Alpha 4 beta 7 integrin modulators and uses thereof

Abstract

The present disclosure provides small molecule compounds (I) and pharmaceutical compositions for the modulation of alpha 4 beta 7 integrin, useful for the treatment of inflammatory conditions such as inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

Description

ALPHA 4 BETA 7 INTEGRIN MODULATORS AND USES THEREOF BACKGROUND OF THE INVENTION

[0001] Alpha 4 beta 7 integrin (α4ß7), also known as Lymphocyte Peyer patch adhesion molecule (LPAM) is a powerful signaling molecule embedded in the cell membranes of immune cells. α4ß7is responsible for T-cell homing into gut-associated lymphoid tissues by binding to mucosal vascular addressin cell adhesion molecule (MAdCAM) located on high endothelial venules of mucosal lymphoid organs. It has been demonstrated that α4ß7is implicated in several immune system disorders, including inflammatory bowel disease (IBD) (including, e.g., Crohn’s disease (CD) and ulcerative colitis (UC)) and graft-versus-host disease (GVHD).

[0002] α4ß7is a clinically-validated target for IBD, with ENTYVIO (vedolizumab), an injectable anti-α4ß7mAb, approved for the treatment of UC and CD. However, the accessibility of ENTYVIO is limited by the need for parenteral administration. Further, ENTYVIO causes a range of side effects (including nausea, vomiting, severe diarrhea, stomach cramps, weight loss, and pain), which can be difficult to manage due to ENTYVIO’s long half-life. Therefore, there is a need for highly active and / or selective α4ß7small molecule inhibitors that are orally bioavailable reduced side effects. SUMMARY OF THE INVENTION

[0003] In one aspect, the present disclosure provides a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: R1is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN; R3is selected from hydrogen and C1-6alkyl;Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -N(R12)C(O)O(R12), -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)S(O)2R12, -NO2, =O, =S, =NR12, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -NO2, =O, =S, =NR12, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; R4is independently selected at each occurrence from (iv), (v), and (vi): (iv) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (v) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each ofwhich is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, and C1-6alkyl-OR13; and (vi) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is CF3, each additional R4when present is selected from (a), (b), (c), and (d): (a) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and (d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is -OCH3, each additional R4when present is selected from (e), (f), and (g): (e) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (f) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R13)(R15), -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, , and C1-6alkyl-OR13; and (g) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; R5is selected from:C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -NO2, =O, =S, =NR16, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, - SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, - N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; R11, R12, R13, and R16at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R14is selected from: hydrogen; C1alkyl and C3-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independentlyselected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R15is selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; and n is selected from 0, 1, and 2.

[0004] In some aspects, the present disclosure provides a compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein: X is selected from C(R30) and N;Y is selected from C(R30) and N; wherein at least one of X or Y is N; R21is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R22aand R22bare each independently selected from: hydrogen, halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2,and -CN; R23is selected from hydrogen and C1-6alkyl; Ring B is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -N(R32)C(O)O(R32), -C(O)N(R32)2, -N(R32)C(O)R32, - N(R32)S(O)2R32, -NO2, =O, =S, =NR32, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, =O, =S, =NR32, and - CN; C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - C(O)N(R32)2, -NO2, =O, =S, =NR32, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; R24is independently selected at each occurrence from (a), (b), (c), and (d): (a) halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -N(R33)C(O)O(R33), -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, and-CN; (b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, - C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -NO2, =O, =S, =NR33, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and R30is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R31, R32, and R33at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 1 and 2.

[0005] In some aspects, the present disclosure provides a compound represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein: R41is selected from hydrogen and C1-6alkyl; R42aand R42bare each independently selected from: hydrogen, halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, and -CN; R43is selected from hydrogen and C1-6alkyl; Ring C is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)N(R52)2, -N(R52)C(O)O(R52),-C(O)N(R52)2, -N(R52)C(O)R52, - N(R52)S(O)2R52, -NO2, =O, =S, =NR52, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, - OC(O)R52, -C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR52, - SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, - C(O)N(R52)2, -NO2, =O, =S, =NR52, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, - SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; Ring D is a 7- to 12-membered heterocycle; p is selected from 0, 1, 2, and 3; R44is independently selected at each occurrence from (a), (b), and (c): (a) halogen, -OR53, -SR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - OC(O)N(R53)2, -N(R53)C(O)O(R53),-C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =S, =NR53, and -CN; (b) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -N(R53)(R54), -SR53, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR53, - SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; and (c) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -NO2, =O, =S, =NR53, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN;wherein when Ring D is 2,7-naphthyridinyl or isoquinolinyl, p is selected from 1, 2, and 3; R51, R52, and R53at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and R54at each occurrence is independently selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN. INCORPORATION BY REFERENCE

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, orpatent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION

[0007] Integrin alpha 4 beta 7 is an integrin family adhesion receptor that shares subunits with alpha 4 beta 1 (VLA4) and the E-Cadherin receptor, alpha E beta 7. α4ß7is critical for directing immune cells to intestinal mucosa, and is induced during T cell activation in Peyer’s patches or mesenteric lymph nodes. α4ß7is a clinically validated target for IBD, with selective α4ß7inhibition resulting in significant anti-inflammatory effects and reduction in symptoms. However, off-target binding to α4ß1can result in significant dose-limiting side effects. For example, TYSABRI (natalizumab), binds to both α4ß7and α4ß1, and the binding of α4ß1has been linked to progressive multifocal leukoencephalopathy, which resulted in the FDA restricting the use of TYSABRI in IBD.

[0008] In some aspects, the present disclosure provides an orally available α4ß7integrin antagonist designed in a manner designed to mimic the anti-inflammatory actions of ENTYVIO, specifically its high selectivity for α4ß7over α4ß1. For example, in some embodiments, the present disclosure provides compounds having over 100-fold selectivity for α4ß7over α4ß1. In some embodiments, the present disclosure provides compounds having over 1,000-fold selectivity for α4ß7over α4ß1. Ulcerative Colitis Disease

[0009] UC is a form of IBD characterized by inflammation and ulcers in the large intestine. The clinical symptoms of UC are diarrhea and bloody stool. Its clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to dietary changes, alterations in treatment regimens, other illnesses, or stress.

[0010] UC can be debilitating and can sometimes lead to life-threatening complications. Frequent diarrhea and bloody stools can lead to weight loss, dehydration and anemia. Persistent UC is associated with an increased risk of developing colon cancer. The Centers for Disease Control estimates that there are three million individuals in the United States with IBD, of which roughly half have UC. A similar number of individuals in Europe are estimated to have UC.

[0011] UC is typically treated with anti-inflammatory drugs starting with more moderate and locally delivered drugs, and progressing to systemic immunosuppressive drugs for patients with refractory disease. First line therapy for patients with mild disease consists of 5- aminosalicylates such as mesalamine and sulfasalazine. Patients with more severe disease are treated with systemic corticosteroids, with the intent of inducing remission and transitioning patients to better-tolerated drugs such as 5-aminosalicylates for maintenance. Some patients may be treated with systemic immunomodulatory drugs such as azathioprine, cyclosporine and XELJANZ (tofacitinib). Anti-inflammatory biologics such as TNFα antagonists REMICADE (infliximab), HUMIRA (adalimumab) and SIMPONI (golimumab) and the IL-12 / IL-23 antagonist STELARA (ustekinumab) are effective in inducing remission in patients with moderate to severe UC.

[0012] ENTYVIO (vedolizumab), a monoclonal antibody that selectively targets α4ß7, was first approved by the FDA to treat UC and CD in 2014. In clinical trials, approximately 30% of patients receiving ENTYVIO achieved remission at the end of one year of treatment. ENTYVIO is administered as a 30-minute intravenous infusion at zero, two and six weeks, then every eight weeks thereafter. Long term therapy is generally well-tolerated in patients, but frequent dose adjustments have been reported to be required to maintain efficacy. Crohn’s Disease Background

[0013] CD is a chronic inflammatory disease that most commonly affects the end of the small intestine and the beginning of the large intestine, although it may involve any part of the gastrointestinal tract. Both CD and UC are types of IBD and many of the symptoms and demographics overlap. In addition to the potential of CD developing in other segments of the intestine, CD differs from UC in that there can be normal healthy tissue in between patches of diseased tissue in CD, unlike UC where the inflammation is continuous. CD can also occur in all layers of the intestinal wall unlike UC which is limited to the inner most layer. It is estimated that there are 1.5 million individuals in the United States and 1.1 million individuals in Europe with CD.

[0014] The treatment paradigm for CD is very similar to that of UC with currently approved therapies focused on anti-inflammatory agents. Nearly 60% of CD patients will require surgery within twenty years of diagnosis to treat complications such as fistulas, or abnormal connections between body parts, life-threatening bleeding and intestinal obstructions.

[0015] While there are numerous approved therapeutics for UC and CD, there remains a significant unmet medical need for patients and clinicians to effectively and conveniently manage these chronic diseases, which could be facilitated by effective oral therapies.

[0016] In some aspects, the compounds of the present disclosure are used for the treatment and / or prevention of IBD. In some aspects of the present disclosure, the compounds provided herein are used for the treatment and / or prevention of UC. In some aspects of the present disclosure, the compounds provided herein are used for the treatment and / or prevention of CD. Definitions

[0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0018] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0019] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1- C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec- butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0020] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, andpreferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0021] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0022] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e.,C3-C5alkylene).

[0023] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5alkenylene).

[0024] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene).

[0025] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6carbons. The term -Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0026] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0027] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0028] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0030] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] A “Cx-ycarbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms―any of which is optionally substituted as provided herein.

[0032] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In someembodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0033] "Heterocycloalkyl" refers to a stable 3 to 12 membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl,trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, loxothiomorpholinyl, and l,ldioxothiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0034] The term “heteroaryl” refers to a radical derived from a 3 to 12 membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0035] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0036] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0037] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0038] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.

[0039] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0040] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, - Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0041] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0042] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0043] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carriermust be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0044] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0045] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0046] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0047] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, oradverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0048] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0049] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. Compounds

[0050] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: R1is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2,and -CN; R3is selected from hydrogen and C1-6alkyl; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii):(i) halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -N(R12)C(O)O(R12), -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)S(O)2R12, -NO2, =O, =S, =NR12, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -NO2, =O, =S, =NR12, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; R4is independently selected at each occurrence from (iv), (v), and (vi): (iv) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (v) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, and C1-6alkyl-OR13; and (vi) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is CF3, each additional R4when present is selected from (a), (b), (c), and (d): (a) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and(d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is -OCH3, each additional R4when present is selected from (e), (f), and (g): (e) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (f) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R13)(R15), -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, , and C1-6alkyl-OR13; and (g) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; R5is selected from:C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -NO2, =O, =S, =NR16, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, - SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, - N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; R11, R12, R13, and R16at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R14is selected from: hydrogen; C1alkyl and C3-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independentlyselected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R15is selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; and n is selected from 0, 1, and 2.

[0051] In some embodiments, for the compound or salt of Formula (I), R1is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R1is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R1is selected from hydrogen and C1-3alkyl. In some embodiments, R1is hydrogen.

