, R2, R3, R4, and R5 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R8 is C1-6 alkyl.
    
    


In some embodiments:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl;
        RN1 is selected from H and C1-6 alkyl; and
        R6 and R7 are each independently selected from H and C1-6 alkyl.
    
    


In some embodiments, the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl;
        RN2 is selected from H and C1-6 alkyl; and
        R6 and R7 are each independently selected from H and C1-6 alkyl.
    
    


In some embodiments, the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIIe) is selected from any one of the following compounds:

















BC19338
ZE23-0091







 



BC19339
ZE23-0092







 



BC19340
ZE23-0096







 



BC19341
ZE23-0098














    
    
        or a pharmaceutically acceptable salt thereof.

Formula (IIIf)

    
    


In one general aspect, the present disclosure provides a compound of Formula (IIIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O);
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R6 and R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and R7, together with the C atom to which R6 is attached and N atom to which R7 is attached, from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is selected from S(O) and S(O)2.
In some embodiments, X1 is S.
In some embodiments, X1 is S(O).
In some embodiments, X1 is S(O)2.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1. In some embodiments, R8 is C1-6 alkyl, optionally substituted with OH. In some embodiments, R8 is C1-6 alkyl, optionally substituted with C1-6 alkoxy. In some embodiments, R8 is C1-6 alkyl, optionally substituted with NRc1Rd1.
In some embodiments, R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments:

    
    
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments:

    
    
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R7 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments:

    
    
        R7 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R6 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments:

    
    
        R7 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R6 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments, the compound of Formula (IIIf) has formula:






    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each R10 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments of the compound of Formula (IIIf):
X1 is selected from S(O) and S(O)2;

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIf):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R7 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIf):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIf):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R6 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IVf):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R10 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
Formula (IIIg-2)
In one general aspect, the present disclosure provides a compound of Formula (IIIg):




or a pharmaceutically acceptable salt thereof, wherein:

    
    
        X1 is selected from S, S(O), and S(O)2;
        each  represents a single bond or a double bond, provided that not more than two of  are double bonds;
        each of R1, R2, R3, R4, R5, R6, and R7 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10.
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R9 is selected from C(O)Rb1, C(O)NRc1Rd1, S(O)2Rb1, S(O)2NRc1Rd1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein each of said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R9, together with the N atom to which R9 is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8; or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, the compound of Formula (IIIg-2) has formula (IIIg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each of R1, R2, R3, R4, R5, R6, and R7 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R9 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R9, together with the N atom to which R9 is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, the compound of Formula (IIIg-2) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg-2) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, X1 is selected from S(O) and S(O)2.
In some embodiments, X1 is S(O).
In some embodiments, X1 is S(O)2.
In some embodiments, X1 is S.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, at least one of R1, R2, R3, R4, and R5 is H.
In some embodiments, R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, R6 and R7 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, R6 is H or C1-6 alkyl, and R7 is H or C1-6 alkyl.
In some embodiments, R6 and R7 are each independently selected from H and C1-6 alkyl. In some embodiments, R6 is H. In some embodiments, R7 is H.
In some embodiments, R6 is H or C1-6 alkyl; and R7 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some aspects of these embodiments, R6 is H.
In some embodiments, R7 is H or C1-6 alkyl; and R6 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some aspects of these embodiments, R7 is H.
In some embodiments, R6 is H or C1-6 alkyl; and R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11. In some aspects of these embodiments, R6 is H.
In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments:

    
    
        R7 is H or C1-6 alkyl; and
        R6 and R9, together with the N atom to which R′ is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is C(O)Rb1. In some embodiments, R9 is 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1.
In some embodiments, R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R10 is selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, R10 is selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, R10 is independently selected from C6-12 aryl, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, R11 is selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, R11 is selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from C(O)Rb1, C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl,
        C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from C6-12 aryl, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIg):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10, and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIg):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R6 is H or C1-6 alkyl;
        R7 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10, and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIg):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R7 is H or C1-6 alkyl;
        R6 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl,
        C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIg):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is H or C1-6 alkyl;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIg):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is H or C1-6 alkyl;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound is selected from any one of the compounds of Table 12, or a pharmaceutically acceptable salt thereof.
Formula (IIIh)
In one general aspect, the present disclosure provides a compound of Formula (IIIh)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10,
        X4 is selected from N and CR2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X2 is selected from O, S, and NR6;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X3 is selected from N and CR7;
        R7 is selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from S(O)2Rb1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R9 and R6, together with the carbon atom to which R9 is attached and the N atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R8, together with N atom to which R6 is attached and S atom to which R8 is attached, form 4-10 membered heterocycloalkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino. In some embodiments, if X3 is N and X2 is O, then R9 is selected from S(O)2Rb1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10.
    
    


In some embodiments, the present disclosure provides a compound of Formula (IIIh):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        X4 is selected from N and CR2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X2 is selected from O, S, and NR6;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X3 is selected from N and CR7;
        R7 is selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10,
        R9 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R9 and R6, together with the carbon atom to which R9 is attached and the N atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R8, together with N atom to which R6 is attached and S atom to which R8 is attached, form 4-10 membered heterocycloalkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is selected from S(O) and S(O)2. In some embodiments, X1 is S(O). In some embodiments, X1 is S(O)2. In some embodiments, X1 is S.
In some embodiments, X4 is CR2. In some embodiments, X4 is N.
In some embodiments, X1 is S(O)2 and X4 is CR2. In some embodiments, X1 is S(O)2 and X4 is N.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, at least one of R1, R2, R3, R4, and R5 is H.
In some embodiments, R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R8 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R8 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1.
In some embodiments, R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R7 is selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, R7 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10. In some embodiments, R6 is selected from H and C1-6 alkyl.
In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R9 is selected from C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is S(O)2Rb1.
In some embodiments, R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each R10 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, and NRc1Rd1.
In some embodiments, Cy1 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R11.
In some embodiments, each R10 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, each R11 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from S(O)2Rb1 and C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; or
        R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, and NRc1Rd1, and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIh):

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; or
        R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments of the compound of Formula (IIIh):

    
    
        X1 is selected from S(O) and S(O)2;
        R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R6 is selected from H and C1-6 alkyl;
        R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; or
        R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, the compound of Formula (IIIh) is selected from any one of the compounds of Table 8, Table 9, Table 10, and Table 11, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIh) is selected from any one of the compounds of Table 8, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIh) is selected from any one of the compounds of Table 9, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIh) is selected from any one of the compounds of Table 10, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIh) is selected from any one of the compounds of Table 11, or a pharmaceutically acceptable salt thereof.
Formula (IIIi)
In one general aspect, the present disclosure provides a compound of Formula (IIIi):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        X2 is selected from S and NR7;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R6 and R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and R7, together with the C atom to which R6 is attached and N atom to which R7 is attached, from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, the compound of Formula (IIIi) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IIIi) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each of R1, R2, R3, R4, and R5 is independently selected from H and halo.
In some embodiments, R6 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments:

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H and halo;
        R6 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


In some embodiments, the compound is selected from any one of the compounds of Table 15, or a pharmaceutically acceptable salt thereof.
Formula (IVa)
In one general aspect, the present disclosure provides a compound of Formula (IVa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        or RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R14,
        each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy. In some embodiments, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is H.
In some embodiments, RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl. In some embodiments, RN1 is H. In some embodiments, RN1 is C1-6 alkyl. In some embodiments, RN1 is C2-6 alkenyl.
In some embodiments, RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN2 is H.
In some embodiments, RN2 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is C2-6 alkenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some aspects of these embodiments, the 4-10 membered heterocycloalkyl is selected from pyrrolidine, piperazine, morpholine, and piperidine.
In some embodiments, each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
In some embodiments, each R14 independently selected from Cy1, C1-6 alkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1. In some embodiments, R14 is Cy1. In some embodiments, R14 is C1-6 alkyl. In some embodiments, R14 is ORa1 In some embodiments, R14 is C(O)Rb1. In some embodiments, R14 is C(O)NRc1Rd1 In some embodiments, R14 is C(O)ORa1. In some embodiments, R14 is NRc1Rd1 In some embodiments, each Cy1 is independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1.
In some embodiments, Cy1 is C6-10 aryl, optionally substituted with 1, 2, or 3, substituents independently selected from RCy1. In some embodiments, Cy1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3, substituents independently selected from RCy1. In some embodiments, Cy1 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3, substituents independently selected from RCy1.
In some embodiments, each Cy1 is independently selected from phenyl, piperidine, thiophene, pyridine, piperazine, morpholine, azepane, pyrrolidone, pyrrolidine, and pyrimidine, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1.
In some embodiments, each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R15.
In some embodiments, each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
In some embodiments, each RCy1 is independently selected from halo, C1-6 alkyl, ORa1, SRa1, and NRc1Rd1.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments of the compound of Formula (IVa):

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl;
        RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1;
        RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments of the compound of Formula (IVa):

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl;
        RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2 together with the N atom to which they are attached from pyrrolidine, piperazine, morpholine, or piperidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        each R14 independently selected from Cy1, C1-6 alkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1,
        each Cy1 is independently selected from phenyl, piperidine, thiophene, pyridine, piperazine, morpholine, azepane, pyrrolidone, pyrrolidine, and pyrimidine, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, C1-6 alkyl, ORa1, SRa1, and NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


In some embodiments, the compound of Formula (IVa) is selected from any one of the compounds of Table 4a or Table 4b, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IVa) is selected from any one of the compounds of Table 4a, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IVa) is selected from any one of the compounds of Table 4b, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 4b or Table 4b-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 4b, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from any one of the compounds of Table 4b-2, or a pharmaceutically acceptable salt thereof.
Formula (IVb)
In one general aspect, the present disclosure provides a compound of Formula (IVb)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        each R8 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        R1 and R2 are each independently selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is CR6.
In some embodiments, X1 is N.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8. In some embodiments, R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each R8 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9. In some embodiments, R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R9 is independently selected from C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each R9 is independently selected from C1-6 alkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each R9 is independently selected from C1-6 alkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1. In some embodiments, each R9 is independently selected from ORa1 and NRc1Rd1. In some embodiments, R9 is ORa1. In some embodiments, R9 is NRc1Rd1.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R1 is C1-6 haloalkyl; and R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and R2 is C1-6 haloalkyl.
In some embodiments, R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
In some of the above embodiments, the 5-10 membered heteroaryl is thiophene. In some of the above embodiments, the C6-10 aryl is phenyl.
In some embodiments, each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, each R10 is independently selected from halo and S(O)2Rb1. In some embodiments, R10 is halo. In some embodiments, R10 is S(O)2Rb1.
In some embodiments, each R11 is independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments of the compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1.
    
    


R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;

    
    
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments, of the compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1,
        R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10,
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1.
        R1 is C1-6 haloalkyl;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is trifluoromethyl;
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1.
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C1-6 haloalkyl;
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is trifluoromethyl;
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1.
        R1 is thiophenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments of a compound of Formula (IVb):

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1, R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is thiophenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


In some embodiments, the compound of Formula (IVb) is selected from any one of the compounds of Table 4c, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IVb) is selected from any one of the compounds of Table 4c or Table 4c-2, or a pharmaceutically acceptable salt thereof.
Formula (IVc)
In one general aspect, the present disclosure provides a compound of Formula (IVc)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R4 is selected from C(O)NRN1RN2, C(O)ORa1, and CN;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8 and S(O)2R8;
        R8 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        provided that R1 and R2 are not both C6-10 aryl;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is CR6.
In some embodiments, X1 is N.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, R4 is selected from C(O)NRN1RN2 and C(O)ORa1. In some embodiments, R4 is selected from C(O)NRN1RN2 and CN. In some embodiments, R4 is selected from C(O)ORa1 and CN. In some embodiments, R4 is C(O)NRN1RN2. In some embodiments, R4 is C(O)ORa1. In some embodiments, R4 is CN.
In some embodiments, each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 is selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 is H. In some embodiments, RN1 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN1 is C2-6 alkynyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN1 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN2 is selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN2 is H. In some embodiments, RN2 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is C2-6 alkynyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, each R14 is independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
In some embodiments, each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each R14 is independently selected from C1-6 alkyl and NRc1Rd1. In some embodiments, R14 is C1-6 alkyl. In some embodiments, NRc1Rd1.
In some embodiments, the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R1 is C1-6 haloalkyl; and R2 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10; and R2 is C1-6 haloalkyl.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10, and R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, R1 is C1-6 haloalkyl; and R8 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10; and R8 is C1-6 haloalkyl.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10, and R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some aspects of the above embodiments, the 5-10 membered heteroaryl is selected from thiophenyl and pyridinyl; and the C6-10 aryl is phenyl.
In some embodiments, R1 is C1-6 haloalkyl; and R8 is C1-6 haloalkyl. In some embodiments, each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, each R10 is independently selected from halo and C1-6 alkyl. In some embodiments, R10 is halo. In some embodiments, R10 is C1-6 alkyl.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments of a compound of Formula (IVc):

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


In some aspects of the above embodiments,

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R14 is independently selected from C1-6 alkyl and NRc1Rd1.
    
    


In some embodiments, the compound of Formula (IVc) is selected from any one of the compounds of Table 4d, or a pharmaceutically acceptable salt thereof.
Formula (IVd)
In one general aspect, the present disclosure provides a compound of Formula (IVd):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R3 is selected from C(O)NRN1RN2 and C(O)ORa1;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8 and S(O)2R8;
        R8 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is CR6.
In some embodiments, X1 is N.
In some embodiments, R4, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7.
In some embodiments, R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, R3 is C(O)NRN1RN2.
In some embodiments, R3 is C(O)ORa1.
In some embodiments, each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 is selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 is H. In some embodiments, RN1 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN1 is C2-6 alkynyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN1 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN2 is selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN2 is H. In some embodiments, RN2 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is C2-6 alkynyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14. In some embodiments, RN2 is 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14.
In some embodiments, the compound of Formula (IVd) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, each R14 is independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1. In some embodiments, each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1 In some embodiments, each R14 is independently selected from C1-6 alkyl and NRc1Rd1. In some embodiments, R14 is C1-6 alkyl. In some embodiments, R14 is NRc1Rd1.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, each R10 is independently selected from halo and C1-6 alkyl.
In some embodiments, each R11 is independently selected from ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments of a compound of Formula (IVd):

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14, or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        wherein each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


In some aspects of the above embodiments:

    
    
        R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        each R14 is independently selected from C1-6 alkyl and NRc1Rd1.
    
    


In some embodiments, the compound of Formula (IVd) is selected from any one of the compound of Table 4e, or a pharmaceutically acceptable salt thereof.
Formula (IVe)
In one general aspect, the present disclosure provides a compound of Formula (IVe)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        or R7 and R8 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8 and S(O)2R8;
        R8 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino; and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments:

    
    
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8a and S(O)2R8a;
        R8a is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


In some embodiments, X1 is CR6.
In some embodiments, X1 is N.
In some embodiments, R4, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments, R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
In some embodiments, R7 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, R8 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9.
In some embodiments, each R9 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
In some embodiments, R7 is selected from H and C1-6 alkyl; and R8 is selected from C(O)Rb1 and C(O)ORa1. In some embodiments, R7 is selected from H and C1-6 alkyl; and R8 is C(O)NRc1Rd1.
In some embodiments, each Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted with 1 or 2 independently selected Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Ra1 and Rb1 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
In some embodiments, each Rg is independently selected from OH, halo, C1-6 alkyl, C1-6 alkoxy, 4-10 membered heterocycloalkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl, and any C1-6 alkyl, C1-6 alkoxy, or 4-10 membered heterocycloalkyl of R8 is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl and C1-6 alkoxy.
In some embodiments, each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
In some embodiments, each R8 is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl.
In some embodiments, R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
In some embodiments, each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, each R10 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11. In some embodiments, each R10 is independently selected from halo and C1-6 alkyl.
In some embodiments of a compound of Formula (IVe):

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is selected from H and C1-6 alkyl;
        R8 is selected from C(O)Rb1 and C(O)ORa1;
        each Ra1 and Rb1 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        each Rg is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


In some embodiments:

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH,
        C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is selected from H and C1-6 alkyl;
        R8 is C(O)NRc1Rd1;
        each Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted with 1 or 2 independently selected Rg;
        each Rg is independently selected from OH, halo, C1-6 alkyl, C1-6 alkoxy, 4-10 membered heterocycloalkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl, and any C1-6 alkyl, C1-6 alkoxy, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl and C1-6 alkoxy;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


In some embodiments, the compound of Formula (IVe) is selected from any one of the compounds of Table 4f, or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (IVe) is selected from any one of the compounds of Table 4f or Table 4f-2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IVe) is selected from any one of the compounds of Table 4f-2, or a pharmaceutically acceptable salt thereof.
Formula (IVf)
In one general aspect, the present disclosure provides a compound of Formula (IVf)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        or R7 and R8 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, X is N.
In some embodiments, X is CR6.
In some embodiments, R3, R5, and R6 are each independently selected from H, halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments, R3, R5, and R6 are each H.
In some embodiments:

    
    
        R7 is H; and
        R8 is selected from C1-6 alkyl and C3-10 cycloalkyl, each of which is independently selected from 1 or 2 substituents independently selected from R9. In some embodiments, R9 is independently selected from C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R10.
    
    


In some embodiments:

    
    
        R1 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10; and
        R2 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10.
    
    


In some embodiments, each R10 is independently selected from halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
In some embodiments:

    
    
        R1 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10;
        R2 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10;
        X is CR6;
        R3, R5, and R6 are each independently selected from H, halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino;
        R7 is H;
        R8 is selected from C1-6 alkyl and C3-10 cycloalkyl, each of which is independently selected from 1 or 2 substituents independently selected from R9;
        each R9 is independently selected from C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1; wherein said C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
    
    


In some embodiments, the compound is selected from any one of the compounds of Table 4g, or a pharmaceutically acceptable salt thereof.
Formula (IVg)
In one general aspect, the present disclosure provides a compound of Formula (IVg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        ring A is C3-8 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        or RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R14,
        each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1,
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of R8 is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


In some embodiments, the compound of Formula (IVg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments, the compound of Formula (IVg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


In some embodiments:

    
    
        RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R14,
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10, and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


In some embodiments, the compound is selected from any one of the compounds of Table 17, or a pharmaceutically acceptable salt thereof.
In some embodiments, a salt of any one of the compounds disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.
In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.
In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds disclosed herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH—(C1-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.
In some embodiments, any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, is substantially isolated.
Methods of Making Therapeutic Compounds
Compounds as set forth in any one of the Formulae disclosed herein, including salts thereof, can be prepared using organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. A person skilled in the art knows how to select and implement appropriate synthetic protocols, and appreciates that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein.
Suitable synthetic methods of starting materials, intermediates, and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (J. Heterocyclic Chemistry, 1964-2012); Carreira et al., (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al., (Ed.) Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al., (Ed.) Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.) Comprehensive Organic Synthesis (Pergamon Press, 1991).
The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, Inc., New York (2006).
Pharmaceutical Compositions and Formulations
This document also provides pharmaceutical compositions comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition also can comprise any one of the additional therapeutic agents and/or therapeutic molecules described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions provided herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.
The compositions or dosage forms can contain any one or more of the compounds or therapeutic agents described herein in the range of 0.005 percent to 100 percent with the balance made up from the suitable pharmaceutically acceptable carriers or excipients. The contemplated compositions can contain from about 0.001 percent to about 100 percent (e.g., from about 0.1 percent to about 95 percent, from about 75 percent to about 85 percent, or from about 20 percent to about 80 percent) of any one or more of the compounds or therapeutic agents provided herein, wherein the balance can be made up of any pharmaceutically acceptable carrier or excipient described herein, or any combination of these carriers or excipients.
Routes of Administration and Dosage Forms
The therapeutic compounds and/or pharmaceutical compositions provided herein (e.g., a composition containing one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can include those suitable for any acceptable route of administration. Acceptable routes of administration include, without limitation, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, vaginal, intravitreal, subretinal or other intraocular routes of administrations.
Compositions and formulations described herein can conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and can be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include, without limitation, the step of bringing into association with the molecule to be administered ingredients such as a carrier that constitutes one or more accessory ingredients. In general, the compositions can be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
In some embodiments, any one or more of the compounds or therapeutic agents described herein can be administered orally. Compositions described herein that are suitable for oral administration can be presented as discrete units such as capsules, sachets, granules, or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient(s); a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include, without limitation, lactose, sucrose, glucose, mannitol, silicic acid, and starches. Other acceptable excipients can include, without limitation, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include, without limitation, lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient(s) can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents can be added. Compositions suitable for oral administration include, without limitation, lozenges comprising ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient(s) in an inert basis such as gelatin and glycerin, or sucrose and acacia.
Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions or infusion solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, saline (e.g., 0.9% saline solution), or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The injection solutions can be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation also can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including, without limitation, synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injectables. In some cases, natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, can be used to prepare injectables. These oil solutions or suspensions also can contain a long-chain alcohol diluent or dispersant.
In some cases, a therapeutic compound and/or pharmaceutical composition provided herein can be administered in the form of suppository for rectal administration. These compositions can be prepared by mixing a compound described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active component(s). Such materials include, without limitation, cocoa butter, beeswax, and polyethylene glycols.
In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, U.S. Pat. No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J. Pharm. Pharmacol., 56:3-17 (2004); and Ilium, L., Eur. J. Pharm. Sci., 11:1-18 (2000).
In some cases, a therapeutic compounds and/or pharmaceutical composition provided herein can be prepared as a topical composition and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of a therapeutic compounds and/or pharmaceutical composition provided herein can be useful when the desired treatment involves areas or organs readily accessible by topical application. In some cases, a topical composition can include a combination of any one or more of the compounds or therapeutic agents described herein (e.g., a compound set forth in any one of Formulae (I)-(IV), or a pharmaceutically acceptable salt thereof), and one or more additional ingredients, carriers, excipients, or diluents including, without limitation, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.
In some cases, one or more compounds or therapeutic agent described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) can be incorporated into a composition for coating an implantable medical device such as a prosthesis, artificial valve, vascular graft, stent, or catheter. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings can be biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, or mixture thereof. In some cases, the coating can optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
In some cases, this document provides an implantable drug release device impregnated with or containing one or more compounds or therapeutic agents described herein (e.g., any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof) such that the compound(s) or therapeutic agent(s) are released from the device and are therapeutically active.
Dosages and Regimens
A composition (e.g., pharmaceutical compositions provided herein) containing a compound provided herein, or a pharmaceutically acceptable salt thereof, can include that compound in an effective amount (e.g., a therapeutically effective amount).
Effective doses can vary, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents, and the judgment of the treating physician.
In some embodiments, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.1 mg to about 1000 mg. In some cases, the effective amount can be from about 0.5 mg to about 500 mg of a compound disclosed herein, or any amount in between these two values, for example, one of about 0.5 mg, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. The effective amount can be an amount sufficient to alleviate or reduce one or more of the symptoms associated with a disease, disorder, or condition being treated as described herein.
In some cases, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g., from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg; from about 0.1 mg/kg to about 1 mg/kg; from about 0.1 mg/kg to about 0.5 mg/kg, or from about 0.5 mg/kg to about 500 mg/kg).
In some cases, an effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, can be about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.
The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or on a non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, or once a month). In some cases, the dosages can be administered every 4 hours, 6 hours, 8 hours, 12 hours, or 24 hours.
Kits
This document also provides pharmaceutical kits useful, for example, to inhibit NF-κB within cells within a mammal (e.g., a human). In some cases, this document provides pharmaceutical kits useful, for example, to treat diseases, disorders, and conditions referred to herein. Such pharmaceutical kits can include one or more containers containing a pharmaceutical composition that includes a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some cases, such kits can further include, if desired, one or more of various conventional pharmaceutical kit components such as containers with one or more pharmaceutically acceptable carriers. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components also can be included in a kit provided herein.
Combination Therapies
In some cases, one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more therapeutic molecules. Examples of therapeutic molecules that can be used in combination with one or more compounds provided herein, or a pharmaceutically acceptable salt thereof, include, without limitation, anti-inflammatory agents (e.g., steroids and antibodies against IL-6 or TNF-alpha), antimicrobial agents (e.g., antibiotics, anti-mycobacterial drugs, and anti-viral agents), anti-cancer agents (e.g., chemotherapeutic agents and cellular products such as engineered T cells), therapies for atherosclerosis (e.g., lipid-lowering agents, platelet inhibitors), agents to treat polycystic kidney disease (e.g. tolvaptan), therapies used for metabolic syndrome (e.g., insulin, glucose-lowering therapies), therapies for polycystic ovarian syndrome (e.g., metformin), treatment for muscular dystrophies (e.g., steroids, gene therapy approaches) and therapies for pain relief (e.g., non-steroidal anti-inflammatory medicines, opioids, regional nerve blocks).
One or more compounds provided herein, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic molecules can be administered in any order or simultaneously. If simultaneously administered, they can be provided in a single, unified, form or in multiple forms (e.g., either as a single pill or as two separate pills). One of the items can be given in multiple doses, or both can be given as multiple doses. If not simultaneous, the timing between the multiple doses can vary from more than zero weeks to less than four weeks.
Definitions
As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
At various places in this document, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
At various places in this document various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features described herein which are, for brevity, described in the context of a single embodiment, also can be provided separately or in any suitable subcombination.
The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).
The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like.
As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, without limitation, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms that may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, without limitation, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, without limitation, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
As used herein, the term “Cn-m alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl-linking group having n to m carbons. Examples of alkylene groups include, without limitation, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.
As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula-O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, without limitation, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, “Cn-m haloalkoxy” refers to a group of formula-O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “amino” refers to a group of formula —NH2.
As used herein, the term “Cn-m alkylamino” refers to a group of formula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino), and the like.
As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula-N(alkyl) 2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “Cn-m alkoxycarbonyl” refers to a group of formula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like.
As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, without limitation, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.
As used herein, the term “Cn-m alkylcarbonylamino” refers to a group of formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “Cn-m alkylsulfonylamino” refers to a group of formula —NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “aminosulfonyl” refers to a group of formula —S(O)2NH2.
As used herein, the term “Cn-m alkylaminosulfonyl” refers to a group of formula —S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “di(Cn-m alkyl)aminosulfonyl” refers to a group of formula —S(O)2N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “aminosulfonylamino” refers to a group of formula-NHS(O)2NH2.
As used herein, the term “Cn-m alkylaminosulfonylamino” refers to a group of formula —NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “di(Cn-m alkyl)aminosulfonylamino” refers to a group of formula —NHS(O)2N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula —NHC(O)NH2.
As used herein, the term “Cn-m alkylaminocarbonylamino” refers to a group of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “di(Cn-m alkyl)aminocarbonylamino” refers to a group of formula —NHC(O)N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “carbamyl” to a group of formula —C(O)NH2.
As used herein, the term “Cn-m alkylcarbamyl” refers to a group of formula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula —C(O)N(alkyl) 2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “thio” refers to a group of formula —SH.
As used herein, the term “Cn-m alkylthio” refers to a group of formula —S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “Cn-m alkylsulfinyl” refers to a group of formula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “Cn-m alkylsulfonyl” refers to a group of formula —S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a —C(═O)— group, which may also be written as C(O).
As used herein, the term “carboxy” refers to a —C(O)OH group. In some embodiments, the “carboxy” group also refers to a bioisostere replacement group selected from the group consisting of:




    
    
        and the like, where R refers to a hydrogen, (C1-C8) alkyl, or C6 aryl.
    
    


As used herein, the term “cyano-C1-3 alkyl” refers to a group of formula —(C1-3 alkylene)-CN.
As used herein, the term “HO—C1-3 alkyl” refers to a group of formula —(C1-3 alkylene)-OH.
As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.
As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups can have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.
As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. Example cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Ring-forming carbon atoms of a heteroaryl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)).
As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.
As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C═O), or attached to a heteroatom forming a sulfoxide or sulfone group.
The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Any appropriate method can be used to prepare optically active forms from, for example, optically inactive starting materials. For example, techniques such as resolution of racemic mixtures or stereoselective synthesis can be used to prepare optically active forms of a compound provided herein. Many geometric isomers of olefins, C═N double bonds, N═N double bonds, and the like also can be present in a compound described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds provided herein are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, a compound provided herein has the (R)-configuration. In some embodiments, a compound provided herein has the (S)-configuration.
Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include, without limitation, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. For example, in aqueous solution, pyrazoles can exhibit the following isomeric forms, which are referred to as tautomers of each other:




As readily understood by one skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of compounds as described herein are within the scope provided herein.
As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal (e.g., a human). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal (e.g., a human).
As used herein, the term “contacting” refers to the bringing together of indicated moieties or items in an in vitro system, an ex vivo system, or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the act of administering that compound to a mammal (e.g., a human) containing that cell as well as, for example, introducing that compound into a cell culture containing that cell.
As used herein, the term “mammal” includes, without limitation, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, elephants, deer, non-human primates (e.g., monkeys and apes), house pets, and humans.
As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, mammal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.
As used herein, the term “treating” or “treatment” refers to (a) inhibiting a disease, disorder, or condition, for example, inhibiting a disease, disorder, or condition in a mammal (e.g., human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., arresting further development of the pathology and/or symptomatology), or (b) ameliorating the disease, disorder, or condition, for example, ameliorating a disease, disorder, or condition in a mammal (e.g., a human) that is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (e.g., reversing the pathology and/or symptomatology).
As used herein, the term “preventing” or “prevention” of a disease, disorder, or condition refers to decreasing the risk of occurrence of the disease, disorder, or condition in a mammal or group of mammals (e.g., a mammal or group of mammals predisposed to or susceptible to the disease, disorder, or condition). In some embodiments, preventing a disease, disorder, or condition refers to decreasing the possibility of acquiring the disease, disorder, or condition and/or its associated symptoms. In some embodiments, preventing a disease, disorder, or condition refers to completely or almost completely stopping the disease, disorder, or condition from occurring.
REFERENCES


    1. Giovannini, S., Onder, G., Liperoti, R., Russo, A., Carter, C., Capoluongo, E., Pahor, M., Bernabei, R., and Landi, F. 2011. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals. J Am Geriatr Soc 59:1679-1685.
    2. He, S., and Sharpless, N. E. 2017. Senescence in Health and Disease. Cell 169:1000-1011.
    3. Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. 2017. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 377:1119-1131.


EXAMPLES
Methods
25k THP1-NF-κB-LUC cells were dispensed into 384 well plate (per well). Cells were treated with compounds with various concentrations for 2 hours before addition of LPS (10 ng/mL) for 18 hours. Secreted luciferase activity were measured using quant-luc reagents (1 bag of luc reagent dilute to 40 mL, use 10 μL per well). Data were normalized to vehicle control and graphed. Compound IC50 towards inhibiting NF-κB were determined through Prism. Similarly, 10k human PBMCs cells were cultured in 384 well plate (per well). Cells were treated with compounds with various concentrations for 2 hours before addition of LPS (10 ng/ml) for 18 hours, and supernatants were collected and assayed for TNF ELISA. Compound IC50 towards inhibiting TNF release were determined through Prism.

    
    
        Activity: “+”>10 μM, “++”>1 μM and <10 μM, “+++”>0.1 μM and <1 μM, “++++”<0.1 μM.
    