[0052] In some embodiments, for the compound or salt of Formula (I), R2aand R2bare each independently selected from hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN. In some embodiments, R2aand R2bare each independently selected from hydrogen, halogen, -OR11, -N(R11)2, and -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, and -CN. In some embodiments, R2aand R2bare each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R2aand R2bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R2aand R2bare each independently selected from hydrogen and halogen. In some embodiments, R2aand R2bare each hydrogen.

[0053] In some embodiments, for the compound or salt of Formula (I), R3is selected from hydrogen and C1-6alkyl. In some embodiments, R3is selected from hydrogen and C1-3alkyl. In some embodiments, R3is hydrogen.

[0054] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -N(R12)C(O)O(R12), -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, =O, =S, =NR12, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, =O, =S, =NR12, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, - C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN.

[0055] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, =O, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR12, N(R12)2, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, =O, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0056] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0057] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0058] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0059] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, - N(R12)2, -C(O)N(R12)2, and -N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0060] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0061] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0062] In some embodiments, for the compound or salt of Formula (I), Ring A is C3-10carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0063] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are eachoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0064] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0065] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)N(R12)2, and -N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0066] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0067] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0068] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0069] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0070] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituentsindependently selected from halogen, -OR12, -N(R12)2, -C(O)N(R12)2, and -N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0071] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0072] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0073] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0074] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0075] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, and-N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0076] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0077] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0078] In some embodiments, for the compound or salt of Formula (I), Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0079] In some embodiments, for the compound or salt of Formula (I), Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, and -C(O)N(R12)2; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl.

[0080] In some embodiments, for the compound or salt of Formula (I), Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)N(R12)2, C1-6alkyl and C1-6haloalkyl.

[0081] In some embodiments, for the compound or salt of Formula (I), Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from: CH3,In some embodiments, Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from: CH3and. In some embodiments, Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from

[0082] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from:In some embodiments, Ring A isIn some embodiments, Ring A is selected from .

[0083] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0084] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2,-N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

[0085] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, and -N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6- membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0086] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -NH2, -CH3, -CF3,In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -NH2, -CH3, -CF3,In some embodiments,Ring A is phenyl optionally substituted with one or more substituents independently selectedfrom:In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from:

[0087] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -NH2,

[0088] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with oneor more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, - C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, - OR12, -N(R12)2, and -CN.

[0089] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C1-6alkyl, and C1-6alkyl.

[0090] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -CH3,

[0091] In some embodiments, for the compound or salt of Formula (I), Ring A is phenyl optionally substituted with one or more substituents independently selected from:,In some embodiments, Ring A is phenyl optionally substituted with one or more substituents independently selected from:In some embodiments,

[0092] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from

[0093] In some embodiments, for the compound or salt of Formula (I), Ring A is C6-10bicyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0094] In some embodiments, for the compound or salt of Formula (I), Ring A is C6-10bicyclic carbocycle optionally substituted with one or more substituents independently selected from:halogen, -OR12, and -N(R12)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, and C1-6alkyl, and C1-6haloalkyl.

[0095] In some embodiments, for the compound or salt of Formula (I), Ring A is 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0096] In some embodiments, for the compound or salt of Formula (I), Ring A is 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, and -N(R12)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; andC3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, - C1-6alkyl, and C1-6haloalkyl.

[0097] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from 3- to 8-membered monocyclic heterocycle and 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0098] In some embodiments, for the compound or salt of Formula (I), Ring A is 3- to 8- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0099] In some embodiments, for the compound or salt of Formula (I), Ring A is 3- to 8- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR12, and -N(R12)2, C1-6alkyl and C1-6haloalkyl; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, - C1-6alkyl, and C1-6haloalkyl.

[0100] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0101] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, and - CN; and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; andC3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0102] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, and -N(R12)2, C1-6alkyl and C1-6haloalkyl; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, - C1-6alkyl, and C1-6haloalkyl.

[0103] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: fluoro, -CH3, -CF3, -NH2,In some embodiments, Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: fluoro, -CH3, -CF3, -NH2,In some embodiments, Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from -CH3,In some embodiments, Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with

[0104] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substitutedwith one or more substituents independently selected from: fluoro, -CH3, -CF3, -NH2,

[0105] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from:In some embodiments, Ring A is selected from:andIn some embodiments, Ring A is selected from:and

[0106] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 10- membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0107] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 10- membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, and -N(R12)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0108] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 10- membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0109] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0110] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, and -N(R12)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0111] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0112] The compound or salt of any one of claims 1 to Error! Reference source not found., wherein Ring A is selected from benzo[d]imidazolyl, indazolyl, and 2,3-dihydroindenyl, eachof which is optionally substituted with one or more substituents independently selected from fluoro and

[0113] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from

[0114] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2- 3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1- 6 alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0115] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2- 3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)S(O)2R12, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

[0116] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2- 3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, and -N(R12)S(O)2R12; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C1-6alkyl, and C1-6haloalkyl.

[0117] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2- 3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, and -N(R12)S(O)2R12; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0118] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2- 3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, -CH3, -CF3, -NH2,

[0119] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from:

[0120] In some embodiments, for the compound or salt of Formula (I), n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 0 and 2. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 0.

[0121] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN;wherein when one R4is CF3, each additional R4when present is selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - NO2, =O, =S, =NR13, and -CN; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, where C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - NO2, =O, =S, =NR13, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is -OCH3, each additional R4when present is selected from (e), (f), and (g): halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, - NO2, =O, =S, =NR13, -CN, and C1-6alkly-OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, - C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN

[0122] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN and C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; wherein when one R4is CF3, each additional R4when present is selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle areeach optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; and wherein when one R4is -OCH3, each additional R4when present is selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, and -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

[0123] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from: halogen, -OR13, and -N(R13)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; andC3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, C1-6alkyl, and C1-6haloalkyl; wherein when one R4is CF3, each additional R4when present is selected from: halogen, -OR13, and -N(R13)2,; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2.C1-6alkyl, C1-6haloalkyl; and wherein when one R4is -OCH3, each additional R4when present is selected from: halogen, -OR13, and -C(O)N(R13)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl- OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, C1-6alkyl, and C1-6haloalkyl.

[0124] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN. In some embodiments, R4is independently selected at each occurrence from halogen, -OR13, and -N(R13)2. In some embodiments, R4is -OR13.

[0125] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from:

[0126] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN and C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0127] In some embodiments, for the compound or salt of Formula (I), R4is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, and C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0128] In some embodiments, for the compound or salt of Formula (I), R4is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, and C3-8carbocycle and 3- to 8-membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0129] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from:In some embodimen4ts, R is independently selected at each occurrence from:

[0130] In some embodiments, R4is independently selected at each occurrence from:

[0131] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

[0132] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, C1-6alkyl, and C1-6haloalkyl.

[0133] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, C1-6alkyl, and C1-6haloalkyl.

[0134] In some embodiments, for the compound or salt of Formula (I), R4is independently selected at each occurrence from

[0135] In some embodiments, for the compound or salt of Formula (I), one R4is -CF3, and each additional R4is selected from: halogen, -OR13, -N(R13)2, -OC(O)R13, -N(R13)C(O)R13, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -CN, C3-10carbocycle, 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl;C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

[0136] In some embodiments, for the compound or salt of Formula (I), one R4is -CF3, and each additional R4is selected from: halogen, -OR13, -N(R13)2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C3-6carbocycle and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0137] In some embodiments, for the compound or salt of Formula (I), one R4is -CF3, and each additional R4is selected from halogen, -OR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0138] In some embodiments, for the compound or salt of Formula (I), one R4is -CF3, and each additional R4is selected from halogen, -OR13, and -N(R13)2,; and C1-6alkyl optionally substituted with one or more substituents independently selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0139] In some embodiments, for the compound or salt of Formula (I), one and R4is -CF3, each additional R4is

[0140] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

[0141] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R13)(R15), C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13.

[0142] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from halogen, -OR13, -N(R13)2, and -C(O)N(R13)2; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -N(R13)(R15), C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13.

[0143] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from halogen, -OR13, -N(R13)2, and -C(O)N(R13)2..

[0144] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4 is selected from: chloro, fluoro,

[0145] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), C3-8carbocycle and 3- to 8- membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, - OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13.

[0146] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from: chloro, fluoro, -CH3,

[0147] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from: chloro, fluoro, -CH3,

[0148] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0149] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, C1-6alkyl, and C1-6haloalkyl.

[0150] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0151] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from cyclopropyl, cyclobutyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0152] In some embodiments, for the compound or salt of Formula (I), one R4is -OCH3, and each additional R4is selected from:

[0153] In some embodiments, for the compound or salt of Formula (I), R5is selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -NO2, =O, =S, =NR16, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, - SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, - N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN.

[0154] In some embodiments, for the compound or salt of Formula (I), R5is selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR16, - N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -NO2,-CN; and C1-6alkyloptionally substituted with one or more substituents independently selected from: halogen, -OR16, -N(R16)2, and -CN.

[0155] In some embodiments, for the compound or salt of Formula (I), R5is selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0156] In some embodiments, for the compound or salt of Formula (I), R5is selected from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, and -N(R16)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0157] In some embodiments, for the compound or salt of Formula (I), R5is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, -N(R16)C(O)R16, -NO2, and - CN. In some embodiments, R5is C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, and -N(R16)2. In some embodiments, R5is selected from C1-6alkyl and C1-6haloalkyl. In some embodiments, R5is selected from -CH3and -CHF2.

[0158] In some embodiments, for the compound or salt of Formula (I), R5is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R5is selected from C3-6carbocycle and 3- to 6-membered heterocycle. In some embodiments, R5is C3-6carbocycle. In some embodiments, R5is cyclopropyl.

[0159] In some embodiments, for the compound or salt of Formula (I), R5is selected from C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle.

[0160] In some embodiments, for the compound or salt of Formula (I), R5is selected from -CH3, -CHF2, and cyclopropyl.

[0161] In some embodiments, for the compound or salt of Formula (I), R11, R12, R13, and R16at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0162] In some embodiments, for the compound or salt of Formula (I), R11is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0163] In some embodiments, for the compound or salt of Formula (I), R11is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0164] In some embodiments, for the compound or salt of Formula (I), R12is independently selected at each occurrence from:hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0165] In some embodiments, for the compound or salt of Formula (I), R12is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, =O, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0166] In some embodiments, for the compound or salt of Formula (I), R13is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and3- to 6-membered heterocycle.

[0167] In some embodiments, for the compound or salt of Formula (I), R13is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0168] In some embodiments, for the compound or salt of Formula (I), R13is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-8carbocycle, and 3- to 8-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-8carbocycle and 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0169] In some embodiments, for the compound or salt of Formula (I), R14is selected from: hydrogen; C1alkyl and C3-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-memberedheterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0170] In some embodiments, for the compound or salt of Formula (I), R14is selected from: hydrogen; C1alkyl and C3-6alkyl each optionally substituted with one more substituents independently selected from halogen, -OH, -NH2,C3-6carbocycle, and 3- to 6- membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2alkyl substituted with one more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, - C1-6alkyl, C1-6haloalkyl, and -NH2; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, and -NH2, -

[0171] I In some embodiments, for the compound or salt of Formula (I), R14is selected from: hydrogen, C1alkyl, C1haloalkyl, C3-6alkyl, and C3-6haloalkyl; C2alkyl substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0172] In some embodiments, for the compound or salt of Formula (I), R14is selected from: hydrogen, C1alkyl, C1haloalkyl, C3-6alkyl, and C3-6haloalkyl;C2alkyl substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0173] In some embodiments, for the compound or salt of Formula (I), R15is selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN. C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0174] In some embodiments, for the compound or salt of Formula (I), R15is selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl; C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl; andC3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, and C1-6haloalkyl.