    


Example 1—Bioassay Results for Tested Compounds









TABLE 1a







IC50 


No.
Compound
(NF-κB assay)







BC18300




+++


 


BC18301




++


 


BC18302




++++


 


BC18303




++++


 


BC18304




++


 


BC18305




+++


 


BC18306




+


 


BC18307




+++


 


BC18308




+


 


BC18309




++


 


BC18310




++++


 


BC18311




+


 


BC18312




+


 


BC18318




+


 


BC18320




++++


 


BC18321




+++ 


 


BC18322




++


 


BC18323




+++


 


BC18324




+


 


BC18325




+


 


BC18326




+


 


BC18327




+


 


BC18328




++


 


BC18329




+


 


BC18330




+


 


BC18331




+


 


BC18332




+ 


 


BC18333




+


 


BC18334




+


 


BC18335




+


 


BC18336




+


 


BC18337




+


 


BC18338




+


 


BC18339




+++


 


BC18340




++++


 


BC19001







 


BC19003







 


BC19004







 


BC19005







 


BC19006







 


BC19007






















TABLE 1b







IC50


No.
Compound
(NF-κB assay)







BC18313




+


 


BC18314




+


 


BC18316




+


 


BC18317




+


 


BC18319




+


















TABLE 1c







IC50


No.
Compound
(NF-κB assay)







BC18315




+




















TABLE 1d








IC50
IC50


BC
ZE

(NF-κB 
(TNF


No.
No.
Compound
assay)
assay)







BC19121
ZE22- 0017




+
+


 


BC19122
ZE22- 0018




+
+


 


BC19123
ZE22- 0021




++
+


 


BC19124
ZE22- 0024




+
+


 


BC19160
ZE22- 0019




+
+


 


BC19201
ZE22- 0020




+
+


 


BC19202
ZE22- 0022




+
+


 


BC 19203
ZE22- 0023




++
+


 


BC19256
ZE22- 0016




++
+


 


BC19257
ZE22- 0025




+
+


 


BC19258
ZE22- 0027




++
+


 


BC19259
ZE22- 0029




++
+


 


BC19322
ZE22- 0015




++
+


 


BC19323
ZE22- 0028




+
+


 


BC19409
ZE22- 0013




+
+




















TABLE 1e








IC50
IC50


BC
ZE

(NF-κB 
(TNF


No.
No.
Compound
assay)
assay)







BC19196
ZE22- 0004




+++
+


 


BC19197
ZE22- 0007




+++
+


 


BC19198
ZE22- 0009




++
+


 


BC19199
ZE22- 0010




+++
+


 


BC19200
ZE22- 0011




++
+


 


BC19252
ZE22- 0001




++++
+


 


BC19253
ZE22- 0002




++++
+


 


BC19254
ZE22- 0008




++++
+


 


BC19255
ZE22- 0012




++
+




















TABLE 1f








IC50
IC50


BC
ZE

(NF-κB 
(TNF


No.
No.
Compound
assay)
assay)







BC19324
ZE22-0030




+
+++


 


BC19325
ZE22-0032




+
++


 


BC19326
ZE22-0034




+
++



















TABLE 1g







IC50
IC50


BC

(NF-κB 
(TNF


No.
Structure
assay)
assay)







BC19454




+
+


 


BC19515




+
+


 


BC19516




+
+


 


BC19517




+
+


 


BC19518




+
+


 


BC19519




+
+


 


BC19520




+
+


 


BC19579




+
+


 


BC19580




+
+



















TABLE 1h







IC50
IC50




(NF-κB 
(TNF


BC No.
Structure
assay)
assay)







BC19455




+
+


 


BC19456




+
+


 


BC19457




+
+


 


BC19458




+
+


 


BC19459




+
+


 


BC 19460




+
+


 


BC19461




+
+









Example 2—Bioassay Results for Tested Compounds









TABLE 2a







IC50


BC No.
Compound
NF-κB assay







BC181300




+


 


BC181301




+


 


BC181302




++++


 


BC181303




++++


 


BC181304




+


 


BC181305




++++


 


BC181306




++


 


BC181307




+


 


BC181308




+


 


BC181309




+


 


BC181310




++++


 


BC181311




++++


 


BC181312




++


 


BC181313




+


 


BC181314




++++


 


BC181315




++++


 


BC181316




+


 


BC181317




+


 


BC181318




+


 


BC181319




+


 


BC181320




+


 


BC181321




++++


 


BC181322




+


 


BC181323




+


 


BC181324




+


 


BC181325




+


 


BC181326




+


 


BC181327




+


 


BC181328




+


 


BC181329




++


 


BC181330




++


 


BC181331




++++


 


BC181332




+


 


BC181333




++


 


BC181334




++


 


BC181335




+


 


BC181336




++++


 


BC181337




+


 


BC181338




++


 


BC181339




+


 


BC181340




+


 


BC181341




++


 


BC181342




+++


 


BC181343




++++


 


BC181344




+++


 


BC181345




+


 


BC181346




+


 


BC181347




++


 


BC181348




+


 


BC181349




+


 


BC181350




++


 


BC181351




+


 


BC181352




+


 


BC181353




++++


 


BC181354




++++


 


BC181355




++++ 


 


BC181356




+


 


BC181357




+


 


BC181358




+


 


BC181359




+


 


BC181360




+


 


BC181361




+++


 


BC181362




++


 


BC181363




+


 


BC181364




+++


 


BC181365




++


 


BC181366




++


 


BC181367




++++


 


BC181368




++


 


BC181369




++


 


BC181370




++++


 


BC181371




+


 


BC181372




++


 


BC181373




+


 


BC181374




+


 


BC181375




+++


 


BC181376




+


 


BC181377




++++


 


BC181378




++


 


BC181379




+


 


BC181380




+++


 


BC181381




+


 


BC181382




+


 


BC181383




+++


 


BC181384




++


 


BC181385




+




















TABLE 2c








IC50
IC50





(NF-κB 
(TNF


BC No.
ZE No.
Structure
assay)
assay)







BC19133
ZE24-0004




++++
+


 


BC19135
ZE24-0009




+
+


 


BC19136
ZE24-0010




+
+


 


BC19137
ZE24-0011




+++
+


 


BC19138
ZE24-0015




++++
+


 


BC19161
ZE24-0003




++
+


 


BC19162
ZE24-0005




+
+


 


BC19163
ZE24-0007




+
+


 


BC19164
ZE24-0008




++++
+


 


BC19165
ZE24-0012




+++
+


 


BC19166
ZE24-0014




++++
+


 


BC19167
ZE24-0016




+++
+


 


BC19206
ZE24-0018




++
+


 


BC19207
ZE24-0023




+
+


 


BC19208
ZE24-0024




+
+


 


BC19209
ZE24-0025




++
+


 


BC19210
ZE24-0028




++++
+


 


BC19211
ZE24-0029




+++
+


 


BC19212
ZE24-0030




++++
+


 


BC19213
ZE24-0031




+++
+


 


BC19214
ZE24-0032




+
+


 


BC19215
ZE24-0033




++
+


 


BC19216
ZE24-0034




++++
+


 


BC19217
ZE24-0039




+
+


 


BC19218
ZE24-0040




+
+


 


BC19219
ZE24-0041




+
+


 


BC19220
ZE24-0043




+++
+


 


BC19221
ZE24-0044




+++
+


 


BC19222
ZE24-0045




+
+


 


BC19223
ZE24-0047




+
+


 


BC19224
ZE24-0048




+++
+


 


BC19280
ZE24-0020




++
+


 


BC19281
ZE24-0021




+++
+


 


BC19282
ZE24-0027




+++
+


 


BC19283
ZE24-0036




+++
+


 


BC19284
ZE24-0037




++++
+


 


BC19285
ZE24-0038




++
+


 


BC19286
ZE24-0042




++++
+


 


BC19287
ZE24-0046




++
+


 


BC19354
ZE24-0019




++++
+


 


BC19356
ZE24-0082




++
+


 


BC19357
ZE24-0083




+
+


 


BC19358
ZE24-0084




+
+


 


BC19359
ZE24-0086




+
+


 


BC19360
ZE24-0087




+
+


 


BC19361
ZE24-0088




+
+


 


BC19368
ZE24-0096




+
+


 


BC19369
ZE24-0097




+
+


 


BC19370
ZE24-0098




+
+


 


BC19371
ZE24-0099




++
+


 


BC19372
ZE24-0100




+
+


 


BC19373
ZE24-0102




+
+


 


BC19387
ZE24-0117




+
+


 


BC19388
ZE24-0118




+
+


 


BC19389
ZE24-0119




+
+


 


BC19390
ZE24-0120




++
+


 


BC19391
ZE24-0121




+
+


 


BC19392
ZE24-0122




+
+


 


BC19393
ZE24-0123




+
+



















TABLE 2c-2







IC50





(NF-
IC50




κB
(TNF


BC No.
Structure
assay)
assay)







BC19696




+++
+


 


BC19698




++++
+


 


BC19700




++++
+


 


BC19702




++++
+


 


BC19704




+
+


 


BC19706




++++
+


 


BC19708




++++
+


 


BC19709




++++
+


 


BC19711




++++
+


 


BC19713




+++
++


 


BC19715




++++
++


 


BC19717




++++
+


 


BC19719




+++
+


 


BC19721




++++
++


 


BC19729




+++
+


 


BC19731




+++
+


 


BC19733




++++
+


 


BC19735




++++
+


 


BC19737




+++
+


 


BC19739




++++
+


 


BC19741




++++
+


 


BC19743




++
+


 


BC19745




++
+


 


BC19747




+++
+


 


BC19749




+++
+


 


BC19751




+++
+


 


BC19753




++++
+


 


BC19755




++
+


 


BC19758




+++
+


 


BC19760




++++
+


 


BC19762




+++
+


 


BC19764




++
+


 


BC19766




++
++


 


BC19768




++
+


 


BC19770




+++
+


 


BC19772




+++
+


 


BC19774




+++
+


 


BC19776




+++
+


 


BC19778




+
+


 


BC19778




+
+


 


BC19780




++
+


 


BC19782




++
+


 


BC19784




++
+


 


BC19786




++
+


 


BC19788




++++
+


 


BC19790




++
+


 


BC19792




++
+


 


BC19794




++
+


 


BC19795




+
++


 


BC19797




++
++


 


BC19799




+++
++


 


BC19901




++
+


 


BC19903




+++
+


 


BC19905




++
+


 


BC19907




+
+


 


BC19910




++
+


 


BC19912




+
+


 


BC19914




+++
+


 


BC19916




++
+


 


BC19919




+
+


 


BC19920




+++
+


 


BC19922




++++
+


 


BC19924




++++
++


 


BC19926




++++
+


 


BC19928




+++
++


 


BC19930




+++
+


 


BC19932




++++
++


 


BC19934




+++
++


 


BC19936




++++
+


 


BC19938




+++
++




















TABLE 2d








IC50
IC50


BC No.
ZE No.
Structure
(NF-κB assay)
(TNF assay)







BC19168
ZE24-0050




++++
+


 


BC19169
ZE24-0051




++++
+


 


BC19170
ZE24-0052




++
+


 


BC19171
ZE24-0053




++++
+


 


BC19172
ZE24-0054




++++
+


 


BC19173
ZE24-0055




++++
+


 


BC19174
ZE24-0056




++++
+


 


BC19175
ZE24-0057




++++
+


 


BC19176
ZE24-0058




++++
+


 


BC19177
ZE24-0059




++++
+


 


BC19178
ZE24-0060




++++
++


 


BC19179
ZE24-0061




++++
+


 


BC19180
ZE24-0062




++++
+


 


BC19225
ZE24-0064




+++
+


 


BC19226
ZE24-0065




++
+


 


BC19227
ZE24-0066




+
+


 


BC19228
ZE24-0067




+
+


 


BC19229
ZE24-0068




++
+


 


BC19230
ZE24-0069




++++
+


 


BC19231
ZE24-0070




++++
+


 


BC19232
ZE24-0071




++++
+


 


BC19233
ZE24-0072




++
++


 


BC19234
ZE24-0073




++++
++


 


BC19288
ZE24-0074




++++
+


 


BC19289
ZE24-0075




++++
+


 


BC19290
ZE24-0076




++++
+


 


BC19291
ZE24-0077




++++
+


 


BC19292
ZE24-0078




++++
+


 


BC19293
ZE24-0080




+++
+


 


BC19294
ZE24-0081




++
+


 


BC19355
ZE24-0079




++++
+


 


BC19362
ZE24-0089




+++
+


 


BC19363
ZE24-0090




++++
+


 


BC19364
ZE24-0092




+
+


 


BC19365
ZE24-0093




++
+


 


BC19366
ZE24-0094




+
+


 


BC19367
ZE24-0095




+
+


 


BC19374
ZE24-0103




++++
++


 


BC19375
ZE24-0104




++++
+


 


BC19376
ZE24-0106




++
+


 


BC19377
ZE24-0107




++++
+


 


BC19378
ZE24-0108




+
+


 


BC19379
ZE24-0109




+
+


 


BC19380
ZE24-0110




+
+


 


BC19381
ZE24-0111




+
+


 


BC19382
ZE24-0112




+
+


 


BC19383
ZE24-0113




+
+


 


BC19384
ZE24-0114




++++
+


 


BC19385
ZE24-0115




+
+


 


BC19386
ZE24-0116




+
+


 


BC19394
ZE24-0124




++++
+


 


BC19421
ZE24-0125




++++
+


 


BC19422
ZE24-0127




++++
+


 


BC19423
ZE24-0128




++++
+


 


BC19424
ZE24-0132




++++
+


 


BC19425
ZE24-0135




++++
+


 


BC19426
ZE24-0137




++++
+


 


BC19427
ZE24-0138




++++
+


 


BC19428
ZE24-0140




+++
+


 


BC19429
ZE24-0141




+
+


 


BC19430
ZE24-0142




++++
+


 


BC19431
ZE24-0144




++++
+


 


BC19432
ZE24-0147




+++
+


 


BC19433
ZE24-0150




++++
+


 


BC19434
ZE24-0151




++++
+


 


BC19435
ZE24-0152




++++
+


 


BC19436
ZE24-0153




++++
+


 


BC19437
ZE24-0154




++++
+


 


BC19438
ZE24-0158




++++
+


 


BC19439
ZE24-0161




++++
+


 


BC19440
ZE24-0162




++++
+


 


BC19441
ZE24-0163




++++
+


 


BC19442
ZE24-0165




+++
+


 


BC19443
ZE24-0167




++++
+



















TABLE 2d-2







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19481




++++
+


 


BC19482




+++
+


 


BC19483




++++
+


 


BC19484




++++
+


 


BC19485




++++
+


 


BC19486




++++
+


 


BC19487




+++
+


 


BC19488




++++
+


 


BC19489




++++
+


 


BC19490




++++
+


 


BC19491




++++
+


 


BC19492




++++
+


 


BC19493




++++
+


 


BC19544




++++
+


 


BC19545




++++
+


 


BC19546




++++
+


 


BC19547




+++
+


 


BC19548




++++
+


 


BC19697




++++
+


 


BC19699




++++
+


 


BC19701




++++
+


 


BC19703




++++
+


 


BC19705




++++
+


 


BC19707




++++
+


 


BC19710




++++
+


 


BC19712




++++
+


 


BC19714




++++
++


 


BC19716




++++
++


 


BC19718




++++
++


 


BC19720




++++
+


 


BC19722




++++
++


 


BC19730




++++
+


 


BC19732




++++
++


 


BC19734




++++
+


 


BC19736




++++
+


 


BC19738




++++
+


 


BC19740




++++
+


 


BC19742




++++
++


 


BC19744




++++
++


 


BC19746




++++
+


 


BC19748




++++
+


 


BC19750




++++
+


 


BC19752




++++
+


 


BC19754




++++
++


 


BC19756




++++
+


 


BC19757




++++
+


 


BC19759




++++
+


 


BC19761




+++
+


 


BC19763




+++
++


 


BC19765




++++
+


 


BC19767




++++
+


 


BC19769




++++
+


 


BC19771




++++
+


 


BC19773




++++
+


 


BC19775




++++
+


 


BC19777




++++
+


 


BC19779




+++
++


 


BC19781




++++
++


 


BC19783




++++
+


 


BC19785




++++
+


 


BC19787




++++
+


 


BC19789




++++
++


 


BC19791




++++
+


 


BC19793




++++
+


 


BC19796




++++
++


 


BC19798




++++
++


 


BC19900




+++
+


 


BC19902




++++
+


 


BC19904




++++
+


 


BC19906




++++
++


 


BC19908




++++
+


 


BC19909




+
+


 


BC19911




++++
+


 


BC19913




++++
+


 


BC19915




++++
+


 


BC19921




++++
++


 


BC19923




++++
++


 


BC19925




++++
++


 


BC19927




++++
++


 


BC19929




++++
++


 


BC19931




++++
++


 


BC19933




++++
++


 


BC19935




++++
++


 


BC19937




++++
++




















TABLE 2e








IC50






(NF-κB
IC50


BC No.
ZE No.
Structure
assay)
(TNF assay)







BC19181
ZE25-0002




+
+


 


BC19182
ZE25-0005




+
+


 


BC19183
ZE25-0017




+
+


 


BC19184
ZE25-0026




+
+


 


BC19235
ZE25-0015




+
+


 


BC19236
ZE25-0028




+
+


 


BC19295
ZE25-0001




++++
+


 


BC19296
ZE25-0007




++
+


 


BC19297
ZE25-0030




++
+


 


BC19298
ZE25-0032




++++
+


 


BC19299
ZE25-0033




++
+


 


BC19300
ZE25-0039




+++
+



















TABLE 16







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19917




+
+



















TABLE 2f







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19549




++
+


 


BC19550




++++
+


 


BC19551




+++
+


 


BC19552




+++
+


 


BC19553




++
+


 


BC19603




+++
+


 


BC19604




++
+


 


BC19605




+
+


 


BC19606




++
+


 


BC19607




+++
+


 


BC19608




++
+


 


BC19609




++
+


 


BC19610




+++
+


 


BC19611




++++
+


 


BC19612




++
+


 


BC19613




+
+


 


BC19614




+
+


 


BC19615




+++
+



















TABLE 2g







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19652




++
+


 


BC19653




+
+


 


BC19654




+
+


 


BC19655




+
+


 


BC19656




++
+


 


BC19657




++
+


 


BC19658




+
+


 


BC19659




+
+


 


BC19660




+
+


 