[0175] In some embodiments, for the compound or salt of Formula (I), R15is selected from: hydrogen; and C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl; and

[0176] In some embodiments, for the compound or salt of Formula (I), R15is selected from hydrogen, C2-6alkyl, and C1-6haloalkyl. In some embodiments, R15is selected from hydrogen and C2-6haloalkyl.

[0177] In some embodiments, for the compound or salt of Formula (I), R16is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0178] In some embodiments, for the compound or salt of Formula (I), R16is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -OH, -NH2,C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted withone or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -NH2, C3-6carbocycle, and 3- to 6-membered heterocycle.

[0179] In some embodiments, for the compound or salt of Formula (I), R16is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -OH, and -NH2.

[0180] In some embodiments, for the compound or salt of Formula (I), wherein R16is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0181] In some embodiments, the compound of Formula (I) is a compound or salt selected from Table 1. *Denotes a stereocenter with an undetermined absolute stereochemistry of a single diastereomer.

[0182] Table 1. Selected α4β7 integrin modulators

[0183] In some aspects, the present disclosure provides a compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein: X is selected from C(R30) and N; Y is selected from C(R30) and N; wherein at least one of X or Y is N; R21is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R22aand R22bare each independently selected from: hydrogen, halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2,and -CN; R23is selected from hydrogen and C1-6alkyl;Ring B is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -N(R32)C(O)O(R32), -C(O)N(R32)2, -N(R32)C(O)R32, - N(R32)S(O)2R32, -NO2, =O, =S, =NR32, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, =O, =S, =NR32, and - CN; C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - C(O)N(R32)2, -NO2, =O, =S, =NR32, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; R24is independently selected at each occurrence from (a), (b), (c), and (d): (a) halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -N(R33)C(O)O(R33), -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, and -CN; (b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, - C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -NO2, =O, =S, =NR33, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and R30is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R31, R32, and R33at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and m is selected from 1 and 2.

[0184] In some embodiments, for the compound or salt of Formula (II), R2is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R21is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R21is selected from hydrogen and C1-3alkyl. In some embodiments, R21is hydrogen.

[0185] In some embodiments, for the compound or salt of Formula (II), R22aand R22bare each independently selected from hydrogen, halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, - CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2,and -CN. In some embodiments, R22aand R22bare each independently selected from hydrogen, halogen, -OR31, -N(R31)2, and -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR31, -N(R31)2, and -CN. In some embodiments, R22aand R22bare each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R22aand R22bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R22aand R22bare each independently selected from hydrogen and halogen. In some embodiments, R22aand R22bare each hydrogen.

[0186] In some embodiments, for the compound or salt of Formula (II), R23is selected from hydrogen and C1-6alkyl. In some embodiments, R23is selected from hydrogen and C1-3alkyl. In some embodiments, R23is hydrogen.

[0187] In some embodiments, for the compound or salt of Formula (II), X is selected from C(R30) and N; Y is selected from C(R30) and N; and wherein at least one of X or Y is N. In some embodiments, X is selected from C(H) and N; Y is selected from C(H) and N; and wherein at least one of X or Y is N.

[0188] In some embodiments, for the compound or salt of Formula (II), X is C(R30) and Y is N. In some embodiments, X is C(H) and Y is N.

[0189] In some embodiments, for the compound or salt of Formula (II), X is N and Y is C(R30). In some embodiments, X is N and Y is C(H).

[0190] In some embodiments, for the compound or salt of Formula (II), m is selected from 1 and 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0191] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -N(R32)C(O)O(R32), -C(O)N(R32)2, -N(R32)C(O)R32, - N(R32)S(O)2R32, -NO2, =O, =S, =NR32, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - C(O)N(R32)2, -N(R32)C(O)R32, -NO2, =O, =S, =NR32, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, - OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -NO2, =O, =S, =NR32, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, - C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN.

[0192] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR32, -N(R32)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN.

[0193] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0194] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0195] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, and -N(R32)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, and -N(R32)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0196] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, and -N(R32)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0197] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0198] In some embodiments, for the compound or salt of Formula (II), Ring B is C3-10carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR32, -N(R32)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN.

[0199] In some embodiments, for the compound or salt of Formula (II), Ring B is C3-6monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0200] In some embodiments, for the compound or salt of Formula (II), Ring B is C3-6monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, and -N(R32)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, and -N(R32)2,; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0201] In some embodiments, for the compound or salt of Formula (II), Ring B is C3-6monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, and -N(R32)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0202] In some embodiments, for the compound or salt of Formula (II), Ring B is phenyl optionally substituted with one or more substituents independently selected from: halogen, - OR32, and -N(R32)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0203] In some embodiments, for the compound or salt of Formula (II), Ring B is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -CH3,

[0204] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from

[0205] In some embodiments, for the compound or salt of Formula (II), Ring B is 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR32, -N(R32)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN.

[0206] In some embodiments, for the compound or salt of Formula (II), Ring B is 3- to 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0207] In some embodiments, for the compound or salt of Formula (II), Ring B is 3- to 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR32, and -N(R32)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, and -N(R32)2,; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0208] In some embodiments, for the compound or salt of Formula (II), Ring B is 3- to 6- membered monocyclic heterocycle optionally substituted with one or more substituentsindependently selected from halogen, -OR32, and -N(R32)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0209] In some embodiments, for the compound or salt of Formula (II), Ring B is piperidinyl optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0210] In some embodiments, for the compound or salt of Formula (II), Ring B is piperidinyl optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0211] In some embodiments, for the compound or salt of Formula (II), Ring B is piperidinyl optionally substituted with one or more substituents independently selected from: In some embodiments,

[0212] In some embodiments, for the compound or salt of Formula (II), Ring B is piperidinyl optionally substituted with one or more substituents independently selected from:In some embodiments, Ring B is piperidinyl optionally substituted with one or more substituents independently selected from

[0213] In some embodiments, for the compound or salt of Formula (II), Ring B is

[0214] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with fluoro -CH3, -CF3,In some embodiments, Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with fluoro -CH3, -CF3,

[0215] In some embodiments, for the compound or salt of Formula (II), Ring B is selected from:. In some embodiments, Ring B is selected fromIn some embodiments,

[0216] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -N(R33)C(O)O(R33), -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituentsindependently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, -SR33, - N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, - NO2, =O, =S, =NR33, and -CN; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, - C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, - OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -NO2, =O, =S, =NR33, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, - C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN.

[0217] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, -N(R33)2, and -CN; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR33, -N(R33)2, and -CN; andC3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -NO2, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, and -CN.

[0218] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, -N(R33)2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl. C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR33, -N(R33)2, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, and -CN.

[0219] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, -N(R33)2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle areoptionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0220] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, -NR33, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0221] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0222] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, and -NR33; C1alkyl optionally substituted with one or more substituents independently selected from C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substitutedwith one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0223] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from: halogen, -OR33, and -NR33; and C1alkyl optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-8carbocycle and 3- to 8-membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0224] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from halogen, -OR33, and -NR33; and C1-6alkyl optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0225] In some embodiments, for the compound or salt of Formula (II), R24is selected from chloro,In some em24bodiments, R is selected fromchloro,. In some embodiments, R24is selected from,

[0226] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, -NO2, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, and -CN.

[0227] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, and -CN.

[0228] In some embodiments, for the compound or salt of Formula (II), R24is independently selected at each occurrence from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0229] In some embodiments, for the compound or salt of Formula (II), R24is selected from

[0230] In some embodiments, for the compound or salt of Formula (II), R24is selected from chloro,

[0231] In some embodiments, for the compound or salt of Formula (II), R30is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R30is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R30is hydrogen.

[0232] In some embodiments, for the compound or salt of Formula (II), R31, R32, and R33at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN,

[0233] In some embodiments, for the compound or salt of Formula (II), R31is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

[0234] In some embodiments, for the compound or salt of Formula (II), R31is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0235] In some embodiments, for the compound or salt of Formula (II), R31is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0236] In some embodiments, for the compound or salt of Formula (II), R31is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0237] In some embodiments, for the compound or salt of Formula (II), R32is selected from:hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

[0238] In some embodiments, for the compound or salt of Formula (II), R32is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0239] In some embodiments, for the compound or salt of Formula (II), R32is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0240] In some embodiments, for the compound or salt of Formula (II), R32is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0241] In some embodiments, for the compound or salt of Formula (II), R33is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0242] In some embodiments, for the compound or salt of Formula (II), R33is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10carbocycle and 3- to 10-membered heterocycleoptionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0243] In some embodiments, for the compound or salt of Formula (II), R33is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

[0244] In some embodiments, for the compound or salt of Formula (II), R33is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle.

[0245] In some embodiments, for the compound or salt of Formula (II), the compound of Formula (II) is a compound or salt selected from Table 2. *Denotes a stereocenter with an undetermined absolute stereochemistry of a single diastereomer.

[0246] Table 2. Selected α4β7 integrin modulators

[0247] In some aspects, the present disclosure provides a compound represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein:R41is selected from hydrogen and C1-6alkyl; R42aand R42bare each independently selected from: hydrogen, halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2,and -CN; R43is selected from hydrogen and C1-6alkyl; Ring C is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (iv) halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)N(R52)2, -N(R52)C(O)O(R52),-C(O)N(R52)2, -N(R52)C(O)R52, - N(R52)S(O)2R52, -NO2, =O, =S, =NR52, and -CN; (v) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, - OC(O)R52, -C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR52, - SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; and (vi) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, - C(O)N(R52)2, -NO2, =O, =S, =NR52, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, - SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; Ring D is a 7- to 12-membered heterocycle; p is selected from 0, 1, 2, and 3; R44is independently selected at each occurrence from (a), (b), and (c): (d) halogen, -OR53, -SR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - OC(O)N(R53)2, -N(R53)C(O)O(R53),-C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =S,=NR53, and -CN; (e) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -N(R53)(R54), -SR53, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR53, - SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; and (f) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -NO2, =O, =S, =NR53, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; wherein when Ring D is 2,7-naphthyridinyl or isoquinolinyl, p is selected from 1, 2, and 3; R51, R52, and R53at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and R54at each occurrence is independently selected from: hydrogen;C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; C2-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0248] In some embodiments, for the compound or salt of Formula (III), R41is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for the compound or salt of Formula (III), R41is selected from hydrogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, for the compound or salt of Formula (III), R41is selected from hydrogen and C1-3alkyl. In some embodiments, for the compound or salt of Formula (III), R41is hydrogen.

[0249] In some embodiments, for the compound or salt of Formula (III), R42aand R42bare each independently selected from hydrogen, halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, - CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2,and -CN. In some embodiments, R42aand R42bare each independently selected from hydrogen, halogen, -OR51, -N(R51)2, and -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR51, -N(R51)2, and -CN. In some embodiments, R42aand R42bare each independently selected from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R42aand R42bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R42aand R42bare each independently selected from hydrogen and halogen. In some embodiments, R42aand R42bare each hydrogen.

[0250] In some embodiments, for the compound or salt of Formula (III), R43is selected from hydrogen and C1-6alkyl. In some embodiments, R43is selected from hydrogen and C1-3alkyl. In some embodiments, R43is hydrogen.

[0251] In some embodiments, for the compound or salt of Formula (III), p is selected from 0, 1, 2, and 3. In some embodiments, p is selected from 1,2, and 3. In some embodiments, p is selected from 1 and 2. In some embodiments, p is 2. In some embodiments p is 1.

[0252] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)N(R52)2, -N(R52)C(O)O(R52),-C(O)N(R52)2, -N(R52)C(O)R52, - N(R52)S(O)2R52, -NO2, =O, =S, =NR52, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, - C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, - C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -NO2, =O, =S, =NR52, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, - C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN.

[0253] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR52, -N(R52)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen,-OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN.

[0254] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0255] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0256] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0257] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0258] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0259] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0260] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionallysubstituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0261] In some embodiments, for the compound or salt of Formula (III), Ring C is C3-10carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR52, -N(R52)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN.

[0262] In some embodiments, for the compound or salt of Formula (III), Ring C is C3-6monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0263] In some embodiments, for the compound or salt of Formula (III), Ring C is s C3-6monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0264] In some embodiments, for the compound or salt of Formula (III), Ring C is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0265] In some embodiments, for the compound or salt of Formula (III), Ring C is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0266] In some embodiments, for the compound or salt of Formula (III), Ring C is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0267] In some embodiments, for the compound or salt of Formula (III), Ring C is phenyl optionally substituted with one or more substituents independently selected from fluoro, -CH3,

[0268] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from

[0269] In some embodiments, for the compound or salt of Formula (III), Ring C is 3- to 10- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR52, -N(R52)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN.

[0270] In some embodiments, for the compound or salt of Formula (III), Ring C is 3 to 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0271] In some embodiments, for the compound or salt of Formula (III), Ring C is 3 to 6- membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0272] In some embodiments, for the compound or salt of Formula (III), Ring C is piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0273] In some embodiments, for the compound or salt of Formula (III), Ring C is piperidinyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, and -N(R52)2; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, and -N(R52)2; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

[0274] In some embodiments, for the compound or salt of Formula (III), Ring C is piperidinyl optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0275] In some embodiments, for the compound or salt of Formula (III), Ring C is piperidinyl optionally substituted with one or more substituents independently selected from: C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which isoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0276] In some embodiments, for the compound or salt of Formula (III), Ring C is piperidinyl optionally substituted with one or more substituents independently selected from -CH3, -CF3,In some embodiments, Ring C is piperidinyl optionally substituted with one or more substituents independently selected from -CH3, -CF3,In some embodiments, Ring C is piperidinyl optionally substituted with one or more substituents independently selected from

[0277] In some embodiments, for the compound or salt of Formula (III), Ring C is selected fromIn some embodiments, Ring C is selected fromIn some embodiments, Ring C is selected from ,

[0278] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from phenyl and piperidinyl each of which is optionally substituted with one or more substituents independently selected from fluoro, -CH3, -CF3,

[0279] In some embodiments, for the compound or salt of Formula (III), Ring C is selected from.

[0280] In some embodiments, for the compound or salt of Formula (III), Ring D is 7 to 12- membered heterocycle, wherein when Ring D is 2,7-naphthyridinyl or isoquinolinyl, p is selected from 1, 2, and 3.

[0281] In some embodiments, for the compound or salt of Formula (III), Ring D is 7 to 12- membered bicyclic heterocycle, wherein when Ring D is isoquinolinyl, p is selected from 1, 2, and 3.

[0282] In some embodiments, for the compound or salt of Formula (III), Ring D is isoquinolinyl; and p is selected from 1, 2, and 3.

[0283] In some embodiments, for the compound or salt of Formula (III), Ring D is selected from 7 to 12-membered fused heterocycle, 7 to 12-membered bridged heterocycle, and 7 to 12- membered spirocyclic heterocycle.

[0284] In some embodiments, for the compound or salt of Formula (III), Ring D is selected from 7 to 12-membered fused heterocycle and 7 to 12-membered bridged heterocycle.

[0285] In some embodiments, for the compound or salt of Formula (III), Ring D is 7 to 12- membered fused heterocycle.

[0286] In some embodiments, for the compound or salt of Formula (III), Ring D is selected from 7 to 10-membered fused heterocycle, 7 to 10-membered bridged heterocycle, and 7 to 10- membered spirocyclic heterocycle.

[0287] In some embodiments, for the compound or salt of Formula (III), Ring D is selected from 7 to 10-membered fused heterocycle and 7 to 10-membered bridged heterocycle.

[0288] In some embodiments, for the compound or salt of Formula (III), Ring D is 7 to 10- membered fused heterocycle.

[0289] In some embodiments, for the compound or salt of Formula (III), Ring D is selected from quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydro[1,4]benzodioxinyl, 2,3- dihydropyrido[3,4-b][1,4]oxazinyl, 3,4 dihydrobenzo[b][1,4]oxazinyl, and chromanyl.

[0290] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -SR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, -OC(O)N(R53)2, -N(R53)C(O)O(R53),-C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =S, =NR53, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR53, -N(R53)(R54), -SR53, -C(O)R53, -C(O)OR53, -OC(O)R53, - C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycle are each optionally substituted with one or moresubstituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, - OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -NO2, =O, =S, =NR53, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, - C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN.

[0291] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - C(O)N(R53)2, -N(R53)C(O)R53, -NO2, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR53-N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0292] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - C(O)N(R53)2, -N(R53)C(O)R53, -NO2, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0293] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -N(R53)(R54), and -C(O)R53; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR53, -N(R53)(R54), C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0294] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -C(O)R53; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0295] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: halogen, -OR53, -C(O)R53; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-8carbocycle and 3- to 8-membered heterocycle, wherein the C3-8carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0296] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from: -CH3, -CF3,In someembodiments, R44is independently selected at each occurrence from: -CH3, -CF3,,In some embodiments, R44is independently selected at each occurrence from:

[0297] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR53-N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

[0298] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R44is independently selected at each occurrence from C3-6carbocycle and 3- to 6-membered heterocycle. In some embodiments, R44is C3-6carbocycle.

[0299] In some embodiments, for the compound or salt of Formula (III), R44is independently selected at each occurrence from:.

[0300] In some embodiments, for the compound or salt of Formula (III),selected from:

[0301] In some embodiments, for the compound or salt of Formula (III), R51, R52, and R53at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0302] In some embodiments, for the compound or salt of Formula (III), R51is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN.

[0303] In some embodiments, for the compound or salt of Formula (III), R51is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0304] In some embodiments, for the compound or salt of Formula (III), R51is selected from: hydrogen, C1-6alkyl, C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0305] In some embodiments, for the compound or salt of Formula (III), R51is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0306] In some embodiments, for the compound or salt of Formula (III), R52is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

[0307] In some embodiments, for the compound or salt of Formula (III), R52is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0308] In some embodiments, for the compound or salt of Formula (III), R52is selected from: hydrogen, C1-6alkyl, C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0309] In some embodiments, for the compound or salt of Formula (III), R52is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0310] In some embodiments, for the compound or salt of Formula (III), R53is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

[0311] In some embodiments, for the compound or salt of Formula (III), R53is selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

[0312] In some embodiments, for the compound or salt of Formula (III), R53is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, R53is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein each C3-6carbocycle and 3- to 6-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl

[0313] In some embodiments, for the compound or salt of Formula (III), R54at each occurrence is independently selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl,-NH2,-NO2, =O, and -CN; C2-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

[0314] In some embodiments, for the compound or salt of Formula (III), R54at each occurrence is independently selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogenC1-6alkyl, and C1-6haloalkyl.

[0315] In some embodiments, for the compound or salt of Formula (III), R54at each occurrence is independently selected from: hydrogen, C2-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogenC1-6alkyl, and C1-6haloalkyl.

[0316] In some embodiments, for the compound or salt of Formula (III), R54is independently selected at each occurrence from hydrogen, C2-6alkyl, and C1-6 haloalkyl.

[0317] In some embodiments, the compound of Formula (III) is a compound or salt selected from Table 3. *Denotes a stereocenter with an undetermined absolute stereochemistry of a single diastereomer.

[0318] Table 3. Selected α4β7 integrin modulators

[0319] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0320] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formulas (I), (II) or (III), are intended to include all Z-, E- and tautomeric forms as well.

[0321] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0322] The compounds or salts for Formulas (I), (II), or (III), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0323] In certain embodiments, compounds or salts for Formulas (I), (II), or (III), may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0324] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formulas (I), (La), (II), or (III), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomersdepends on several factors, including physical state, temperature, solvent, and pH. Some non– limiting examples of tautomeric equilibrium include:

[0325] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0326] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0327] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0328] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0329] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0330] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0331] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formulas (I), (II), or (III). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0332] The methods and compositions of Formulas (I), (II), or (III), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0333] Compounds of Formulas (I), (II), or (III), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0334] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formulas (I), (II), or (III). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0335] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0336] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above- defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0337] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieserand Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations

[0338] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formulas (I), (II), or (III) and at least one pharmaceutically acceptable excipient.

[0339] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically acceptable salt form.

[0340] Methods for formulation of the compositions can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compounds, salts or compositions can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0341] A compound or salt of any one of Formulas (I), (II), or (III) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formulas (I), (II), or (III), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0342] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. Preparations for such pharmaceutical formulations or compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, ThirdEdition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).Methods of Treatment

[0343] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0344] In some embodiments, a method of treating a subject in need thereof may comprise administering to the subject a therapeutically effective amount of a compound of the present disclosure. As used herein, the term “therapeutically effective amount” means the amount of an inhibitor that is sufficient to reduce the expression and / or activity of α4β7 integrin in a subject or in a cell.

[0345] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0346] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0347] In some embodiments, the present disclosure provides a method of modulating α4β7 integrin in a subject in need thereof, comprising administering to the subject a compound of Formulas (I), (II), or (III) or pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of modulating α4β7 integrin in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of Formulas (I), (II), or (III) or a pharmaceutically acceptable salt thereof, and an excipient.

[0348] In some embodiments, the present disclosure provides a method of treating an disease or condition comprising administering to a subject in need thereof a compound of Formulas (I), (II), or (III) or pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formulas (I), (II), or (III) or a pharmaceutically acceptable salt thereof, and an excipient. In some embodiments, the disease or condition is an inflammatory disease or condition.