BC19661




+
+


 


BC19689




+
++


 


BC19690




+
+


 


BC19691




+
++


 


BC19692




+
+


 


BC19693




+
+


 


BC19694




+
+


 


BC19695




+
++



















TABLE 2h







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19648




++++
+


 


BC19649




++++
+


 


BC19650




++++
+


 


BC19651




+++
+


 


BC19685




++++
++


 


BC19686




++++
+


 


BC19687




++++
+


 


BC19688




+
+









Example 3—Bioassay Results for Tested Compounds









TABLE 3a







IC50




(NF-κB 


BC No.
Compound
assay)







BC18500




++++


 


BC18501




+


 


BC18502




+


 


BC18503




++


 


BC18504




++


 


BC18505




++


 


BC18506




+


 


BC18507




++


 


BC18508




++++


 


BC18509




++++


 


BC18510




+++


 


BC18511




++++


 


BC18512




++


 


BC18513




+


 


BC18514




++


 


BC18515




+


 


BC18516




++


 


BC18517




++


 


BC18518




++


 


BC18519




+


 


BC18520




++++


 


BC18521




++++


 


BC18522




++++


 


BC18523




+


 


BC18524




++


 


BC18525




+


 


BC18526




++


 


BC18527




++


 


BC18528




+


 


BC18529




++


 


BC18530




++


 


BC18531




++++


 


BC18532




++++


 


BC18533




++++


 


BC18534




+


 


BC18535




++


 


BC18536




+


 


BC18537




++


 


BC18538




+


 


BC18539




+


 


BC18540




+


 


BC18541




+


 


BC18542




++++


 


BC18543




++++


 


BC18544




+++


 


BC18545




++


 


BC18546




++


 


BC18547




+


 


BC18548




++


 


BC18549




+


 


BC18550




+


 


BC18551




+


 


BC18552




+


 


BC18553




++++


 


BC18554




++++


 


BC18555




++++


 


BC18556




++


 


BC18557




++


 


BC18558




+


 


BC18559




++


 


BC18560




++


 


BC18561




++


 


BC18562




+


 


BC18563




+


 


BC18564




++++


 


BC18565




++++


 


BC18566




++++


 


BC18567




+


 


BC18568




++


 


BC18569




++


 


BC18570




++


 


BC18571




++


 


BC18572




+


 


BC18573




++


 


BC18574




+


 


BC18575




++++


 


BC18576




++++


 


BC18577




++++


 


BC18578




++


 


BC18579




++


 


BC18580




+


 


BC18581




++


 


BC18582




++


 


BC18583




++


 


BC18584




+


 


BC18585




++


 


BC18586




++++


 


BC18587




++++


 


BC18588




++++




















TABLE 3b








IC50
IC50





(NF-κB
(TNF


BC No.
ZE No.
Structure
assay)
assay)







BC19125
ZE23-0008




++++
++++


 


BC19126
ZE23-0009




++
+++


 


BC19127
ZE23-0010




++++
++


 


BC19128
ZE23-0012




++
+++


 


BC19129
ZE23-0013




++++
+++


 


BC19130
ZE23-0014




+++
+++


 


BC19146
ZE23-0004




++++
+++


 


BC19147
ZE23-0007




+++
+++


 


BC19260
ZE23-0016




++++
++++


 


BC19261
ZE23-0018




++++
+


 


BC19262
ZE23-0019




+++
++++


 


BC19263
ZE23-0022




+++
+++


 


BC19264
ZE23-0023




++++
+++


 


BC19265
ZE23-0024




++++
+++


 


BC19266
ZE23-0025




++++
++++


 


BC19267
ZE23-0026




++++
+++


 


BC19268
ZE23-0028




+++
++++


 


BC19269
ZE23-0030




+++
++++


 


BC19270
ZE23-0031




++++
++++


 


BC19271
ZE23-0032




+++
++++


 


BC19272
ZE23-0033




++++
++++


 


BC19273
ZE23-0039




+++
+++


 


BC19274
ZE23-0040




++++
+++


 


BC19275
ZE23-0041




++++
++++


 


BC19276
ZE23-0044




+++
++++


 


BC19277
ZE23-0045




++++
+++


 


BC19278
ZE23-0051




++++
++++


 


BC19279
ZE23-0065




+++
+++


 


BC19327
ZE23-0037




++
++


 


BC19328
ZE23-0038




++++
+++


 


BC19329
ZE23-0047




++++
++++


 


BC19330
ZE23-0052




+++
+++


 


BC19331
ZE23-0055




++++
++++


 


BC19332
ZE23-0057




+++
++++


 


BC19333
ZE23-0058




++++
++++


 


BC19334
ZE23-0064




+
++


 


BC19335
ZE23-0066




+
+


 


BC19336
ZE23-0083




+
+


 


BC19337
ZE23-0087




+
+


 


BC19342
ZE23-0102




++++
++++


 


BC19343
ZE23-0103




++
++++


 


BC19344
ZE23-0104




+++
+++


 


BC19345
ZE23-0105




+++
+++


 


BC19346
ZE23-0106




++++
++++


 


BC19347
ZE23-0108




++++
++++


 


BC19348
ZE23-0109




++++
+++


 


BC19349
ZE23-0110




+++
++++


 


BC19350
ZE23-0111




++
++


 


BC19351
ZE23-0112




+++
++++


 


BC19352
ZE23-0113




+++
++++


 


BC19353
ZE23-0116




+++
+++


 


BC19410
ZE23-0082




+++
+


 


BC19411
ZE23-0107




++++
++++


 


BC19412
ZE23-0117




+++
+++


 


BC19413
ZE23-0127




+
++


 


BC19414
ZE23-0128




+
+


 


BC19415
ZE23-0129




+
++


 


BC19416
ZE23-0131




+
+


 


BC19417
ZE23-0133




+++
++


 


BC19418
ZE23-0134




++
++


 


BC19419
ZE23-0136




++
+++


 


BC19420
ZE23-0145




+
+



















TABLE 3b-2







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19463




++++
+++


 


BC19464




+++
++++


 


BC19521




++++
+++




















TABLE 3c








IC50
IC50





(NF-κB
(TNF


BC No.
ZE No.
Structure
assay)
assay)







BC19204
ZE23-0020




+
+


 


BC19205
ZE23-0021




++
+


 


BC19338
ZE23-0091




+
+


 


BC19339
ZE23-0092




+
+


 


BC19340
ZE23-0096




+
+


 


BC19341
ZE23-0098




+
+



















TABLE 8







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19543




+++
++++


 


BC19635




+
+


 


BC19636




+
+


 


BC19637




+
+


 


BC19638




+
+


 


BC19639




+
+


 


BC19640




+
+


 


BC19641




+
+


 


BC19642




+
+


 


BC19645




+
+


 


BC19646




+
+


 


BC19679




++
+++


 


BC19724




++
++


 


BC19725




+
+



















TABLE 9







IC50
IC50


BC No.
Structure
(NF-κB assay)
(TNF assay)







BC19542




+
+


 


BC19647




+
++



















TABLE 10







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19279




+++
+++


 


BC19334




+
++


 


BC19413




+
++


 


BC19414




+
+


 


BC19415




+
++


 


BC19416




+
+


 


BC19471




++
++


 


BC19472




+
+


 


BC19473




+
+


 


BC19474




++
+


 


BC19475




++
++


 


BC19476




+
+


 


BC19477




+
+


 


BC19478




+
++


 


BC19479




+
+


 


BC19480




+
+


 


BC19525




++
++


 


BC19526




++
++


 


BC19527




++
++


 


BC19528




++
+++


 


BC19529




+
++


 


BC19530




++
++


 


BC19531




++
+++


 


BC19532




+
+


 


BC19533




++
++


 


BC19534




++
++


 


BC19535




++
++


 


BC19536




++
+++


 


BC19537




+
+


 


BC19538




++
++


 


BC19539




++
++


 


BC19540




++
++


 


BC19541




++
++


 


BC19583




+
+


 


BC19587




++
++


 


BC19588




++
+


 


BC19589




++
++


 


BC19590




++
++


 


BC19591




++
++


 


BC19592




++
++


 


BC19593




+++
++


 


BC19594




+
+


 


BC19595




+++
+++


 


BC19596




+++
++


 


BC19597




++
+


 


BC19598




++
++


 


BC19599




++
++


 


BC19620




+
+


 


BC19621




++
++


 


BC19622




++
++


 


BC19623




+
+


 


BC19624




++
++


 


BC19625




++
++


 


BC19626




++
++


 


BC19627




++
+


 


BC19628




+
+


 


BC19629




+
+


 


BC19630




+
++


 


BC19631




++
+


 


BC19632




+
+


 


BC19633




++
++


 


BC19671




++
++++


 


BC19672




++
+++


 


BC19673




++
+


 


BC19674




++
+


 


BC19675




++
++


 


BC19676




++
+


 


BC19677




++
++


 


BC19678




++
++



















TABLE 11







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19335




+
+


 


BC19336




+
+


 


BC19337




+
+


 


BC19410




+++
+


 


BC19420




+
+


 


BC19462




++
+


 


BC19465




++
+


 


BC19466




++
+


 


BC19467




++
++


 


BC19468




++
+


 


BC19469




++
+


 


BC19470




+
+


 


BC19522




++
+


 


BC19523




++
+


 


BC19524




+
+


 


BC19581




+
+


 


BC19582




++
+


 


BC19584




++
+


 


BC19585




++
+


 


BC19586




++
+


 


BC19600




+
+


 


BC19601




+
+


 


BC19602




+
+


 


BC19634




+
+


 


BC19644




+
+



















TABLE 12







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19643




+
+


 


BC19670




++
++


 


BC19683




+
++


 


BC19684




+
+



















TABLE 15







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19680




+
+


 


BC19681




+++
++++


 


BC19682




+++
++++


 


BC19726




+
+


 


BC19727




++
++


 


BC19728




+
++









Example 4—Bioassay Data for Tested Compounds









TABLE 4a







IC50




(NF-κB


BC No.
Compound
assay)







BC18400




++++


 


BC18401




+++


 


BC18402




++


 


BC18403




++++


 


BC18404




++++


 


BC18405




++++


 


BC18406




++++


 


BC18407




++


 


BC18408




+++


 


BC18409




++++


 


BC18410




++++


 


BC18411




++


 


BC18412




++


 


BC18413




+++


 


BC18414




+


 


BC18415




++++


 


BC18416




++++


 


BC18417




++++


 


BC18418




+++


 


BC18419




++


 


BC18420




+++


 


BC18421




+


 


BC18422




++++


 


BC18423




++++


 


BC18424




+++


 


BC18425




++


 


BC18426




++++


 


BC18427




++++


 


BC18428




++++


 


BC18429




++++


 


BC18430




++


 


BC18431




+++


 


BC18432




+++


 


BC18433




+


 


BC18434




+++


 


BC18435




+++


 


BC18436




++


 


BC18437




++++


 


BC18438




++++


 


BC18439




++++


 


BC18440




++++


 


BC18441




++


 


BC18442




++++


 


BC18443




++++


 


BC18444




+


 


BC18445




+++


 


BC18446




+


 


BC18447




++++


 


BC18448




++++


 


BC18449




++++


 


BC18450




++++


 


BC18451




+++


 


BC18452




++


 


BC18453




++


 


BC18454




+++


 


BC18455




+


 


BC18456




++++


 


BC18457




+


 


BC18458




++++


 


BC18459




++++


 


BC18460




++++


 


BC18461




++++


 


BC18462




++++


 


BC18463




++


 


BC18464




++++


 


BC18465




+++


 


BC18466




+


 


BC18467




+++


 


BC18468




+


 


BC18469




++++


 


BC18470




++++


 


BC18471




++++


 


BC18472




+++


 


BC18473




++++


 


BC18474




++


 


BC18475




+


 


BC18476




+++


 


BC18477




++


 


BC18478




+++


 


BC18479




++


 


BC18480




++++


 


BC18481




++++


 


BC18482




++++


 


BC18483




++++


 


BC18484




++


 


BC18485




++


 


BC18486




+


 


BC18487




++++


 


BC18488




++




















TABLE 4b








IC50
IC50





(NF-κB
(TNF


BC No.
ZE No.
Structure
assay)
assay)







BC19118
ZE18- 0085




++
+


 


BC19154
ZE18- 0097




++++
+


 


BC19192
ZE18- 0147




+++
+


 


BC19194
ZE18- 0149




++++
+


 


BC19237
ZE18- 0150




++++
+


 


BC19316
ZE18- 0198




+++
+


 


BC19317
ZE18- 0199




++++
+


 


BC19318
ZE18- 0200




++++
+


 


BC19319
ZE18- 0204




++
+


 


BC19398
ZE18- 0203




+++
+


 


BC19399
ZE18- 0205




+
+


 


BC19405
ZE18- 0216




+++
+


 


BC19406
ZE18- 0217




+++
+


 


BC19403
ZE18- 0214




+++
+


 


BC19407
ZE18- 0224




+++
+


 


BC19408
ZE18- 0225




+++
+



















TABLE 4b-2







IC50





(NF-
IC50




κB
(TNF


BC No.
Structure
assay)
assay)







BC19445




+
+


 


BC19446




+
+


 


BC19447




+
+


 


BC19449




+
+


 


BC19450




++
+


 


BC19451




+++
+


 


BC19452




+++
+


 


BC19453




+
+


 


BC19495




+++
+


 


BC19497




++++
+


 


BC19498




+
+


 


BC19499




++
+


 


BC19500




+
+


 


BC19501




+
+


 


BC19502




+
+


 


BC19503




++
++


 


BC19513




++++
+


 


BC19514




+++
++


 


BC19577




+++
+


 


BC19578




+
+


 


BC19512




+++
+


 


BC19448




+++
+


 


BC19618




+++
+


 


BC19666




+++
+


 


BC19668




+++
+




















TABLE 4c








IC50






(NF-
IC50





κB
(TNF


BC No.
ZE No.
Structure
assay)
assay)







BC19101
ZE18- 0001




++++
+


 


BC19102
ZE18- 0006




+++
+


 


BC19139
ZE18- 0003




++++
+


 


BC19140
ZE18- 0004




++
+


 


BC19141
ZE18- 0005




+++
+


 


BC19143
ZE18- 0031




+++
+


 


BC19144
ZE18- 0033




++
+


 


BC19145
ZE18- 0046




++
+


 


BC19148
ZE18- 0002




++++
+


 


BC19150
ZE18- 0032




+++
++


 


BC19190
ZE18- 0119




+++
+


 


BC19193
ZE18- 0148




+++
+


 


BC19238
ZE18- 0151




++++
+


 


BC19240
ZE18- 0156




++++
+


 


BC19241
ZE18- 0157




++
+


 


BC19242
ZE18- 0163




+++
+


 


BC19243
ZE18- 0165




+++
+


 


BC19244
ZE18- 0169




+
+


 


BC19245
ZE18- 0171




++
+


 


BC19246
ZE18- 0177




++
+


 


BC19247
ZE18- 0178




++
+


 


BC19250
ZE18- 0182




++++
+


 


BC19301
ZE18- 0155




++++
+


 


BC19302
ZE18- 0162




++
+


 


BC19303
ZE18- 0164




+
+


 


BC19304
ZE18- 0167




++
+


 


BC19305
ZE18- 0170




+
+


 


BC19306
ZE18- 0180




+++
+


 


BC19396
ZE18- 0188




++++
+


 


BC19401
ZE18- 0212




++++
+


 


BC19402
ZE18- 0213




++++
+


 


BC19404
ZE18- 0215




++
+


 


BC19111
ZE18- 0061




+
+


 


BC19112
ZE18- 0062




+
+


 


BC19113
ZE18- 0063




+
+


 


BC19114
ZE18- 0064




+
+


 


BC19115
ZE18- 0065




+
+


 


BC19116
ZE18- 0067




+
+


 


BC19151
ZE18- 0066




+
+


 


BC19152
ZE18- 0079




+
+


 


BC19153
ZE18- 0080




+
+


 


BC19159
ZE18- 0144




+
+


 


BC19186
ZE18- 0071




++
+


 


BC19248
ZE18- 0179




+
+


 


BC19249
ZE18- 0181




++
+


 



ZE18- 0075








 



ZE18- 0591








 



ZE18- 0592








 



ZE18- 0593








 



ZE18- 0594








 



ZE18- 0595








 



ZE18- 0596








 



ZE18- 0597








 



ZE18- 0598








 



ZE18- 0600








 



ZE18- 0601























TABLE 4c-2








IC50




IC50 (NF-
(TNF


BC No.
Structure
κB assay)
assay)







BC19444




+++
+


 


BC19496




++++
+


 


BC19619




++
+


 


BC19664




+++
+++


 