[0349] In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, immune- mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, immune-mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, and primary sclerosing cholangitis. In some embodiments, the disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, the disease or condition is ulcerative colitis. In some embodiments, the disease or condition is Crohn’s disease. In some embodiments, the disease or condition is graft-versus-host disease. In some embodiments, the disease or condition is type 1 diabetes. In some embodiments, the disease or condition is immune-mediated colitis, checkpoint inhibitor induced colitis. In some embodiments, the disease or condition is primary sclerosing cholangitis.EXAMPLES

[0350] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0351] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0352] Examples A and 1 to 7 show general and exemplary procedures for the preparation of the claimed compounds of Formulas (I), (II), and (III). One of ordinary skill in the art will appreciate that variations on the following synthetic procedures may be necessary to obtain compounds of Formulas (I), (II), and (III), including changes in protecting group chemistry, reaction conditions, and / or order of synthetic steps. Such variations are within the ability of the ordinarily skilled artisan. EXAMPLE A: Common Intermediate

[0353] The following common intermediate was synthesized by the following procedure.

[0354] Synthetic Preparation of common intermediate:

[0355] Step 1: Zn (107 g, 1.64 mol, 3.00 eq) was added to a three necked flask, and heated at 110 °C under vacuum for 10 minutes, then cooled to 25 °C. To the flask was added a solution of TMSCl (11.8 g, 109 mmol, 13.8 mL, 0.200 eq) in DMF (600 mL). The mixture was stirred at 25 °C for 20 minutes, and then the supernatant liquor was removed by syringe. Then a mixture of compound 0-2 (180 g, 546 mmol, 1.00 eq) in DMF (1800 mL) was added to the precipitate, and the inner temperature increased rapidly from 25 °C to 45 °C. And the resulting mixture was stirred at 20 °C for 1 hr under N2. Compound 0-3 (1700 g, 8 batches in total) was obtained as a gray oil, which is used for the next step directly.

[0356] Step 2: To a solution of compound 0-1 (100 g, 450 mmol, 1.00 eq) in DMF (200 mL) was added Pd2(dba)3(20.6 g, 22.5 mmol, 0.05 eq) and SPhos (36.9 g, 90.0 mmol, 0.2 eq) under N2. Then a solution of compound 0-3 (213 g, 540 mmol, 1.20 eq) in DMF (1500 mL) was added under N2. The mixture was stirred at 90 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. Compound 0-4 (650 g, 1.89 mol, 54.1% yield, 8 batches) was obtained as a white solid. LC-MS: (M-55)+: 289.1.1H NMR: (400 MHz, CDCl3). δ 7.79 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.28 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 5.06 (d, J = 7.6 Hz, 1H), 4.77 - 4.68 (m, 1H), 3.71 (d, J = 2.4 Hz, 3H), 3.62 - 3.39 (m, 2H), 1.51 - 1.31 (m, 9H).

[0357] Step 3: To a solution of BPD (147 g, 580 mmol, 2.00 eq) in MeCN (1200 mL) was added t-BuONO (89.8 g, 871 mmol, 103 mL, 3.00 eq) at 20 °C under N2, the mixture was warmed to 50 °C. Then a solution of compound 0-4 (100 g, 290 mmol, 1.00 eq) in MeCN (300 mL) was added dropwise at 50 °C. The mixture was stirred at 50 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase HPLC. Common intermediate 1 (100 g, 210 mmol, 96.0% purity) was obtained as a yellow solid. LC-MS: (M-99)+: 356.0.1H NMR: (400 MHz, CDCl3) δ 8.73 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.8 EHz, 1H), 8.12 - 8.07 (m, 1H), 7.59 - 7.52 (m, 1H), 7.48 -7.42 (m, 1H), 7.30 - 7.28 (m, 1H), 5.08 - 4.95 (m, 1H), 4.76 - 4.65 (m, 1H), 3.66 - 3.46 (m, 5H), 1.48 - 1.39 (m, 21H). EXAMPLE 1: Series A

[0358] Example 1-1: Series A1

[0359] General Scheme of Series A1

[0360] Synthetic preparation of Series A1 compound, Compound 1

[0361] Step 1: A mixture of compound A1-1 (200 mg, 439 μmol, 1.00 eq), compound A1-2 (95.3 mg, 439 μmol, 1.00 eq), Pd(dtbpf)Cl2(28.6 mg, 43.9 μmol, 0.100 eq), K3PO4(186 mg, 878 μmol, 2.00 eq) in dioxane (3.00 mL), H2O (1.00 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2atmosphere. The reaction mixture was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-3 (180 mg, 386 μmol, 88.0% yield) was obtained as a yellow solid. LC-MS: (M+Na)+: 488.0.

[0362] Step 2: To a solution of compound A1-3 (150 mg, 322 μmol, 1.00 eq) in DCM (0.50 mL) was added HCl / dioxane (2.00 M, 1.15 mL, 7.16 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Compound A1-4 (130 mg, crude, HCl) was obtained as a yellow solid. LC-MS: (M+H)+: 366.0.1H NMR: (400 MHz, CDCl3). δ 8.89 (br s, 3H), 8.12 (d, J = 8.8 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.37 - 7.24 (m, 4H), 6.82 (dd, J1= 8.4 Hz, J1= 2.4 Hz, 2H), 4.28 - 4.23 (m, 1H), 3.79 - 3.73 (m, 1H), 3.58 (s, 3H), 3.57 - 3.55 (m, 6H), 3.53 - 3.47 (m, 1H).

[0363] Step 3: To a solution of compound A1-4 (100 mg, 249 μmol, 1.00 eq, HCl), compound A1-5 (76.5 mg, 249 μmol, 1.00 eq) in pyridine (2.00 mL) was added EDCI (143 mg, 746 μmol, 3.00 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-6 (90.0 mg, 137 μmol, 55.3% yield) was obtained as yellow solid. LC-MS: (M+H)+: 677.4.1H NMR: (400 MHz, CDCl3). δ 8.16 (d, J = 8.8 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.45 - 7.36 (m, 3H), 7.33 - 7.29 (m, 1H), 7.26 - 7.22 (m, 1H), 6.72 (d, J = 8.0 Hz, 2H), 6.47 - 6.43 (m, 2H), 6.37 (dd, J1= 13.2 Hz, J2= 2.0 Hz, 1H), 5.22 (q, J = 7.2 Hz, 1H), 4.31 (d, J = 12.4 Hz, 1H), 4.14 - 4.10 (m, 1H), 4.07 - 4.03 (m, 1H), 3.86 - 3.79 (m, 1H), 3.76 - 3.72 (m, 1H), 3.70 - 3.66 (m, 4H), 3.66 - 3.63 (m, 7H), 3.56 - 3.49 (m, 1H), 3.27 - 3.24 (m, 1H), 2.33 (s, 3H).

[0364] Step 4: To a solution of compound A1-6 (80.0 mg, 122 μmol, 1.00 eq) in H2O (1.00 mL) was added HCl / dioxane (2.00 M, 2.00 mL, 32.7 eq). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC. Compound 1 (44.72 mg, 69.8 μmol, 57.1% yield, 100% purity) was obtained as off-white solid. LC-MS: (M+H)+: 641.2.1H NMR: (400 MHz, DMSO- d6) δ 13.10 - 12.67 (m, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.45 - 7.39 (m, 2H), 7.34 - 7.17 (m, 3H), 6.81 (dd, J1= 8.4 Hz, J1= 4.4 Hz, 2H), 6.75 - 6.59 (m, 2H), 4.90 - 4.79 (m, 1H), 4.78 - 4.70 (m, 1H), 4.14 (d, J = 12.8 Hz, 1H), 3.96 - 3.92 (m, 1H), 3.75 - 3.71 (m, 2H), 3.57 (d, J = 12.0 Hz, 8H), 3.30 - 3.20 (m, 2H), 2.02 (s, 3H).

[0365] The following Series A1 compounds provided in Table 4 were prepared according to procedures analogous to those described in Example 1-1 using intermediates Int A1 described below.

[0366] Table 4.

[0367] Series A1 Intermediate: IntA1-1

[0368] Synthetic preparation of Int A1-1

[0369] Step 1: To a solution of compound A1-1a (2.00 g, 6.19 mmol, 1.20 eq) in THF (15.0 mL) was added dropwise n-BuLi (2.50 M, 3.25 mL, 1.58 eq) at -78 °C. The mixture was stirred for 0.5 hr. The mixture of compound A1-1b (361 mg, 5.16 mmol, 385 μL, 1.00 eq) in THF (3.00 mL) was added at -78 °C and stirred for 1 hr. The reaction mixture was quenched by addition sat. aq. NH4Cl solution 50.0 mL at 0 °C, and then extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-1c (663 mg, 2.11 mmol, 40.9% yield) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 2H), 7.41 - 7.30 (m, 3H), 7.00 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.01 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.56 (br s, 1H), 2.56 - 2.45 (m, 2H), 2.42 - 2.31 (m, 2H), 2.19 - 2.07 (m, 1H), 1.79 - 1.65 (m, 1H).

[0370] Step 2: To a solution of Pd / C (100 mg, 10.0% purity) in MeOH (7.00 mL) was added compound A1-1c (663 mg, 2.11 mmol, 1.00 eq) and HCl (4.00 M, 52.7 μL, 0.100 eq). The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(20 Psi) at 25 °C for 2 hrs. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-1d (344 mg, 1.65 mmol, 78.3% yield) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3) δ 6.76 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 5.51 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.79 - 3.68 (m, 1H), 2.37 - 2.26 (m, 2H), 2.17 - 1.94 (m, 3H), 1.90 - 1.78 (m, 1H).

[0371] Step 3: To a solution of compound A1-1d (304 mg, 1.46 mmol, 1.00 eq) in DCM (5.00 mL) was added TEA (739 mg, 7.30 mmol, 1.02 mL, 5.00 eq) and Tf2O (1.24 g, 4.38 mmol, 723 μL, 3.00 eq) at 0 °C, the mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was diluted with sat. aq. NaHCO3solution (15.0 mL) and sat. aq. NH4Cl solution (15.0 mL). The water layer was extracted with DCM 60.0 mL (30.0 mL*2). The combined organic layers were washed with brine (15.0 mL), dried over Na2SO4, filtered and concentrated under reducedpressure to give a residue. The residue was purified by Prep-TLC. Intermediate Int Al-1 (436 mg, 1.28 mmol, 87.8% yield) was obtained as light-yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.23 (d, J= 8.8 Hz, 1H), 6.78 (d, J= 8.8 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.77 - 3.66 (m, 1H), 2.40 - 2.29 (m, 2H), 2.18 - 1.99 (m, 3H), 1.92 - 1.80 (m, 1H).

[0372] Series Al Intermediate: Int Al-2

[0373] Synthetic preparation of Int Al-2

[0374] Step 1: To a solution of compound Al-2a (1.00 g, 3.09 mmol, 1.00 eq), compound Al- 2b (265 mg, 3.09 mmol, 1.00 eq) and CS2CO3 (2.02 g, 6.19 mmol, 2.00 eq) in toluene (4.00 mL) with H2O (1.00 mL) was added RuPhos Pd G3 (258 mg, 309 pmol, 0.100 eq) under N2atmosphere. The suspension was degassed and purged with N2 for 3 times. The mixture was stirred at 60 °C for 2 hrs under N2atmosphere. The reaction mixture was diluted with H2O (20.0 mL) and extracted with ethyl acetate (20.0 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound Al-2c (871 mg, 3.06 mmol, 98.9% yield) was obtained as a yellow liquid. LC-MS: (M+H)+: 285.1.1H NMR: (400 MHz, DMSO-d6) δ 7.44 (d, J= 7.2 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.30 (br d, J= 7.2 Hz, 1H), 6.37 (s, 2H), 4.82 (s, 2H), 3.77 - 3.72 (m, 6H), 1.92 - 1.81 (m, 1H), 0.93 - 0.85 (m, 2H), 0.71 - 0.64 (m, 2H).