BC19665




++++
++


 


BC19667




+
+




















TABLE 4d









IC50



ZE

IC50 (NF-
(TNF


BC No.
No.
Structure
κB assay)
assay)







BC19103
ZE18- 0007




+
+


 


BC19104
ZE18- 0008




+
+


 


BC19105
ZE18- 0010




+
+


 


BC19106
ZE18- 0012




+
+


 


BC19107
ZE18- 0013




+
+


 


BC19108
ZE18- 0014




+
+


 


BC19142
ZE18- 0011




+
+


 


BC19149
ZE18- 0009




+
+


 


BC19110
ZE18- 0034




+
+


 


BC19109
ZE18- 0017




+++
+


 


BC19191
ZE18- 0125




+
+


 


BC19185
ZE18- 0026




++++
+


 


BC19307
ZE18- 0185




+++
++++


 


BC19308
ZE18- 0155




+++
++++


 


BC19395
ZE18- 0184




+++
++++


 


BC19117
ZE18- 0083




+
+


 


BC19158
ZE18- 0124




+
+


 


BC19119
ZE18- 0103




++++
++++


 


BC19120
ZE18- 0105




++++
++++


 


BC19155
ZE18- 0099




+++
++


 


BC19157
ZE18- 0104




+
+


 


BC19156
ZE18- 0101




++
+


 


BC19187
ZE18- 0114




+++
+


 


BC19188
ZE18- 0115




+++
+


 


BC19189
ZE18- 0116




+++
+




















TABLE 4e









IC50





IC50
(TNF


BC No.
ZE No.
Structure
(NF-κB assay)
assay)







BC19320
ZE18-0209




+
+


 


BC19321
ZE18-0211




++
+


 


BC19400
ZE18-0210




+
+




















TABLE 4f








IC50
IC50





(NF-
(TNF


BC No.
ZE No.
Structure
κB assay)
assay)







BC19195
ZE18-0152




++
+


 


BC19239
ZE18-0154




+++
+


 


BC19251
ZE18-0187




++++
++


 


BC19309
ZE18-0189




+++
++


 


BC19310
ZE18-0190




++++
+


 


BC19311
ZE18-0192




++++
+


 


BC19312
ZE18-0193




++++
++


 


BC19313
ZE18-0194




+++
++


 


BC19314
ZE18-0196




++++
++


 


BC19315
ZE18-0197




+++
+


 


BC19397
ZE18-0195




++++
+++


 



ZE18-0568








 



ZE18-0569








 



ZE18-0570








 



ZE18-0571








 



ZE18-0581








 



ZE18-0586








 



ZE18-0588























TABLE 4f-2







IC50





(NF-
IC50




κB
(TNF


BC No.
Structure
assay)
assay)







BC19494




+++
+


 


BC20317








 


BC20321








 


BC20330








 


BC20333








 


BC20334








 


ZEIS-0567








 


BC19510




+++
+


 


BC19511




++++
+


 


BC20218








 


BC20219








 


BC20226








 


BC20277








 


BC20291








 


BC19563




++++
+


 


BC20297








 


BC19564




++++
++


 


BC20312








 


BC19565




++++
+


 


BC20298








 


BC19566




++++
+


 


BC19567




+++
++


 


BC20299








 


BC20300








 


BC20217








 


BC20225








 


BC20237








 


BC20238








 


BC20239








 


BC20255








 


BC20256








 


BC20269








 


BC20293








 


BC19568




+++
+


 


BC19569




+++
+


 


BC19570




+++
+


 


BC20207








 


BC19571




+++
++


 


BC20310








 


BC20311








 


BC20224








 


BC20254








 


BC20213








 


BC20316








 


BC20216








 


BC20268








 


BC20314








 


BC20315








 


BC20318








 


BC20320








 


BC20331








 


BC20319








 


BC19572




+++
+


 


BC19573




+++
+++


 


BC19574




+++
+


 


BC19575




+++
+


 


BC19576




+++
+


 


BC19616




+++
++


 


BC19617




+++
+



















TABLE 4g







IC50





(NF-
IC50




κB
(TNF


BC No.
Structure
assay)
assay)







BC19504




+++
+


 


BC19505




+++
+


 


BC19506




+++
+


 


BC19507




++++
+


 


BC19508




+++
++


 


BC19509




++++
+


 


BC19554




++++
+


 


BC19555




++++
++


 


BC19556




+++
+


 


BC19557




++++
+


 


BC19558




+++
+


 


BC19559




++++
+


 


BC19560




++++
+


 


BC19561




+++
+


 


BC19562




+++
++



















TABLE 17







IC50
IC50




(NF-κB
(TNF


BC No.
Structure
assay)
assay)







BC19663




+++
+


 


BC19723




+++
+









NUMBERED PARAGRAPHS
1. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Ia):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        Y1 is selected from C(O) and S(O)2;
        Y2 is selected from C(O) and S(O)2;
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        X3 is selected from N and CR3;
        X4 is selected from N and CR4;
        provided that no more than two of X1, X2, X3, and X4 are N;
        each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R5 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from R4;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1.
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


2. The method of paragraph 1, wherein Y1 is C(O).
3. The method of paragraph 1, wherein Y1 is S(O)2.
4. The method of any one of paragraphs 1-3, wherein Y2 is C(O).
5. The method of any one of paragraphs 1-3, wherein Y2 is S(O)2.
6. The method of paragraph 1, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


7. The method of paragraph 1, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


8. The method of paragraph 1, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


9. The method of paragraph 1, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


10. The method of any one of paragraphs 1-9, wherein ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA.
11. The method of any one of paragraphs 1-9, wherein ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
12. The method of any one of paragraphs 1-9, wherein ring A is 5-10 membered heteroaryl, optionally substituted with 1-6 substituents independently selected from RA.
13. The method of any one of paragraphs 1-9, wherein ring A is selected from any one of the following moieties:




14. The method of paragraph 1, wherein the compound of Formula (Ia) is selected from any one of the following compounds:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


15. The method of any one of paragraphs 1-14, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
16. The method of any one of paragraphs 1-15, wherein each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
17. The method of any one of paragraphs 1-15, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy.
18. The method of any one of paragraphs 1-17, wherein each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7.
19. The method of any one of paragraphs 1-17, wherein each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, and ORa1.
20. The method of any one of paragraphs 1-17, wherein:

    
    
        R1, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R2, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R3, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R4, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R6, if present in the compound of Formula (Ia), is selected from H and OH.
    
    


21. The method of any one of paragraphs 1-18, wherein R7 is selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
22. The method of any one of paragraphs 1-21, wherein R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
23. The method of any one of paragraphs 1-22, wherein R8 is selected from Cy1, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
24. The method of paragraph 23, wherein R8 is selected from Cy1 and C(O)NRc1Rd1.
25. The method of any one of paragraphs 1-21, wherein R5 is Cy1.
26. The method of any one of paragraphs 1-21, wherein R5 is C1-6 alkyl, optionally substituted with Cy1.
27. The method of any one of paragraphs 1-26, wherein Cy1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1.
28. The method of any one of paragraphs 1-26, wherein Cy1 is C6-10 aryl, optionally substituted with RCy1.
29. The method of any one of paragraphs 1-28, wherein RCy1 is selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl.
30. The method of any one of paragraphs 1-28, wherein Cy1 is C6-10 aryl, optionally substituted with halo.
31. The method of any one of paragraphs 1-21, wherein R5 is H.
32. The method of any one of paragraphs 1-21, wherein R5 is C1-6 alkyl, optionally substituted with C(O)NRc1Rd1.
33. The method of any one of paragraphs 1-32, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
34. The method of any one of paragraphs 1-32, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
35. The method of any one of paragraphs 1-34, wherein each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
36. The method of any one of paragraphs 1-34, wherein each Rg is independently selected from halo and C1-6 alkyl.
37. The method of any one of paragraphs 1-14, wherein:

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        R7 is selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


38. The method of any one of paragraphs 1-14, wherein:

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, C1-6 alkyl, and ORa1;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1 and C(O)NRc1Rd1,
        Cy1 is C6-10 aryl, optionally substituted with RCy1;
        RCy1 is selected from halo, CN, NO2, C1-6 alkyl, C1-6 alkoxy, and C1-6 haloalkyl;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        wherein each Rg is independently selected from halo and C1-6 alkyl.
    
    


39. The method of any one of paragraphs 1-14, wherein:

    
    
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy;
        R1, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R2, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R3, if present in the compound of Formula (Ia), is selected from H, CN, halo, C1-6 alkoxy, and C1-6 alkyl;
        R4, if present in the compound of Formula (Ia), is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R6, if present in the compound of Formula (Ia), is selected from H and OH.
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from Cy1 and C(O)NRc1Rd1;
        Cy1 is C6-10 aryl, optionally substituted with halo;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        wherein each Rg is independently selected from halo and C1-6 alkyl.
    
    


40. The method of any one of paragraphs 1-39, wherein the compound of Formula (Ia) is selected from any one of the compounds of Table 1a, Table 1d, or Table 1e, or a pharmaceutically acceptable salt thereof. 41. A compound of Formula (Ib):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        X3 is selected from N and CR3;
        X4 is selected from N and CR4;
        provided that at least one of X1, X2, X3, and X4 is N;
        each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN,
        NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1,
        S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R5 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Cy1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from Cy1, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R7 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


42. The compound of paragraph 41, wherein the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


43. The compound of paragraph 41, wherein the compound of Formula (Ib) is selected from:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


44. The compound of paragraph 41, wherein the compound of Formula (Ib) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


45. The compound of any one of paragraphs 41-44, wherein R7 and R8 are each independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
46. The compound of any one of paragraphs 41-44, wherein R7 and R8 are each independently selected from H, halo, and C1-6 alkyl.
47. The compound of any one of paragraphs 41-46, wherein each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
48. The compound of any one of paragraphs 41-46, wherein each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, and ORa1.
49. The compound of any one of paragraphs 41-46, wherein:

    
    
        each of R1, R2, R3, and R4, if present in the compound of Formula (Ib), is independently selected from H, halo, and C1-6 alkoxy; and
        R6 is selected from H and OH.
    
    


50. The compound of any one of paragraphs 41-49, wherein R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
51. The compound of any one of paragraphs 41-49, wherein R5 is selected from H and C1-6 alkyl.
52. The compound of any one of paragraphs 41-49, wherein R5 is H.
53. The compound of any one of paragraphs 41-52, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
54. The compound of any one of paragraphs 41-52, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
55. The compound of paragraph 41, wherein:

    
    
        R7 and R8 are each independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ib), is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 is selected from H, C1-6 alkyl, and Cy1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, wherein said C1-6 alkyl and C6-10 aryl are optionally substituted with 1, 2, or 3 substituents independently selected from R8.
    
    


56. The compound of paragraph 41, wherein:

    
    
        R7 and R8 are each independently selected from H, halo, and C1-6 alkyl; each of R1, R2, R3, and R4, if present in the compound of Formula (Ib), is independently selected from H, halo, and C1-6 alkoxy;
        R6 is selected from H and OH;
        R5 is selected from H and C1-6 alkyl; and
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
    
    


57. The compound of paragraph 41, wherein the compound of Formula (Ib) is selected from any one of the compounds of Table 1d, or a pharmaceutically acceptable salt thereof.
58. A compound selected from any one of the compounds of Table 1e, or a pharmaceutically acceptable salt thereof.
59. A pharmaceutical composition comprising a compound of any one of paragraphs 41-58, or a pharmaceutically acceptable salt thereof, and a pharmaceutically available carrier.
60. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Ic):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1,
        C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


61. The method of paragraph 60, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RB.
62. The method of paragraph 60 or 61, wherein each RB is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
63. The method of paragraph 60, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, and C1-6 alkoxy.
64. The method of any one of paragraphs 60-63, wherein each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RC.
65. The method of paragraph 64, wherein each RC is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
66. The method of any one of paragraphs 60-63, wherein each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, and C1-6 alkyl.
67. The method of any one of paragraphs 60-66, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg.
68. The method of any one of paragraphs 60-66, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl.
69. The method of any one of paragraphs 60-67, wherein each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
70. The method of paragraph 60, wherein:

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
    
    


71. The method of paragraph 60, wherein:

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, and C1-6 alkoxy; and
        each of R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, and C1-6 alkyl.
    
    


72. The method of paragraph 60, wherein the compound of Formula (Ic) is selected from any one of the compound of Table 1b, or a pharmaceutically acceptable salt thereof.
73. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (Id):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R2, R3, and R4 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R5, R6, R7, R8, and R9 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


74. The method of paragraph 73, wherein R1 is H.
75. The method of paragraph 73 or 74, wherein each of R2, R3, and R4 is independently selected from H and C1-6 alkyl.
76. The method of any one of paragraphs 73-75, wherein each of R5, R6, R7, R8, and R9 is independently selected from H and halo.
77. The method of paragraph 73, wherein:

    
    
        R1 is H;
        each of R2, R3, and R4 is independently selected from H and C1-6 alkyl; and
        each of R5, R6, R7, R8, and R9 is independently selected from H and halo.
    
    


78. The method of paragraph 73, wherein the compound of Formula (Id) is selected from any one of the compounds of Table 1c, or a pharmaceutically acceptable salt thereof.
79. A compound of Formula (Ie):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR1;
        X2 is selected from N and CR2;
        each R1, R2, R3, R4, R5, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R7 is selected from ORa2 and NRc2Rd2;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


80. The compound of paragraph 79, wherein the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


81. The compound of paragraph 79, wherein the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


82. The compound of paragraph 79, wherein the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


83. The compound of any one of paragraphs 79-82, wherein each of R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
84. The compound of any one of paragraphs 79-83, wherein each R8 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
85. The compound of any one of paragraphs 79-82, wherein each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, OH, C1-6 alkyl, and C1-6 alkoxy.
86 The compound of any one of paragraphs 79-85, wherein R7 is ORa2.
87. The compound of any one of paragraphs 79-85, wherein R7 is NRc2Rd2.
88. The compound of any one of paragraphs 79-87, wherein ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA.
89. The compound of any one of paragraphs 79-87, wherein ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
90. The compound of any one of paragraphs 79-87, wherein ring A is 5-10 membered heteroaryl, optionally substituted with 1-6 substituents independently selected from RA.
91. The compound of any one of paragraphs 79-87, wherein ring A is selected from any one of the following moieties:




92. The compound of paragraph 79, wherein the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


93. The compound of paragraph 79, wherein the compound of Formula (Ie) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


94. The compound of any one of paragraphs 79-93, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
95. The compound of any one of paragraphs 79-94, wherein each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2.
96. The compound of any one of paragraphs 79-93, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy.
97. The compound of any one of paragraphs 79-96, wherein each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
98. The compound of any one of paragraphs 79-97, wherein each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
99. The compound of any one of paragraphs 79-96, wherein each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H and C1-6 alkyl.
100. The compound of paragraph 79, wherein

    
    
        R1, R2, R3, R4, and R6 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA,
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)ORa1 NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, NH2, and S(O)2NH2;
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


101. The compound of paragraph 79, wherein:

    
    
        each of R1, R2, R3, R4, and R6, if present in the compound of Formula (Ia), is independently selected from H, halo, CN, OH, C1-6 alkyl, and C1-6 alkoxy;
        ring A is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, and C1-6 alkoxy; and
        each Ra1, Ra2, Rb1, Rc1, Rc2, Rd1, and Rd2 is independently selected from H and C1-6 alkyl.
    
    


102. The compound of paragraph 79, wherein the compound of Formula (Ie) is selected from any one of the compounds of Table If, or a pharmaceutically acceptable salt thereof.
103. A pharmaceutical composition comprising a compound of any one of paragraphs 79-102, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
104. A compound of Formula (If):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R1, R3, R4, R5, and R6 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


105. The compound of paragraph 104, wherein X1 is S.
106. The compound of paragraph 104, wherein X1 is S(O).
107. The compound of paragraph 104, wherein X1 is S(O)2.
108. The compound of any one of paragraphs 104-107, wherein R1, R3, R4, R5, and R6 is independently selected from H, halo, OH, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
109. The compound of any one of paragraphs 104-107, wherein R1, R3, R4, R5, and R6 are each H.
110. The compound of any one of paragraphs 104-109, wherein R2 is selected from H, C1-6 alkyl, and C1-6 haloalkyl.
111. The compound of any one of paragraphs 104-110, wherein ring A is C6-10 aryl, optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl.
112. The compound of paragraph 104, wherein:

    
    
        R1, R3, R4, R5, and R6 is independently selected from H, halo, OH, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino;
        R2 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and ring A is C6-10 aryl, optionally substituted with 1 or 2 substituents independently selected from halo and C1-6 alkyl.
    
    


113. The compound of paragraph 104, wherein the compound is selected from any one of the compound of Table 1g, or a pharmaceutically acceptable salt thereof.
114. A pharmaceutical composition of comprising a compound of any one of paragraphs 104-113, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
115. A compound of Formula (Ig):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R2, R3, and R4 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RB;
        each RB independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each of R5, R6, R7, R8, and R9 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from RC;
        each RC is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


116. The compound of paragraph 115, wherein X1 is selected from S(O) and S(O)2.
117. The compound of paragraph 115, wherein R1 is H.
118. The compound of any one of paragraphs 115-117, wherein each of R2, R3, and R4 is independently selected from H and C1-6 alkyl.
119. The compound of any one of paragraphs 115-118, wherein each of R5, R6, R7, R8, and R9 is independently selected from H, halo, and C1-6 alkyl.
120. The compound of paragraph 115, wherein:

    
    
        X1 is S(O) or S(O)2;
        R1 is H;
        each of R2, R3, and R4 is independently selected from H and C1-6 alkyl; and
        each of R5, R6, R7, R8, and R9 is independently selected from H, C1-6 alkyl and halo.
    
    


121. The compound of paragraph 115, wherein the compound of Formula (Ig) is selected from any one of the compounds of Table 1h, or a pharmaceutically acceptable salt thereof.
122. A pharmaceutical composition comprising a compound of any one of paragraphs 115-121, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
123. A method of inhibiting activation of an NF-κB pathway within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from O and NR1;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and oxo, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R1 and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
    
    


R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;

    
    
        R5 and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, S(O)2NRc1Rd1, and a group of formula (i):
    
    






    
    
        wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R7 and R8 is a group of formula (i);
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, for a -10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10− is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


124. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


125. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


126. The method of paragraph 123, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


127. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


128. The method of any one of paragraphs 123-127, wherein:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rb1, and C(O)NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


129. The method of paragraph 128, wherein R1 is selected from C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1.
130. The method of paragraph 123, wherein the compound of Formula (IIa) is selected from:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


131. The method of paragraph 123, wherein the compound of Formula (IIa) is selected from:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


132. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


133. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


134. The method of paragraph 123, wherein the compound of Formula (Ia) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


135. The method of paragraph 123, wherein the compound of Formula (IIa) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


136. The method of any one of paragraphs 132-135, wherein R2 is selected from H and C1-6 alkyl.
137. The method of any one of paragraphs 123-136, wherein R4 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
138. The method of any one of paragraphs 123-136, wherein R4 is H.
139. The method of any one of paragraphs 123-138, wherein R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
140. The method of any one of paragraphs 123-138, wherein R5 and R6 are each independently selected from H, halo, C1-6 alkyl, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with R9.
141. The method of paragraph 140, wherein R5 is H and R6 is C1-6 alkyl, optionally substituted with NRc1Rd1.
142. The method of paragraph 140, wherein R5 is H and R6 is halo.
143. The method of paragraph 140, wherein R5 is H and R6 is S(O)2Rb1.
144. The method of any one of paragraphs 123-143, wherein R7 is selected from H and C1-6 alkyl.
145. The method of any one of paragraphs 123-144, wherein R8 is selected from H and C1-6 alkyl.
146. The method of any one of paragraphs 123-145, wherein RN is selected from H and C1-6 alkyl.
147. The method of any one of paragraphs 123-146, wherein R11 is ring A.
148. The method of any one of paragraphs 123-146, wherein R11 is C1-6 alkyl, optionally substituted with ring A.
149. The method of any one of paragraphs 123-145, wherein RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
150. The method of any one of paragraphs 123-148, wherein ring A is selected from any one of the following moieties:




151. The method of any one of paragraphs 123-150, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
152. The method of any one of paragraphs 123-150, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
153. The method of any one of paragraphs 123-152, wherein each R10 is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1 154. The method of any one of paragraphs 123-150, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with C(O)ORa1.
155. The method of any one of paragraphs 123-154, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
156. The method of any one of paragraph 123-155, wherein each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
157. The method of paragraph 123, wherein:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rb1, and C(O)NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H and oxo;
        R4 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R6 are each independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are independently selected from H, C1-6 alkyl, and a moiety of formula (i);
        RN is selected from H and C1-6 alkyl; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R10 is independently selected from ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


158. The method of paragraph 123, wherein:

    
    
        R2 is selected from H and C1-6 alkyl;
        R1 is selected from C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1,
        R1 and R2, together with N atom to which R1 is attached and C atom to which R2 is attached, form a 4-10 membered heterocycloalkyl ring, which is substituted with 1, 2, or 3 substituents independently selected from R9;
        R3 is selected from H and oxo;
        R4 is H;
        R5 and R6 are each independently selected from H, halo, C1-6 alkyl, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with R9;
        R7 and R8 are independently selected from H, C1-6 alkyl, and a moiety of formula (i);
        RN is selected from H and C1-6 alkyl; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)Rb1, C(O)ORa1, NRc1Rd1, and NRc1C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with C(O)ORa1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


159. The method of paragraph 123, wherein the compound of Formula (IIa) is selected from any one of the compounds of Table 2a, Table 2c, Table 2c-2, Table 2d, Table 2d-2, Table 2e, or Table 16, or a pharmaceutically acceptable salt thereof.
160. The method of paragraph 123, wherein the compound of Formula (IIa) is selected from any one of the compounds of Table 2a, Table 2c, Table 2d, or Table 2e, or a pharmaceutically acceptable salt thereof.
161. A compound selected from any one of the compounds of Table 16, or a pharmaceutically acceptable salt thereof.
162. A pharmaceutical composition comprising a compound of any one of paragraphs 123-161, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
163. A compound of Formula (IIb):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        Hal is a halogen;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, for a -10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


164. The compound of paragraph 163, wherein R2 is selected from H and C1-6 alkyl.
165. The compound of paragraph 163 or 164, wherein R4, R5, and R8 are each H.
166. The compound of any one of paragraphs 163-165, wherein RN is H.
167. The compound of any one of paragraphs 163-165, wherein RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
168. The compound of any one of paragraphs 163-166, wherein ring A is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from RA.
169. The compound of any one of paragraphs 163-168, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R11.
170. The compound of any one of paragraphs 163-168, wherein each RA is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
171. The compound of paragraphs 163, wherein:

    
    
        R2 is selected from H and C1-6 alkyl;
        R4, R5, and R8 are each H;
        RN is H; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        ring A is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from R4; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


172. The compound of paragraph 171, wherein RA is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, and C(O)Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
173. The compound of any one of paragraphs 163-172, wherein the compound of Formula (IIb) is selected from any one of the compounds of Table 2c or Table 2c-2, or a pharmaceutically acceptable salt thereof.
174. The compound of paragraph 163, wherein the compound of Formula (IIb) is selected from any one of the compounds of Table 2c, or a pharmaceutically acceptable salt thereof.
175. A pharmaceutical composition comprising a compound of any one of paragraphs 163-174, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
176. A compound of Formula (IIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1,
        C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1,
        C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


177. The compound of paragraph 176, wherein RB is a halogen.
178. The compound of paragraph 176, wherein RB is S(O)2Rb1.
179. The compound of any one of paragraphs 176-178, wherein R2 is selected H and C1-6 alkyl.
180. The compound of any one of paragraphs 176-179, wherein R4 is H.
181. The compound of any one of paragraphs 176-180, wherein R5 is H.
182. The compound of any one of paragraphs 176-181, wherein R7 is selected H and C1-6 alkyl.
183. The compound of any one of paragraphs 176-182, wherein RN is H.
184. The compound of any one of paragraphs 176-182, wherein RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
185. The compound of any one of paragraphs 176-183, wherein ring A is selected from C6-10 aryl and C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA.
186. The compound of any one of paragraphs 176-185, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
187. The compound of any one of paragraphs 176-179, wherein:

    
    
        R2 is selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H; or
        RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        ring A is selected from C6-10 aryl and C3-10 cycloalkyl, optionally substituted with 1-10 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


188. The compound of paragraph 176, wherein the compound of Formula (IIc) is selected from any one of the compounds of Table 2d or Table 2d-2, or a pharmaceutically acceptable salt thereof.
189. The compound of paragraph 176, wherein the compound of Formula (IIc) is selected from any one of the compounds of Table 2d, or a pharmaceutically acceptable salt thereof.
190. A pharmaceutical composition comprising a compound of any one of paragraphs 176-189, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
191. A compound of Formula (IId):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 and R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5, R6, and R8 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


192. The compound of paragraph 191, wherein R2 is selected from H and C1-6 alkyl.
193. The compound of paragraph 191 or paragraph 192, wherein R4 is H.
194. The compound of any one of paragraphs 191-193, wherein R5, R6, and R8 are each H.
195. The compound of any one of paragraphs 191-194, wherein R1 is selected from H, C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
196. The compound of any one of paragraphs 191-195, wherein each RA is H.
197. The compound of paragraph 191, wherein:

    
    
        R2 is selected from H and C1-6 alkyl;
        R4 is H;
        R5, R6, and R8 are each H;
        R1 is selected from H, C1-6 alkyl, C(O)Rb1, and C(O)NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from OH, C1-6 alkoxy, carboxy, C(O)NH2, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino; and
        each RA is H.
    
    


198. The compound of paragraph 191, wherein the compound of Formula (IId) is selected from any one of the compounds of Table 2e, or a pharmaceutically acceptable salt thereof.
199. A pharmaceutical composition comprising a compound of any one of paragraphs 191-198, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
200. A compound of Formula (IIe)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


201. The compound of paragraph 200, wherein RB is a halogen.
202. The compound of paragraph 200, wherein RB is S(O)2Rb1.
203. The compound of any one of paragraphs 200-202, wherein R2a and R2b are each independently selected from H and C1-6 alkyl.
204. The compound of any one of paragraphs 200-203 wherein R4 is H.
205. The compound of any one of paragraphs 200-204, wherein R5 is H.
206. The compound of any one of paragraphs 200-205, wherein R7 is selected H and C1-6 alkyl.
207. The compound of any one of paragraphs 200-206, wherein RN is H.
208. The compound of any one of paragraphs 200-207, wherein ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
209. The compound of any one of paragraphs 200-208, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
210. The compound of paragraph 200, wherein:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


211. The compound of paragraph 200, wherein the compound of Formula (IIe) is selected from any one of the compounds of Table 2f, or a pharmaceutically acceptable salt thereof.
212. A pharmaceutical composition comprising a compound of any one of paragraphs 200-211, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
213. A compound of Formula (IIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


214. The compound of paragraph 213, wherein RB is a halogen.
215. The compound of paragraph 213, wherein RB is S(O)2Rb1.
216. The compound of any one of paragraphs 213-215, wherein R2a and R2b are each independently selected from H and C1-6 alkyl.
217. The compound of any one of paragraphs 213-216, wherein R4 is H.
218. The compound of any one of paragraphs 213-217, wherein R5 is H.
219. The compound of any one of paragraphs 213-218, wherein R7 is selected H and C1-6 alkyl.
220. The compound of any one of paragraphs 213-219, wherein RN is H.
221. The compound of any one of paragraphs 213-220, wherein ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
222. The compound of any one of paragraphs 213-221, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
223. The compound of paragraph 213, wherein:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA, and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


224. The compound of paragraph 213, wherein the compound of Formula (IIf) is selected from any one of the compounds of Table 2g, or a pharmaceutically acceptable salt thereof.
225. A pharmaceutical composition comprising a compound of any one of paragraphs 213-224, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
226. A compound of Formula (IIg):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        RB is selected from halogen and S(O)2Rb1;
        R2a and R2b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R4 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R5 and R7 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R11 is selected from C1-6 alkyl and ring A, wherein said C1-6 alkyl is optionally substituted with ring A;
        RN is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9; or
        R11 and RN, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        ring A is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
        each RA is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


227. The compound of paragraph 226, wherein RB is a halogen.
228. The compound of paragraph 226, wherein RB is S(O)2Rb1.
229. The compound of any one of paragraphs 226-228, wherein R2a and R2b are each independently selected from H and C1-6 alkyl.
230. The compound of any one of paragraphs 226-229, wherein R4 is H.
231. The compound of any one of paragraphs 226-230, wherein R5 is H.
232. The compound of any one of paragraphs 226-231, wherein R7 is selected H and C1-6 alkyl.
233. The compound of any one of paragraphs 226-232, wherein RN is H.
234. The compound of any one of paragraphs 226-233, wherein ring A is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA.
235. The compound of any one of paragraphs 226-234, wherein each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, and ORa1; wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
236. The compound of paragraph 226, wherein:

    
    
        R2a and R2b are each independently selected H and C1-6 alkyl;
        R4 is H;
        R5 is H;
        R7 is selected H and C1-6 alkyl;
        RN is H;
        R11 is C6-10 aryl, optionally substituted with 1-5 substituents independently selected from RA; and
        each RA is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


237. The compound of paragraph 226, wherein the compound of Formula (IIg) is selected from any one of the compounds of Table 2h, or a pharmaceutically acceptable salt thereof.
238. A pharmaceutical composition comprising a compound of any one of paragraphs 226-237, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
239. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IIIa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from O, S, and NRN;
        RN is selected from H and C1-6 alkyl;
        X2 is selected from S, S(O), and S(O)2;
        RS is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        or any two adjacent R1, R2, R3, R4, and R5 groups, together with the carbon atoms to which they are attached, form a C6-10 aryl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1.
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1,
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


240. The method of paragraph 239, wherein:

    
    
        X1 is selected from O, S, and NRN,
        RN is selected from H and C1-6 alkyl;
        X2 is selected from S, S(O), and S(O)2;
        RS is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each R12 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


241. The method of paragraph 239 or 240, wherein X1 is O.
242. The method of paragraph 239 or 240, wherein X1 is S.
243. The method of paragraph 239 or 240, wherein X1 is NRN.
244. The method of any one of paragraphs 239-243, wherein X2 is S.
245. The method of any one of paragraphs 239-243, wherein X2 is S(O).
246. The method of any one of paragraphs 239-243, wherein X2 is S(O)2.
247. The method of any one of paragraphs 239-246, wherein RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11.
248. The method of paragraph 247, wherein RS is C1-6 alkyl, optionally substituted with Cy1, ORa1, C(O)Rb1, NRc1Rd1, and C(O)NRc1Rd1 249. The method of paragraph 247, wherein RS is C1-6 alkyl, optionally substituted with Cy1, ORa1, C(O)Rb1, and C(O)NRc1Rd1 250. The method of paragraph 247, wherein RS is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo and C1-6 alkyl.
251. The method of any one of paragraphs 239-250, wherein each R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1 252. The method of any one of paragraphs 239-251, wherein each Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from 253. The method of any one of paragraphs 239-252, wherein each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, (O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R12.
254. The method of any one of paragraphs 239-252, wherein each RCy1 is independently selected from halo, CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and S(O)2NH2.
255. The method of any one of paragraphs 239-254, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
256. The method of any one of paragraphs 239-254, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
257. The method of any one of paragraphs 239-256, wherein each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
258. The method of paragraph 239, wherein:

    
    
        RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, NRc1Rd1, and C(O)NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, (O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R12;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


259. The method of paragraph 258, wherein R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1.
260. The method of paragraph 239, wherein:

    
    
        RS is selected from C1-6 alkyl, C6-10 aryl, and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, NRc1Rd1, and C(O)NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, OH, C1-6 alkoxy, C(O)NH2, C(O)OH, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and S(O)2NH2;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C6-10 aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


261. The method of paragraph 260, wherein R11 independently selected from Cy1, halo, C1-6 alkyl, ORa1, C(O)Rb1, and C(O)NRc1Rd1;
262. The method of paragraph 239, wherein the compound of Formula (IIIa) is selected from any one of the compounds of Table 3a, Table 3b, Table 3b-2, Table 10, or Table 11.
263. The method of paragraph 239, wherein the compound of Formula (IIIa) is selected from any one of the compounds of Table 3a or Table 3b, or a pharmaceutically acceptable salt thereof.
264. A compound selected from any one of the compounds of Table 3b or Table 3b-2, or a pharmaceutically acceptable salt thereof.
265. A compound selected from any one of the compounds of Table 3b, or a pharmaceutically acceptable salt thereof.
266. A pharmaceutical composition comprising a compound of paragraph 264 or 265, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
267. A compound of Formula (IIIc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R13;
        each R13 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


268. The compound of paragraph 267, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy.
269. The compound of paragraph 267, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy.
270. The compound of paragraph 267, wherein the compound of Formula (IIIc) is:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


271. A pharmaceutical composition comprising a compound of any one of paragraphs 267-270, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
272. A compound of Formula (IIId):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1,
        NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R13;
        each R13 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


273. The compound of paragraph 272, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
274. The compound of paragraph 272, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy.
275. The compound of paragraph 272, wherein the compound of Formula (IIId) is:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


276. A pharmaceutical composition comprising a compound of any one of paragraphs 272-275, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
277. A compound of Formula (IIIe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each  represents a single bond or a double bond, provided that not more than two of  are double bonds;
        RN2 is absent if  between the N atom to which RN2 is attached and the C atom to which X1 is attached is a double bond; or
        RN2 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        RN1 is absent if  between the N atom to which RN1 is attached and the C atom to which NR6R7 is attached is a double bond; or
        RN1 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and RN1 together with the N atoms to which they are attached from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


278. The compound of paragraph 277, wherein X1 is selected from S(O) and S(O)2.
279. The compound of paragraph 277, wherein X1 is S(O).
280. The compound of paragraph 277, wherein X1 is S(O)2.
281. The compound of any one of paragraphs 277-280, wherein the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


282. The compound of paragraph 281, wherein RN1 is selected from H and C1-6 alkyl.
283. The compound of paragraph 282, wherein RN1 is H.
284. The compound of any one of paragraphs 281-283, wherein the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


285. The compound of any one of paragraphs 277-284, wherein R6 and R7 are each independently selected from H and C1-6 alkyl.
286. The compound of paragraph 285, wherein R6 and R7 are both H.
287. The compound of any one of paragraphs 277-281, wherein R6 and RN1 together with the N atoms to which they are attached from a 5-10 membered heteroaryl, substituted with 1, 2, or 3 substituents independently selected from R10.
288. The compound of paragraph 287, wherein the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


289. The compound of any one of paragraphs 277-288, wherein each R10 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
290. The compound of any one of paragraphs 277-288, wherein each R10 is independently selected from H, halo, OH, C1-6 alkyl, and C1-6 alkoxy.
291. The compound of any one of paragraphs 277-288, wherein each R10 is independently selected from H, OH, and C1-6 alkyl.
292. The compound of any one of paragraphs 284-291, wherein RN2 is selected from H and C1-6 alkyl.
293. The compound of paragraph 292, wherein RN2 is H.
294. The compound of any one of paragraphs 277-293, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
295. The compound of paragraph 294, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
296. The compound of any one of paragraphs 277-295, wherein R8 is C1-6 alkyl.
297. The compound of paragraph 288, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each R10 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy;
        RN2 is selected from H and C1-6 alkyl;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R8 is C1-6 alkyl.
    