[0375] Step 2: To a solution of compound Al-2c (671 mg, 2.36 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd / C (251. mg, 10.0% purity) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(30.0 psi) at 25°C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound Al-2d (415 mg, 2.14 mmol, 90.5% yield) was obtained as a yellow solid. LC-MS: (M+H)+: 195.0.1H NMR: (400 MHz, DMSO-d6) δ 8.00 (br s, 1H), 6.31 (s, 2H), 3.82 - 3.65 (m, 6H), 1.85 - 1.76 (m, 1H), 0.89 - 0.76 (m, 2H), 0.66 - 0.53 (m, 2H).

[0376] Step 3: To a solution of compound A1-2d (375 mg, 1.93 mmol, 1.00 eq) in DCM (5.00 mL) was added TEA (586 mg, 5.79 mmol, 806 μL, 3.00 eq) and Tf2O (1.09 g, 3.86 mmol, 637 μL, 2.00 eq) in DCM (5.00 mL) at 0°C for 30 mins. The reaction mixture was diluted with H2O (70.0 mL), and extracted with ethyl acetate (50.0 mL*2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Intermediate Int A1-2 (534 mg, 1.64 mmol, 84.7% yield) was obtained as a red solid.1H NMR: (400 MHz, DMSO-d6) δ 6.54 (s, 2H), 3.84 (s, 6H), 1.98 - 1.92 (m, 1H), 1.01 - 0.93 (m, 2H), 0.84 - 0.77 (m, 2H).

[0377] Series A1 Intermediate: IntA1-3

[0378] Synthetic preparation of IntA1-3

[0379] Step 1: A mixture of compound A1-3a (5.00 g, 16.9 mmol, 1.00 eq), MeB(OH)2(8.09 g, 135 mmol, 8.00 eq), Pd(dtbpf)Cl2(2.20 g, 3.38 mmol, 0.200 eq) and K3PO4(14.3 g, 67.6 mmol, 4.00 eq) in dioxane (50.0 mL) and H2O (20.0 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 40 °C for 12 hrs under N2atmosphere. The reaction mixture was filtered, and concentrated under reduced pressure to give a residue. The mixture wasdiluted with H2O (150 mL), and extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine (450 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography Compound A1-3b (2.61 g, 15.7 mmol, 92.9% yield) was obtained as white solid.1H NMR: (400 MHz, CDCl3). δ 6.89 (s, 1H), 6.43 (s, 1H), 3.84 (s, 6H), 2.14 (s, 6H).

[0380] Step 2: To a solution of compound A1-3b (1.56 g, 9.39 mmol, 1.00 eq) in DCM (40.0 mL) was added BBr3(5.88 g, 23.5 mmol, 2.26 mL, 2.50 eq) at -78 °C. The mixture was stirred at 25 °C for 2 hrs under N2atmosphere. The reaction mixture was quenched by MTBE (40.0 mL) at 0 °C, and then diluted with H2O (40.0 mL). The mixture was extracted with dichloromethane (40.0 mL*3). The combined organic layers were washed with brine (120 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-3c (1.10 g, 7.96 mmol, 84.8% yield) was obtained as off-white solid.1H NMR: (400 MHz, CDCl3). δ 6.84 (s, 1H), 6.32 (s, 1H), 4.58 (br s, 2H), 2.15 (s, 6H).

[0381] Step 3: To a solution of compound A1-3c (1.05 g, 7.60 mmol, 1.00 eq) in THF (5.00 mL) was added dropwise a solution of tetrabutylammonium tribromide (3.66 g, 7.60 mmol, 1.00 eq) in THF (10.0 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-3d (1.50 g, 6.91 mmol, 90.9% yield) was obtained as off-white solid. LC-MS: (M-H)+: 214.9.1H NMR: (400 MHz, CDCl3). δ 6.85 (s, 1H), 5.17 (s, 2H), 2.21 (s, 6H).

[0382] Step 4: To a solution of compound A1-3d (1.50 g, 6.91 mmol, 1.00 eq) in MeCN (15.0 mL) was added MeI (3.92 g, 27.6 mmol, 1.72 mL, 4.00 eq) and KOH (1.55 g, 27.6 mmol, 4.00 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was quenched by NH3•H2O (90.0 mL) at 0 °C, and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (90.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Intermediate Int A1-3 (1.50 g, 6.12 mmol, 88.6% yield) was obtained as white solid.1H NMR: (400 MHz, CDCl3). δ 6.94 (s, 1H), 3.79 (s, 6H), 2.27 (d, J = 0.8 Hz, 6H).

[0383] Series A1 Intermediate: Int A1-4

[0384] Synthetic preparation of Int A1-4

[0385] Step 1: To a solution of compound A1-4b (2.10 g, 6.12 mmol, 1.50 eq) in THF (5.00 mL) was added t-BuOK (1.00 M, 8.16 mL, 2.00 eq) at 0 °C under N2atmosphere, the suspension was allowed to stirred at 0 °C for 1 hr. Compound A1-4a (1.00 g, 4.08 mmol, 1.00 eq) in THF (10 mL) was added dropwise, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by sat. aq. NH4Cl solution (30.0 mL), and then diluted with H2O (10.0 mL). The mixture was extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-4c (631 mg, 2.31 mmol, 56.6% yield) was obtained as colorless.1H NMR: (400 MHz, CDCl3) δ 7.98 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 12.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.16 (d, J = 7.2 Hz, 1H), 5.95 (d, J = 12.8 Hz, 1H), 5.51 (d, J = 7.2 Hz, 1H), 3.90 (br s, 2H), 3.89 (s, 3H), 3.80 (s, 5H), 3.78 (s, 2H), 3.71 (s, 3H).

[0386] Step 2: To a solution of compound A1-4c (581 mg, 2.13 mmol, 1.00 eq) in DCM (4.00 mL), H2O (1.00 mL) was added TFA (4.61 g, 40.4 mmol, 3.00 mL, 19.0 eq), the mixture was stirred at 40 °C for 3 hrs. The reaction mixture was diluted with sat. aq. NaHCO3solution (50.0 mL) and extracted with ethyl acetate (50.0 mL*3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-4d (447 mg, 1.73 mmol, 81.1% yield) was obtained as yellow gum.1H NMR: (400 MHz, CDCl3) δ 9.72 (t, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.70 (d, J = 2.0 Hz, 2H).

[0387] Step 3: To a solution of compound A1-4d (397 mg, 1.53 mmol, 1.00 eq) and compound A1-4e (371 mg, 3.06 mmol, 2.00 eq) in DCM (5.00 mL) was added NaBH(OAc)3(650 mg, 3.06 mmol, 2.00 eq), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (30.0 mL), and extracted with dichloromethane (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Intermediate Int A1- 4 (370 mg, 932 μmol, 543% yield, 91.7% purity) was obtained as yellow oil. LC-MS: (M+H)+: 364.1.1H NMR: (400 MHz, CDCl3) δ 7.10 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.86 - 2.77 (m, 2H), 2.68 - 2.59 (m, 6H), 2.10 - 1.96 (m, 4H).

[0388] Series A1 Intermediate: Int A1-5

[0389] Synthetic preparation of Int A1-5

[0390] Step 1: To a solution of compound A1-5a (500 mg, 2.04 mmol, 1.00 eq) in THF (10.0 mL) was added NaBH4(155 mg, 4.10 mmol, 2.01 eq) at 0 °C, the mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition sat. aq. NH4Cl (30.0 mL) at 0 °C, and then diluted with H2O (10.0 mL). The mixture was extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*3), dried over Na2SO4, filteredand concentrated under reduced pressure to give a residue. Compound A1-5b (500 mg, 2.02 mmol, 99.2% yield) was obtained colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.10 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 3H).

[0391] Step 2: To solution of compound A1-5b (300 mg, 1.21 mmol, 1.00 eq) in DCM (5.00 mL) was added SOCl2(361 mg, 3.04 mmol, 220 μL, 2.50 eq) at 0 °C, and then stirred at 25 °C for 2 hrs. The reaction solution was quenched by H2O (10.0 mL), and extracted with ethyl acetate (5.00 mL*2). The organic layers were washed with sat. aq. Na2CO3(5.00 mL), dried over Na2SO4, filtered and concentrated to give crude under reduced pressure without purification. The product compound A1-5c (280 mg, 1.05 mmol, 86.8% yield) was obtained as colorless oil.1H NMR: (400 MHz, DMSO-d6). δ 7.46 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

[0392] Step 3: To solution of compound A1-5c (230 mg, 866 μmol, 1.00 eq) and compound A1-5d (121 mg, 866 μmol, 1.00 eq) in toluene (4.00 mL), EtOH (2.00 mL) and H2O (1.00 mL) was added Na2CO3(183 mg, 1.73 mmol, 2.00 eq) and Pd(PPh3)4(100 mg, 86.6 μmol, 0.100 eq). The reaction mixture was stirred under N2at 80 °C for 2 hrs. The reaction solution was quenched by H2O (5.00 mL) and extracted with ethyl acetate (5.00 mL*2). The organic layers were washed with H2O (5.00 mL), dried over Na2SO4, filtered and concentrated to give crude under reduced pressure. The crude was purified by Prep-TLC. The intermediate Int A1-5 (135 mg, 415 μmol, 47.9% yield) was obtained as yellow oil. LC-MS: (M+1)+: 326.9.1H NMR: (400 MHz, DMSO-d6). δ 7.30 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.85 (s, 1H), 4.11 - 3.94 (m, 4H), 3.81 (s, 3H), 3.68 (s, 3H), 1.30 - 1.15 (m, 3H).

[0393] Series A1 Intermediate: Int A1-6

[0394] General scheme of Int A1-6

[0395] Synthetic preparation of IntA1-6

[0396] Step 1: To a solution of compound A1-6a (1.00 g, 6.13 mmol, 1.00 eq) in MeOH (10.0 mL) was added Pd / C (100 mg, 10.0% purity) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(50 Psi) at 50 °C for 20 hrs. The reaction mixture was filtered. The filtrate was concentrated under the vacuum. Compound A1-6b (960 mg, 5.74 mmol, 93.7% yield) was obtained as white solid.1H NMR: (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 3.24 - 3.13 (m, 2H), 2.92 - 2.87 (m, 1H), 2.40 - 2.29 (m, 1H), 2.23 - 2.07 (m, 1H), 2.02 - 1.90 (m, 1H), 1.69 - 1.53 (m, 1H).

[0397] Step 2: To a solution of compound A1-6c (1.00 g, 3.77 mmol, 1.00 eq), compound A1- 6b (944 mg, 5.65 mmol, 1.50 eq), TBAI (556 mg, 1.51 mmol, 0.400 eq) in THF (100 mL) was added t-BuOK (1.00 M, 11.3 mL, 3.00 eq) at 25 °C. The mixture was stirred at 40 °C for 8 hrs. The reaction mixture was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-6d (450 mg, 1.12 mmol, 29.8% yield, 98.8% purity) was obtained as yellow oil. LC-MS: (M+H)+: 398.0.

[0398] Step 3: To a solution of compound A1-6d (250 mg, 631 μmol, 1.00 eq) in THF (6.00 mL) was added LiHMDS (1.00 M, 2.52 mL, 4.00 eq) at -78 °C. The mixture was stirred at -78 °C for 2 hrs. PhSeCl (217 mg, 1.14 mmol, 1.80 eq) in THF (1.00 mL) was added dropwise at - 78 °C. The resulting mixture was stirred at -78 °C for 2 hrs. The reaction mixture was quenched by sat. aq. NH4Cl (10.0 mL) at 0 °C, and then extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-6e (160 mg, 290 μmol, 46.0% yield) was obtained as yellow oil. LC-MS: (M+H)+: 551.9.

[0399] Step 4: To a solution of compound A1-6e (160 mg, 290 μmol, 1.00 eq) in THF (2.00 mL) was added H2O2(170 mg, 1.50 mmol, 144 μL, 30.0% purity, 5.17 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched by addition sat. Na2SO3(aq.) (10.0 mL) at 0 °C, and then extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-6f (60.0 mg, 152 μmol, 52.4% yield) was obtained as yellow oil. LC-MS: (M+H)+: 395.9.

[0400] Series A1 Intermediate: Int A1-7

[0401] Synthetic preparation of Int A1-7

[0402] Step 1: To a solution of compound A1-7a (500 mg, 1.88 mmol, 1.00 eq) and compound A1-7b (263 mg, 1.88 mmol, 1.00 eq) in toluene (10.0 mL), EtOH (5.00 mL) and H2O (5.00 mL) was added Na2CO3(598 mg, 5.65 mmol, 3.00 eq) and Pd(PPh3)4(217 mg, 188 μmol, 0.100 eq). The mixture was stirred at 90 °C for 2 hrs. The reaction mixture was diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Intermediate Int A1-7 (400 mg, 1.23 mmol, 65.3% yield) was obtained as yellow oil. LC-MS: (M+H)+: 325.0.1H NMR: (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 6.61 (s, 2H), 6.00 (s, 1H), 4.05 - 4.01 (m, 4H), 3.77 (s, 6H), 1.20 (m, 3H).

[0403] Series A1 Intermediate: Int A1-8

[0404] General scheme of Int A1-8

[0405] Synthetic preparation of A1-8

[0406] Step 1: To a solution of compound A1-8a (400 mg, 1.72 mmol, 1.00 eq) and compound A1-8b (518 mg, 2.57 mmol, 1.50 eq) and PPh3(900 mg, 3.43 mmol, 2.00 eq) in THF (5.00 mL) was added DIAD (694 mg, 3.43 mmol, 665 μL, 2.00 eq) under N2at 0 °C. The mixture was stirred at 25 °C for 12 hrs under N2. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-8c (270 mg, 481 μmol, 28.0% yield, 74.2% purity) was obtained as yellow oil. LC-MS: (M-99)+: 316.1.1H NMR: (400 MHz, CDCl3). δ 6.20 (s, 2H), 4.51 - 4.41 (m, 1H), 3.87 (d, J = 1.6 Hz, 6H), 3.71 - 3.66 (m, 2H), 3.41 - 3.35 (m, 2H), 1.96 - 1.87 (m, 2H), 1.84 - 1.71 (m, 2H), 1.48 (d, J = 1.6 Hz, 9H).

[0407] Step 2: To a solution of compound A1-8c (270 mg, 481 μmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (2.00 M, 1.00 mL, 4.16 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with water (10.0 mL), and extracted with DCM (10.0 mL*3). The combined aqueous phase was adjusted to pH = 7 - 8 with sat. aq. NaHCO3, and extracted with DCM (10.0 mL*3). The combined organic layers were dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. Compound A1-8d (170 mg, 357 μmol, 74.3% yield, 66.5% purity) was obtained as yellow oil. LC-MS: (M+H)+: 317.9.

[0408] Step 3: To a solution of compound A1-8d (170 mg, 357 μmol, 1.00 eq, 66.5% purity) in dioxane (2.00 mL) was added DIEA (138 mg, 1.07 mmol, 186 μL, 3.00 eq) and compound A1- 8e (105 mg, 536 μmol, 1.50 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-8f (120 mg, 258 μmol, 72.3% yield, 78.1% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 364.0.

[0409] Series A1 Intermediate: Int A1-9

[0410] General Scheme of A1-9

[0411] Synthetic preparation of A1-9

[0412] Step 1: To a solution of compound A1-9a (5.00 g, 18.8 mmol, 1.00 eq) and compound A1-9b (3.79 g, 18.8 mmol, 1.00 eq) in THF (50.0 mL) was added TBAI (3.48 g, 9.42 mmol, 0.500 eq) and t-BuOK (1.00 M, 56.4 mL, 3.00 eq). The mixture was stirred at 25 °C for 12 hrs.The reaction mixture was diluted with water (50.0 mL), and extracted with DCM (50.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-9c (5.40 g, 10.7 mmol, 57.2% yield, 85.9% purity) was obtained as yellow oil. LC-MS: (M- 99)+: 329.9.1H NMR: (400 MHz, DMSO-d6). δ 6.69 (s, 2H), 4.50 (s, 2H), 3.82 (s, 6H), 3.67 - 3.61 (m, 2H), 3.56 - 3.52 (m, 1H), 3.05 - 3.00 (m, 2H), 1.85 - 1.80 (m, 2H), 1.44 - 1.38 (m, 2H), 1.36 (s, 9H).

[0413] Step 2: To a solution of compound A1-9c (5.40 g, 10.7 mmol, 1.00 eq) in DCM (30.0 mL) was added HCl / dioxane (2.00 M, 20.0 mL, 3.71 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound A1-9d (4.40 g, crude, HCl) was obtained as a white solid. LC-MS: (M+H)+: 331.9.

[0414] Step 3: To a solution of compound A1-9d (400 mg, 1.09 mmol, 1.00 eq, HCl) in dioxane (5.00 mL) was added DIEA (422 mg, 3.27 mmol, 570 μL, 3.00 eq) and compound A1- 9e (320 mg, 1.64 mmol, 1.50 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-9f (270 mg, 713 μmol, 65.3% yield, 99.4% purity) was obtained as yellow oil. LC-MS: (M+H)+: 377.9.1H NMR: (400 MHz, CDCl3). δ 6.58 (s, 2H), 4.63 (t, J = 5.2 Hz, 1H), 4.51 - 4.49 (m, 3H), 3.90 (s, 6H), 3.44 - 3.42 (m, 1H), 2.87 - 2.82 (m, 2H), 2.74 - 2.65 (m, 2H), 2.30 - 2.24 (m, 2H), 1.97 - 1.93 (m, 2H), 1.77 - 1.71 (m, 2H).

[0415] Series A1 Intermediate: Int A1-10

[0416] General Scheme of Int A1-10

[0417] Synthetic preparation of Int A1-10

[0418] Step 1: To a solution of compound A1-10a (2.00 g, 7.53 mmol, 1.00 eq) and compound A1-10b (973 mg, 7.53 mmol, 1.00 mL, 1.00 eq) in THF (20.0 mL) was added TBAI (1.39 g, 3.77 mmol, 0.500 eq) and then t-BuOK (1.00 M, 22.6 mL, 3.00 eq) was added dropwise at 25 °C. The resulting mixture was stirred at 40 °C for 12 hrs. The reaction mixture was filtered, and the filter liquid was diluted with H2O (50.0 mL), and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC. Compound A1-10c (840 mg, 2.29 mmol, 30.3% yield, 97.5% purity) was obtained as a brown oil. LC-MS: (M+H)+: 358.1.1H NMR: (400 MHz, CDCl3). δ 6.58 (s, 2H), 4.51 (s, 2H), 3.90 (s, 6H), 3.61 (t, J=5.60 Hz, 2H), 2.61 (t, J=6.00 Hz, 2H), 2.45 (s, 4H), 1.57 - 1.64 (m, 4H), 1.30 - 1.48 (m, 2H).

[0419] Series A1 Intermediate: Int A1-11

[0420] Synthetic preparation of Int A1-11

[0421] Step 1: To a solution of compound A1-11a (500 mg, 2.15 mmol, 1.00 eq), compound A1-11b (2.02 g, 10.7 mmol, 809 μL, 5.00 eq) in DMF (5.00 mL) was added K2CO3(889 mg, 6.44 mmol, 3.00 eq). The mixture was stirred at 60 °C for 3 hrs. The reaction mixture was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A1-11c (754 mg, crude) was obtained as yellow solid.

[0422] Step 2: To a solution of compound A1-11c (754 mg, 2.22 mmol, 1.00 eq), compound A1-11d (537 mg, 4.44 mmol, 2.00 eq) in DMF (10.0 mL) was added K2CO3(919 mg, 6.65 mmol, 3.00 eq). The mixture was stirred at 60 °C for 3 hrs. The reaction mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mL*3). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-11e (320 mg, 841 μmol, 37.9% yield) was obtained as yellow oil. LC-MS: (M+H)+: 379.9.

[0423] Series A1 Intermediate: IntA1-12

[0424] Synthetic preparation of Int A1-12

[0425] Step 1: To a solution of compound A1-12a (5.00 g, 15.5 mmol, 1.00 eq), compound A1-12b (3.98 g, 46.7 mmol, 4.61 mL, 3.00 eq) in DCM (50.0 mL) was added NaBH(OAc)3(6.60 g, 31.1 mmol, 2.00 eq). The mixture was stirred at 25 °C for 4 hrs. The reaction mixture was diluted with H2O (60.0 mL), and extracted with DCM (60.0 mL*3). The combined organic layers were washed with brine (60.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-12c (5.60 g, 14.3 mmol, 92.1% yield) was obtained as a white solid. LC-MS: (M+H)+: 392.0.1H NMR: (400 MHz, DMSO-d6) δ 7.44 - 7.30 (m, 5H), 7.20 (s, 1H), 7.06 (s, 1H), 5.08 (s, 2H), 3.76 (s, 3H), 3.40 (s, 2H), 2.37 (s, 4H), 1.53 - 1.37 (m, 6H).

[0426] Step 2: To a solution of compound A1-12c (2.00 g, 5.12 mmol, 1.00 eq) in THF (20.0 mL) was added n-BuLi (2.50 M, 3.07 mL, 1.50 eq) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. Then a solution of compound A1-12d (1.18 g, 10.2 mmol, 1.03 mL, 2.00 eq) in THF (2.00 mL) was added at -78 °C, the mixture was stirred at -78 °C for 2 hrs. The reaction mixture was quenched by addition sat. NH4Cl (20.0 mL) at 0 °C, and then extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-12e (1.20 g, 3.54 mmol, 69.0% yield) was obtained as a yellow oil. LC-MS: (M+H)+: 340.1.1H NMR: (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.46 - 7.37 (m, 5H), 7.36 - 7.33 (m, 1H), 7.03 (s, 1H), 5.13 (s, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 2.34 (s, 4H), 1.43 - 1.38 (m, 6H).