    


298. The compound of paragraph 288, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each R10 is independently selected from H, OH, and C1-6 alkyl;
        RN2 is H;
        R1, R2, R3, R4, and R5 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R8 is C1-6 alkyl.
    
    


299. The compound of paragraph 281, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN,
        NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl;
        RN1 is selected from H and C1-6 alkyl; and
        R6 and R7 are each independently selected from H and C1-6 alkyl.
    
    


300. The compound of paragraph 299, wherein the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


301. The compound of paragraph 284, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl;
        RN2 is selected from H and C1-6 alkyl; and
        R6 and R7 are each independently selected from H and C1-6 alkyl.
    
    


302. The compound of paragraph 301, wherein the compound of Formula (IIIe) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


303. The compound of paragraph 277, wherein the compound of Formula (IIIe) is selected from any one of the following compounds:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


304. A pharmaceutical composition comprising a compound of any one of paragraphs 277-303, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
305. A compound of Formula (IIIf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R6 and R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and R7, together with the C atom to which R6 is attached and N atom to which R7 is attached, from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


306. The compound of paragraph 305, wherein X1 is selected from S(O) and S(O)2.
307. The compound of paragraph 305, wherein X1 is S(O).
308. The compound of paragraph 305, wherein X1 is S(O)2.
309. The compound of any one of paragraphs 305-308, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
310. The compound of any one of paragraphs 305-308, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
311. The compound of any one of paragraphs 305-310, wherein R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1.
312. The compound of any one of paragraphs 305-308, wherein R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
313. The compound of any one of paragraphs 305-312, wherein:

    
    
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


314. The compound of any one of paragraphs 305-312, wherein:

    
    
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R7 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


315. The compound of any one of paragraphs 305-312, wherein:

    
    
        R7 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R6 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


316. The compound of any one of paragraphs 305-312, wherein:

    
    
        R7 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R6 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


317. The compound of any one of paragraphs 305-312, wherein the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


318. The compound of any one of paragraphs 305-312, wherein the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


319. The compound of any one of paragraphs 305-312, wherein the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


320. The compound of any one of paragraphs 305-312, wherein the compound of Formula (IIIf) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


321. The compound of any one of paragraphs 305-320, wherein each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
322. The compound of any one of paragraphs 305-321, wherein each R10 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
323. The compound of paragraph 305, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


324. The compound of paragraph 305, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R7 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


325. The compound of paragraph 305, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R6 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


326. The compound of paragraph 305, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 is selected from H, C1-6 alkyl, and C1-6 haloalkyl; and
        R6 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl,
        C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


327. The compound of any one of paragraphs 305 and 319-321, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R10 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


328. A pharmaceutical composition comprising a compound of any one of paragraphs 305-327, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
329. A compound of Formula (IIIg-2):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each  represents a single bond or a double bond, provided that not more than two of  are double bonds;
        each of R1, R2, R3, R4, R5, R6, and R7 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R9 is selected from C(O)Rb1, C(O)NRc1Rd1, S(O)2Rb1, S(O)2NRc1Rd1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein each of said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R9, together with the N atom to which R9 is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


330. The compound of paragraph 329, wherein the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        each of R1, R2, R3, R4, R5, R6, and R7 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R9 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R9, together with the N atom to which R9 is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


331. The compound of paragraph 329, having formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


332. The compound of paragraph 329, having formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


333. The compound of any one of paragraphs 329-332, wherein X1 is selected from S(O) and S(O)2.
334. The compound of any one of paragraphs 329-332, wherein X1 is S(O).
335. The compound of any one of paragraphs 329-332, wherein X1 is S(O)2.
336. The compound of any one of paragraphs 329-335, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
337. The compound of any one of paragraphs 329-335, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
338. The compound of any one of paragraphs 329-337, wherein R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
339. The compound of any one of paragraphs 329-337, wherein:

    
    
        R6 is H or C1-6 alkyl; and
        R7 is H or C1-6 alkyl.
    
    


340. The compound of any one of paragraphs 329-337, wherein:

    
    
        R6 is H or C1-6 alkyl; and
        R7 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


341. The compound of any one of paragraphs 329-337, wherein:

    
    
        R7 is H or C1-6 alkyl; and
        R6 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


342. The compound of any one of paragraphs 329-337, wherein:

    
    
        R6 is H or C1-6 alkyl; and
        R7 and R9, together with the N atom to which R9 is attached and C atom to which R7 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11.
    
    


343. The compound of paragraph 342, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


344. The compound of paragraph 342, wherein the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


345. The compound of paragraph 342, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


346. The compound of paragraph 342, having formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


347. The compound of paragraph 342, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


348. The compound of paragraph 342, wherein the compound has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


349. The compound of paragraph 342, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


350. The compound of paragraph 342, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


351. The compound of any one of paragraphs 329-337, wherein:

    
    
        R7 is H or C1-6 alkyl; and
        R6 and R9, together with the N atom to which R9 is attached and C atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11.
    
    


352. The compound of paragraph 351, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


353. The compound of paragraph 351, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


354. The compound of paragraph 351, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


355. The compound of paragraph 351, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


356. The compound of paragraph 351, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


357. The compound of paragraph 351, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


358. The compound of paragraph 351, wherein the compound of Formula (IIIg) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


359. The compound of paragraph 351, wherein the compound has the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


360. The compound of any one of paragraphs 329-341, wherein R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
361. The compound of any one of paragraphs 329-341, wherein R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
362. The compound of any one of paragraphs 329-341, wherein R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
363. The compound of any one of paragraphs 329-341, wherein R9 is C(O)Rb1.
364. The compound of any one of paragraphs 329-341, wherein R9 is 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
365. The compound of any one of paragraphs 329-364, wherein R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1.
366. The compound of any one of paragraphs 329-365, wherein R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
367. The compound of any one of paragraphs 329-366, wherein R10 is independently selected from C6-12 aryl, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
368. The compound of any one of paragraphs 329-366, wherein R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
369. The compound of any one of paragraphs 329-368, wherein R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
370. The compound of paragraph 329, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from C(O)Rb1, C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from C6-12 aryl, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


371. The compound of paragraph 329, wherein:


    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 and R7 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl,
        C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


372. The compound of paragraph 329, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R6 is H or C1-6 alkyl;
        R7 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl,
        C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


373. The compound of paragraph 329, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R7 is H or C1-6 alkyl;
        R6 is selected from halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl,
        C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


374. The compound of paragraph 329, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is H or C1-6 alkyl;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


375. The compound of paragraph 329, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is H or C1-6 alkyl;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


376. The compound of paragraph 329, wherein the compound is selected from any one of the compounds of Table 12, or a pharmaceutically acceptable salt thereof.
377. A pharmaceutical composition comprising a compound of any one of paragraphs 329-376, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
378. A compound of Formula (IIIh):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        X4 is selected from N and CR2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X2 is selected from O, S, and NR6;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X3 is selected from N and CR7;
        R7 is selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from S(O)2Rb1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R9 and R6, together with the carbon atom to which R9 is attached and the N atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R8, together with N atom to which R6 is attached and S atom to which R8 is attached, form 4-10 membered heterocycloalkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each R8 is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
        provided that if X3 is N and X2 is O, then R9 is selected from S(O)2Rb1, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10.
    
    


379. A compound of Formula (IIIh):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        X4 is selected from N and CR2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X2 is selected from O, S, and NR6;
        R6 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        X3 is selected from N and CR7;
        R7 is selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10; or
        R9 and R6, together with the carbon atom to which R9 is attached and the N atom to which R6 is attached, form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11; or
        R6 and R8, together with N atom to which R6 is attached and S atom to which R8 is attached, form 4-10 membered heterocycloalkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R11;
        each R10 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1 NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R11 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


380. The compound of paragraph 378 or 379, wherein X1 is selected from S(O) and S(O)2.
381. The compound of paragraph 378 or 379, wherein X1 is S(O).
382. The compound of paragraph 378 or 379, wherein X1 is S(O)2.
383. The compound of any one of paragraphs 378-382, wherein X4 is CR2.
384. The compound of any one of paragraphs 378-383, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
385. The compound of any one of paragraphs 378-383, wherein each of R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
386. The compound of any one of paragraphs 378-385, wherein X4 is N.
387. The compound of any one of paragraphs 378-386, wherein R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1.
388. The compound of any one of paragraphs 378-387, wherein R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
389. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


390. The compound of any one of paragraphs 378-389, wherein R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
391. The compound of any one of paragraphs 378-389, wherein R7 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
392. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


393. The compound of any one of paragraphs 378-392, wherein R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
394. The compound of any one of paragraphs 378-393, wherein R6 is selected from H and C1-6 alkyl.
395. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


396. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


397. The compound of any one of paragraphs 378-396, wherein R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
398. The compound of any one of paragraphs 378-396, wherein R9 is S(O)2Rb1.
399. The compound of any one of paragraphs 378-396, wherein R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
400. The compound of any one of paragraphs 378-396, wherein R9 is selected from C3-10 cycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
401. The compound of paragraph 399, wherein R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
402. The compound of any one of paragraphs 378-392, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


403. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


404. The compound of any one of paragraphs 378-392, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


405. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


406. The compound of any one of paragraphs 378-392, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


407. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


408. The compound of any one of paragraphs 378-392, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


409. The compound of any one of paragraphs 378-388, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


410. The compound of any one of paragraphs 378-401, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


411. The compound of any one of paragraphs 378-401, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


412. The compound of any one of paragraphs 378-401, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


413. The compound of any one of paragraphs 378-401, wherein the compound of Formula (IIIh) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


414. The compound of any one of paragraphs 378-409, wherein each R10 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, and NRc1Rd1.
415. The compound of any one of paragraphs 378-409, wherein Cy1 is C3-10 cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R11.
416. The compound of any one of paragraphs 378-409, wherein each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
417. The compound of any one of paragraphs 378-409, wherein each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
418. The compound of paragraph 378, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1, or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10.
        R9 is selected from S(O)2Rb1 and C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; or
        R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, and NRc1Rd1, and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


419. The compound of paragraph 378, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R6 is selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; or
        R9 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


420. The compound of paragraph 378, wherein:

    
    
        X1 is selected from S(O) and S(O)2;
        R1, R2, R3, R4, and R5 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R8 is C1-6 alkyl, optionally substituted with ORa1 or NRc1Rd1; or
        R8 is selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R7 is selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R6 is selected from H and C1-6 alkyl;
        R9 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10, or
        R9 is selected from phenyl, naphthyl, pyridinyl, cyclohexyl, tetrahydropyranyl, and piperidinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        each R10 is independently selected from halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and
        each R11 is independently selected from H, halo, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


421. The compound of paragraph 378, wherein the compound of Formula (IIIh) is selected from any one of the compounds of Table 8, Table 9, Table 10, and Table 11, or a pharmaceutically acceptable salt thereof.
422. A pharmaceutical composition comprising a compound of any one of paragraphs 378-421, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
423. A compound of Formula (IIIi):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from S, S(O), and S(O)2;
        X2 is selected from S and NR7;
        each of R1, R2, R3, R4, and R5 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R8 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R9;
        R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        provided that at least one of R6 and R7 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        or R6 and R7, together with the C atom to which R6 is attached and N atom to which R7 is attached, from a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R9 independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each R10 independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


424. The compound of paragraph 423, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


425. The compound of paragraph 423, having the formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


426. The compound of any one of paragraphs 423-425, wherein each of R1, R2, R3, R4, and R5 is independently selected from H and halo.
427. The compound of any one of paragraphs 423-426, wherein R6 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
428. The compound of any one of paragraphs 423-427, wherein R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
429. The compound of paragraph 423, wherein:

    
    
        each of R1, R2, R3, R4, and R5 is independently selected from H and halo;
        R6 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R9; and
        R8 is C1-6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9.
    
    


430. The compound of paragraph 423, wherein the compound is selected from any one of the compounds of Table 15, or a pharmaceutically acceptable salt thereof.
431. A pharmaceutical composition comprising a compound of any one of paragraphs 423-430, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
432. A method for inhibiting NF-κB activity within a cell within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (IVa):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        or RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R14;
        each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


433. The method of paragraph 432, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
434. The method of paragraph 432, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
435. The method of any one of paragraphs 432-434, wherein RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl.
436. The method of any one of paragraphs 432-435, wherein RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
437. The method of any one of paragraphs 432-436, wherein RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
438. The method of paragraph 437, wherein the 4-10 membered heterocycloalkyl is selected from pyrrolidine, piperazine, morpholine, and piperidine.
439. The method of any one of paragraphs 432-438, wherein each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
440. The method of any one of paragraphs 432-438, wherein each R14 independently selected from Cy1, C1-6 alkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
441. The method of any one of paragraphs 432-440, wherein each Cy1 is independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1.
442. The method of any one of paragraphs 432-440, wherein each Cy1 is independently selected from phenyl, piperidine, thiophene, pyridine, piperazine, morpholine, azepane, pyrrolidone, pyrrolidine, and pyrimidine, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1.
443. The method of any one of paragraphs 432-442, wherein each RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, SRa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1.
444. The method of any one of paragraphs 432-442, wherein each RCy1 is independently selected from halo, C1-6 alkyl, ORa1, SRa1, and NRc1Rd1.
445. The method of any one of paragraphs 432-444, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
446. The method of any one of paragraphs 432-444, wherein each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
447. The method of any one of paragraphs 432-446, wherein each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
448. The method of paragraph 432, wherein

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl;
        RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
        Cy1 is independently selected from C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1;
        RCy1 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1 SRa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


449. The method of paragraph 432, wherein:

    
    
        each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 is independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        RN1 is selected from H, C1-6 alkyl, and C2-6 alkenyl;
        RN2 is selected from H, C1-6 alkyl, C2-6 alkenyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2 together with the N atom to which they are attached from pyrrolidine, piperazine, morpholine, or piperidine, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 independently selected from Cy1, C1-6 alkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1;
        each Cy1 is independently selected from phenyl, piperidine, thiophene, pyridine, piperazine, morpholine, azepane, pyrrolidone, pyrrolidine, and pyrimidine, each of which is optionally substituted with 1, 2, or 3, substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, C1-6 alkyl, ORa1, SRa1, and NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and C6-10 aryl-C1-4 alkylene, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, and carboxy.
    
    


450. The method of paragraph 432, wherein the compound of Formula (IVa) is selected from any one of the compounds of Table 4a, or a pharmaceutically acceptable salt thereof.
451. A compound selected from any one of the compounds of Table 4b or Table 4b-2, or a pharmaceutically acceptable salt thereof.
452. A compound selected from any one of the compounds of Table 4b, or a pharmaceutically acceptable salt thereof.
453. A pharmaceutical composition comprising a compound of paragraph 451 or 452, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
454. A compound of Formula (IVb):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1 and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1 NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        each R8 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R8;
        R1 and R2 are each independently selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


455. The compound of paragraph 454, wherein X1 is CR6.
456. The compound of any one of paragraphs 454-455, wherein R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
457. The compound of any one of paragraphs 454-455, wherein R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
458. The compound of paragraphs 454, wherein X1 is N.
459. The compound of any one of paragraphs 454-458, wherein R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
460. The compound of any one of paragraphs 454-459, wherein each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9.
461. The compound of any one of paragraphs 454-460, wherein each R9 is independently selected from ORa1 and NRc1Rd1.
462. The compound of any one of paragraphs 454-461, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


463. The compound of any one of paragraphs 454-461, wherein:

    
    
        R1 is C1-6 haloalkyl; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


464. The compound of any one of paragraphs 454-461, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C1-6 haloalkyl.
    
    


465. The compound of any one of paragraphs 454-461, wherein:

    
    
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


466. The compound of any one of paragraphs 454-461, wherein

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


467. The compound of any one of paragraphs 465-466, wherein the 5-10 membered heteroaryl is thiophene.
468. The compound of any one of paragraphs 462-466, wherein the C6-10 aryl is phenyl.
469. The compound of any one of paragraphs 454-468, wherein each R10 is independently selected from halo and S(O)2Rb1.
470. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


471. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1 wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1, R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


472. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is C1-6 haloalkyl;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


473. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is trifluoromethyl;
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


474. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C1-6 haloalkyl;
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


475. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10, and
        R2 is trifluoromethyl;
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


476. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


477. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is thiophenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


478. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R4 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


479. The compound of paragraph 454, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        R4 is selected from 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, indolyl, pyrimidinyl, pyrrolopyridinyl, benzoxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, thiazolyl, pyridinyl, benzoxazinyl, pyrazolyl, and indazolyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R8;
        each R8 is independently selected from halo, C1-6 alkyl, ORa1, and S(O)2Rb1, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from ORa1 and NRc1Rd1;
        R1 is phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        R2 is thiophenyl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        each R10 is independently selected from halo and S(O)2Rb1.
    
    


480. The compound of paragraph 454, wherein the compound of Formula (IVb) is selected from any one of the compounds of Table 4c or Table 4c-2, or a pharmaceutically acceptable salt thereof.
481. The compound of paragraph 454, wherein the compound of Formula (IVb) is selected from any one of the compounds of Table 4c, or a pharmaceutically acceptable salt thereof.
482. A pharmaceutical composition comprising a compound of any one of paragraphs 454-481, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
483. A compound of Formula (IVc):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R4 is selected from C(O)NRN1RN2, C(O)ORa1, and CN;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8 and S(O)2R8;
        R8 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        provided that R1 and R2 are not both C6-10 aryl;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


484. The compound of paragraph 483, wherein X1 is CR6.
485. The compound of any one of paragraphs 483-484, wherein R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
486. The compound of any one of paragraphs 483-484, wherein R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
487. The compound of any one of paragraphs 483-486, wherein R4 is C(O)NRN1RN2.
488. The compound of any one of paragraphs 483-486, wherein R4 is C(O)ORa1.
489. The compound of any one of paragraphs 483-486, wherein R4 is CN.
490. The compound of any one of paragraphs 483-489, wherein each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
491. The compound of any one of paragraphs 483-489, wherein RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14.
492. The compound of any one of paragraphs 483-491, wherein each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
493. The compound of any one of paragraphs 483-491, wherein each R14 is independently selected from C1-6 alkyl and NRc1Rd1.
494. The compound of paragraph 483, wherein the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


495. The compound of any one of paragraphs 483-494, wherein:

    
    
        R1 is C1-6 haloalkyl; and
        R2 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10.
    
    


496. The compound of any one of paragraphs 483-494, wherein:

    
    
        R1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10; and
        R2 is C1-6 haloalkyl.
    
    


497. The compound of any one of paragraphs 483-494, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R2 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


498. The compound of any one of paragraphs 483-494, wherein:

    
    
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


499. The compound of paragraph 483, wherein the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


500. The compound of paragraph 499, wherein the compound of Formula (IVc) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


501. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is C1-6 haloalkyl; and
        R8 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10.
    
    


502. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is selected from C6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 independently selected R10; and
        R8 is C1-6 haloalkyl.
    
    


503. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


504. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


505. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R8 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


506. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R8 is 5-10 membered heteroaryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


507. The compound of any one of paragraphs 499-500, wherein:

    
    
        the 5-10 membered heteroaryl is selected from thiophenyl and pyridinyl; and
        the C6-10 aryl is phenyl.
    
    


508. The compound of any one of paragraphs 499-500, wherein:

    
    
        R1 is C1-6 haloalkyl; and
        R8 is C1-6 haloalkyl.
    
    


509. The compound of any one of paragraphs 483-508, wherein each R10 is independently selected from halo and C1-6 alkyl.
510. The compound of paragraph 483, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


511. The compound of paragraph 510, wherein:

    
    
        R3, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy; and
        R14 is independently selected from C1-6 alkyl and NRc1Rd1.
    
    


512. The compound of paragraph 483, wherein the compound of Formula (IVc) is selected from any one of the compounds of Table 4d, or a pharmaceutically acceptable salt thereof.
513. A pharmaceutical composition comprising a compound of any one of paragraphs 483-512, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
514. A compound of Formula (IVd):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R7;
        each R7 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R3 is selected from C(O)NRN1RN2 and C(O)ORa1;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        each R14 independently selected from H, Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1 and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8 and S(O)2R8;
        R8 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1 NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


515. The compound of paragraph 514, wherein X1 is CR6.
516. The compound of any one of paragraphs 514-515, wherein R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
517. The compound of any one of paragraphs 514-515, wherein R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
518. The compound of any one of paragraphs 514-517, wherein R3 is C(O)NRN1RN2.
519. The compound of any one of paragraphs 514-517, wherein R3 is C(O)ORa1.
520. The compound of any one of paragraphs 514-519, wherein each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14.
521. The compound of any one of paragraphs 514-519, wherein RN1 and RN2 together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14.
522. The compound of any one of paragraph 521, wherein the compound of Formula (IVd) has formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


523. The compound of any one of paragraphs 514-522, wherein each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1 524. The compound of any one of paragraphs 514-522, wherein each R14 is independently selected from C1-6 alkyl and NRc1Rd1.
525. The compound of any one of paragraphs 514-524, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


526. The compound of any one of paragraphs 514-525, wherein each R10 is independently selected from halo and C1-6 alkyl.
527. The compound of paragraph 514, wherein:

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14; or
        RN1 and RN2, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl, which is substituted with 1, 2, or 3 substituents independently selected from R14;
        wherein each R14 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, ORa1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


528. The compound of paragraph 527, wherein:

    
    
        R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy;
        each R14 is independently selected from C1-6 alkyl and NRc1Rd1.
    
    


529. The compound of paragraph 514, wherein the compound of Formula (IVd) is selected from any one of the compound of Table 4e, or a pharmaceutically acceptable salt thereof.
530. A pharmaceutical composition comprising a compound of any one of paragraphs 514-529, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
531. A compound of Formula (IVe):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        or R7 and R8 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8a and S(O)2R8a,
        R8a is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


532. The compound of paragraph 531, wherein:

    
    
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from R8a and S(O)2R8a;
        R8a is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino.
    
    


533. The compound of paragraph 531 or 532, wherein X1 is CR6.
534. The compound of any one of paragraphs 531-533, wherein R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
535. The compound of any one of paragraphs 531-534, wherein R4, R5, and R6 are each independently selected from H, halo, C1-6 alkyl, and C1-6 alkoxy.
536. The compound of any one of paragraphs 531-535, wherein:

    
    
        R7 is selected from H and C1-6 alkyl; and
        R8 is selected from C(O)Rb1 and C(O)ORa1.
    
    


537. The compound of any one of paragraphs 531-535, wherein:

    
    
        R7 is selected from H and C1-6 alkyl;
        R8 is C(O)NRc1Rd1.
    
    


538. The compound of any one of paragraphs 531-537, wherein:
each Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted with 1 or 2 independently selected Rg.
539. The compound of any one of paragraphs 531-538, wherein each Ra1 and Rb1 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg.
540. The compound of any one of paragraphs 531-539, wherein each Rg is independently selected from OH, halo, C1-6 alkyl, C1-6 alkoxy, 4-10 membered heterocycloalkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl, and any C1-6 alkyl, C1-6 alkoxy, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl and C1-6 alkoxy.
541. The compound of any one of paragraphs 531-539, wherein each Rg is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl.
542. The compound of any one of paragraphs 531-541, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10.
    
    


543. The compound of any one of paragraphs 531-542, wherein each R10 is independently selected from halo and C1-6 alkyl.
544. The compound of paragraph 531, wherein:

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is selected from H and C1-6 alkyl;
        R8 is selected from C(O)Rb1 and C(O)ORa1;
        each Ra1 and Rb1 is independently selected from C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        each Rg is independently selected from halo, C1-6 alkyl, 4-10 membered heterocycloalkyl, amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


545. The compound of paragraph 531, wherein:

    
    
        R4, R5, and R6 are each independently selected from H, halo, CN, NO2, OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;
        R7 is selected from H and C1-6 alkyl;
        R8 is C(O)NRc1Rd1;
        each Rc1 and Rd1 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl, wherein said C1-6 alkyl and C3-10 cycloalkyl are each optionally substituted with 1 or 2 independently selected Rg;
        each Rg is independently selected from OH, halo, C1-6 alkyl, C1-6 alkoxy, 4-10 membered heterocycloalkyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, C1-6 alkylcarbamyl, and C1-6 alkylcarbonyl, and any C1-6 alkyl, C1-6 alkoxy, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl and C1-6 alkoxy;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10;
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 independently selected R10; and
        each R10 is independently selected from halo and C1-6 alkyl.
    
    


546. The compound of paragraph 531, wherein the compound of Formula (IVe) is selected from any one of the compounds of Table 4f or Table 4f-2, or a pharmaceutically acceptable salt thereof.
547. The compound of paragraph 531, wherein the compound of Formula (IVe) is selected from any one of the compounds of Table 4f, or a pharmaceutically acceptable salt thereof.
548. A pharmaceutical composition comprising a compound of any one of paragraphs 531-547, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
549. A compound of Formula (IVf):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        X1 is selected from N and CR6;
        R3, R5, and R6 are each independently selected from H, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        R7 and R8 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
        each R9 is independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R10;
        or R7 and R8 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1 S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of R8 is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


550. The compound of paragraph 549, wherein X is N.
551. The compound of paragraph 549, wherein X is CR6.
552. The compound of any one of paragraphs 549-551, wherein R3, R5, and R6 are each independently selected from H, halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
553. The compound of paragraph 552, wherein R3, R5, and R6 are each H.
554. The compound of any one of paragraphs 549-553, wherein:

    
    
        R7 is H; and
        R8 is selected from C1-6 alkyl and C3-10 cycloalkyl, each of which is independently selected from 1 or 2 substituents independently selected from R9.
    
    


555. The compound of any one of paragraphs 549-554, wherein R9 is independently selected from C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1, wherein said C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R10.
556. The compound of any one of paragraphs 549-555, wherein

    
    
        R1 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10; and
        R2 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10.
    
    


557. The compound of any one of paragraphs 549-556, wherein each R10 is independently selected from halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
558. The compound of paragraph 549, wherein:

    
    
        R1 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10;
        R2 is C6-10 aryl, optionally substituted with 1 or 2 independently selected R10;
        X is CR6;
        R3, R5, and R6 are each independently selected from H, halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino;
        R7 is H;
        R8 is selected from C1-6 alkyl and C3-10 cycloalkyl, each of which is independently selected from 1 or 2 substituents independently selected from R9;
        each R9 is independently selected from C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, C1-6 alkyl, C1-6 haloalkyl, CN, ORa1, C(O)NRc1Rd1, C(O)ORa1, and NRc1Rd1; wherein said C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R10; and
        each R10 is independently selected from halo, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, and di(C1-6 alkyl)amino.
    
    


559. The compound of paragraph 549, wherein the compound is selected from any one of the compounds of Table 4g, or a pharmaceutically acceptable salt thereof.
560. A pharmaceutical composition comprising a compound of any one of paragraphs 549-559, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
561. A compound of Formula (IVg)




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        ring A is C3-8 cycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        each of RN1 and RN2 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        or RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R14;
        each R14 independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1 NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Cy1 is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy1;
        each RCy1 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R15;
        each R15 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        R1 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        R2 is selected from C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R10;
        each R10 is independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R11;
        each R11 is independently selected from CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
        each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, and (4-10 membered heterocycloalkyl)-C1-4 alkylene are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
        or any Rc1 and Rd1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
        each Rg is independently selected from OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkylene, HO—C1-3 alkylene, C6-10 aryl, C6-10 aryloxy, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkylene, C3-10 cycloalkyl-C1-4 alkylene, (5-10 membered heteroaryl)-C1-4 alkylene, (4-10 membered heterocycloalkyl)-C1-4 alkylene, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, thio, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, carboxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino, and any C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl of Rg is optionally substituted with 1, 2, or 3 substituents independently selected from OH, NO2, CN, halo, C1-6 alkyl, C1-4 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
    
    


562. The compound of paragraph 561, having a formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


563. The compound of paragraph 561, having a formula:




    
    
        or a pharmaceutically acceptable salt thereof.
    
    


564. The compound of paragraph 561, wherein:

    
    
        RN1 and RN2 together with the N atom to which they are attached from a 4-10 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from R14;
        R1 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10; and
        R2 is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R10.
    
    


565. The compound of paragraph 561, wherein the compound is selected from any one of the compounds of Table 17, or a pharmaceutically acceptable salt thereof.
566. A pharmaceutical composition comprising a compound of any one of paragraphs 561-565, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
567. A method of treating a mammal having a disease, disorder, or condition responsive to inhibiting NF-κB activity within a cell, wherein said method comprises administering, to said mammal,

    
    
        a compound selected from (i) a compound of any one of paragraphs 41-58, 79-102, 104-113, 115-121, 161, 163-174, 176-189, 191-198, 200-211, 213-224, 226-237, 264, 265, 267-270, 272-275, 277-303, 305-327, 329-376, 378-421, 423-430, 451, 452, 454-481, 483-512, 514-529, 531-547, 549-559, and 561-565, or a pharmaceutically acceptable salt thereof; and (ii) a compound as recited in any one of paragraphs 1-40, 60-72, 73-78, 123-160, 239-263, and 432-450, or a pharmaceutically acceptable salt thereof; or
        a pharmaceutical composition of any one of paragraphs 59, 103, 114, 122, 162, 175, 190, 199, 212, 225, 238, 266, 271, 276, 304, 328, 377, 422, 431, 453, 482, 513, 530, 548, 560, and 566.
    
    


568. The method of paragraph 567, wherein the mammal is human.
569. The method of any one of paragraphs 567-568, wherein said method comprises treating a mammal having a cancer.
570. The method of any one of paragraphs 567-569, wherein said method comprises treating a mammal having an inflammation.
571. The method of paragraph 570, wherein the inflammation is an autoimmune disease.
572. A method for inhibiting NF-κB activity within cells of a mammal, wherein said method comprises administering, to said mammal,

    
    
        a compound selected from (i) a compound of any one of paragraphs 41-58, 79-102, 104-113, 115-121, 161, 163-174, 176-189, 191-198, 200-211, 213-224, 226-237, 264, 265, 267-270, 272-275, 277-303, 305-327, 329-376, 378-421, 423-430, 451, 452, 454-481, 483-512, 514-529, 531-547, 549-559, and 561-565, or a pharmaceutically acceptable salt thereof; and (ii) a compound as recited in any one of paragraphs 1-40, 60-72, 73-78, 123-160, 239-263, and 432-450, or a pharmaceutically acceptable salt thereof; or
        a pharmaceutical composition of any one of paragraphs 59, 103, 114, 122, 162, 175, 190, 199, 212, 225, 238, 266, 271, 276, 304, 328, 377, 422, 431, 453, 482, 513, 530, 548, 560, and 566.
    
    


573. The method of paragraph 572, wherein the mammal is human.
OTHER EMBODIMENTS
It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.