[0427] Step 3: To a solution of compound A1-12e (1.20 g, 3.54 mmol, 1.00 eq) in MeOH (20.0 mL) was added NaBH4(410 mg, 10.8 mmol, 3.07 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by sat. NH4Cl (20.0 mL) at 0 °C, and then extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-12f (850 mg,1.80 mmol, 51.0% yield, 72.5% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 342.5.1H NMR: (400 MHz, DMSO-d6) δ 7.46 - 7.33 (m, 5H), 7.07 (s, 1H), 6.89 (s, 1H), 5.98 (t, J = 5.2 Hz, 1H), 5.06 (s, 2H), 4.41 (d, J = 4.8 Hz, 2H), 3.75 (s, 3H), 3.42 (s, 2H), 2.38 - 2.29 (m, 4H), 1.44 - 1.38 (m, 6H).

[0428] Step 4: To a solution of compound A1-12f (650 mg, 1.90 mmol, 1.00 eq) in THF (8.00 mL) was added NaH (228 mg, 5.71 mmol, 60.0% purity, 3.00 eq) at 0 °C. The mixture was stirred at 20 °C for 0.5 hr. Then EtI (1.48 g, 9.52 mmol, 761 μL, 5.00 eq) was added and stirred at 30 °C for 6 hrs. The reaction mixture was quenched by addition sat. NH4Cl (20.0 mL) at 0 °C, and then extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (30.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-12g (550 mg, 1.05 mmol, 55.3% yield, 70.7% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 370.6.

[0429] Step 5: To a solution of compound A1-12g (550 mg, 1.05 mmol, 1.00 eq, 70.7% purity) in MeOH (6.00 mL) was added Pd / C (70.0 mg, 10.0% purity) under N2atmosphere. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 Psi) at 25 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated under the vacuum. Compound A1-12h (450 mg, 892 μmol, 84.7% yield, 55.4% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 280.2.

[0430] Step 6: To a solution of compound A1-12h (450 mg, 892 μmol, 1.00 eq) in DCM (6.00 mL) was added Tf2O (755 mg, 2.68 mmol, 441 μL, 3.00 eq) and pyridine (353 mg, 4.46 mmol, 360 μL, 5.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with water (20.0 mL), and extracted with DCM (20.0 mL*3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Intermediate A1-12i (120 mg, 429 μmol, 48.1% yield, 55.4% purity) was obtained as a yellow oil. LC-MS: (M+H)+: 412.2.

[0431] Series A1 Intermediate: IntA1-13

[0432] Synthetic preparation of Int A1-13

[0433] Step 1: To a solution of compound A1-13a (4.50 g, 18.2 mmol, 1.00 eq) in DMF (45.0 mL) was added K2CO3(7.55 g, 54.7 mmol, 3.00 eq) and BnBr (2.80 g, 16.4 mmol, 1.95 mL, 0.900 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was diluted with H2O (20.0 mL). HCl (1.00 M) was added into solution to adjust pH to 7 at 0 °C. The mixture was extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-13b (1.94 g, 5.75 mmol, 31.6% yield) was obtained as light-yellow oil. LC-MS: (M+H)+: 336.9.1H NMR: (400 MHz, CDCl3). δ 7.51 - 7.48 (m, 2H), 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 7.24 (d, J = 1.6 Hz, 1H), 5.76 (s, 1H), 5.21 (s, 2H), 3.92 (s, 3H).

[0434] Step 2: To a solution of compound A1-13b (1.94 g, 5.75 mmol, 1.00 eq) in DMF (20.0 mL) was added K2CO3(2.39 g, 17.3 mmol, 3.00 eq) and MeI (1.23 g, 8.63 mmol, 537 μL, 1.50 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H2O (20.0 mL), and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A1-13c (1.93 g, 5.50 mmol, 95.5% yield) was obtained as light-yellow oil.1H NMR: (400 MHz, DMSO-d6). δ 7.51 - 7.48 (m, 2H), 7.44 - 7.39 (m, 2H), 7.36 - 7.32 (m, 2H), 7.24 (d, J = 1.6 Hz, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H).

[0435] Step 3: To a solution of compound A1-13c (1.93 g, 5.50 mmol, 1.00 eq) in THF (20.0 mL) was added DIBAL-H (1.00 M, 13.7 mL, 2.50 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by HCl (1.00 M) 30.0 mL at 0 °C, and then diluted with H2O (50.0 mL). The reaction mixture was extracted with ethyl acetate (50.0 mL*3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A1-13d (1.80 g,crude) was obtained as light-yellow oil.1H NMR: (400 MHz, CDCl3). δ 7.51 - 7.49 (m, 2H), 7.42 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1H), 6.66 (s, 1H), 6.62 (s, 1H), 5.18 (s, 2H), 4.66 (s, 2H), 3.93 (s, 3H).

[0436] Step 4: To a solution of compound A1-13d (1.80 g, 5.57 mmol, 1.00 eq) in THF (20.0 mL) was added KOH (937 mg, 16.7 mmol, 3.00 eq) and EtI (1.74 g, 11.1 mmol, 891 μL, 2.00 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The resulting mixture was diluted with H2O (30.0 mL) and extracted with ethyl acetate (30.0 mL*3). The combined organic layers were washed with brine (90.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound Int A1-13 (1.60 g, 4.56 mmol, 81.8% yield) was obtained as light-yellow oil.1H NMR: (400 MHz, CDCl3). δ 7.51 - 7.48 (m, 2H), 7.42 - 7.37 (m, 2H), 7.34 - 7.29 (m, 1H), 6.63 (s, 1H), 6.59 (s, 1H), 5.18 (s, 2H), 4.46 (s, 2H), 3.92 (s, 3H), 3.52 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 6.8 Hz, 3H).

[0437] Series A1 Intermediate: IntA1-14

[0438] Synthetic preparation of Int A1-14

[0439] Step 1: To a solution of compound A1-14a (5.00 g, 15.5 mmol, 1.00 eq) in MeOH (50.0 mL) was added NaBH4 (1.77 g, 46.0 mmol, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by addition sat. aq. NH4Cl (50.0 mL) at 0 °C, and then extracted with ethyl acetate (50.0 mL*3). The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A1-14b (5.80 g, crude) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6). δ 7.51 (d, J = 6.8 Hz, 2H), 7.41 - 7.30 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.31 (t, J = 5.6 Hz, 1H), 4.94 (s, 2H), 4.45 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H).

[0440] Step 2: To a solution of compound A1-14b (1.00 g, 3.09 mmol, 1.00 eq) in THF (10.0 mL) was added NaH (247 mg, 6.19 mmol, 60.0% purity, 2.00 eq) at 0 °C and stirred for 0.5 hr. Then, EtI (2.41 g, 15.4 mmol, 1.24 mL, 5.00 eq) was added at 0 °C under N2. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by sat. aq. NH4Cl (20.0 mL) at 0 °C, and then extracted with ethyl acetate (20.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound A1-14c (1.00 g, 2.85 mmol, 92.0% yield) was obtained as yellow oil.1H NMR: (400 MHz, DMSO-d6). δ 7.51 (d, J = 8.4 Hz, 2H), 7.41 - 7.34 (m, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.42 (s, 2H), 3.85 (s, 3H), 3.51 (q, J = 14.0 Hz, 2H), 1.16 (t, J = 6.8 Hz, 3H).

[0441] Step 3: To a solution of compound A1-14c (500 mg, 1.42 mmol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 854 μL, 1.50 eq) under N2at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. Then, DMF (520 mg, 7.12 mmol, 547 μL, 5.00 eq) was added. The mixture was stirred at -78°C for 3 hrs. The reaction mixture was quenched by sat. aq. NH4Cl (10.0 mL) at 0 °C, diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound A1-14d (400 mg, crude) was obtained as yellow oil.1H NMR: (400 MHz, CDCl3). δ 10.4 (s, 1H), 7.39 - 7.35 (m, 5H), 6.88 - 6.87 (m, 2H), 5.16 (d, J = 6.8 Hz, 2H), 4.77 (s, 2H), 4.40 (s, 3H), 3.88 (s, 2H), 1.20 (t, J = 6.8Hz, 3H).

[0442] Step 4: To a solution of compound A1-14d (400 mg, 1.33 mmol, 1.00 eq) and compound A1-14e (340 mg, 4.00 mmol, 394 μL, 3.00 eq) in DCM (5.00 mL) was stirred at 25 °C for 0.5 hr. NaBH(OAc)3(846 mg, 4.00 mmol, 3.00 eq) was added into reaction mixture. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL) and extracted with DCM (10.0 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-14f (180 mg, 466 μmol, 35.0% yield, 95.8% purity) was obtained as yellow oil. LC-MS: (M+H)+: 370.3.1H NMR: (400 MHz, CDCl3). δ 7.45 - 7.35 (m, 5H), 7.15 (d, J = 8.4 Hz, 1H), 7.00 - 6.92 (m, 1H), 5.02 (s, 2H), 4.70 (s, 2H), 3.90 (s, 3H), 3.62 - 3.31 (m, 4H), 1.80 (s, 4H), 1.71 - 1.54 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[0443] Step 5: To a solution of compound A1-14f (180 mg, 466 μmol, 1.00 eq) in MeOH (5.00 mL) was added Pd / C (30.0 mg, 10.0% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 Psi) at 25°C for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound A1-14g (120 mg, crude) was obtained as yellow oil. LC- MS: (M+H)+: 280.0.

[0444] Step 6: To a solution of compound A1-14g (120 mg, 429 μmol, 1.00 eq) in DCM (3.00 mL) was added Tf2O (484 mg, 1.72 mmol, 283 μL, 4.00 eq) and pyridine (169 mg, 2.15 mmol, 173 μL, 5.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water (10.0 mL), and extracted with DCM (10.0 mL*3). The combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Intermediate Int A1-14 (100 mg, 243 μmol, 56.5% yield) was obtained as yellow oil. LC-MS: (M+H)+:412.1.1H NMR: (400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 3.88 (s, 3H), 3.58 - 3.53 (m, 4H), 2.34 (s, 4H), 1.52 - 1.40 (m, 6H), 1.27 - 1.24 (m, 3H).

[0445] Series A1 Intermediate: IntA1-15

[0446] Synthetic preparation of A1-15

[0447] Step 1: To a solution of compound A1-15a (500 mg, 2.15 mmol, 1.00 eq) and BnBr (550 mg, 3.22 mmol, 382 μL, 1.50 eq) in ACN (5.00 mL) was added K2CO3(889 mg, 6.44mmol, 3.00 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep- TLC. Compound A1-15b (560 mg, 1.73 mmol, 80.8% yield) was obtained as colorless oil.

[0448] Step 2: To a solution of compound A1-15b (200 mg, 618 μmol, 1.00 eq) and compound A1-15c (263 mg, 3.09 mmol, 305 μL, 5.00 eq) in t-Amyl-OH (5.00 mL) was added Cs2CO3(604 mg, 1.86 mmol, 3.00 eq) and Pd‐PEPPSI‐IHeptCl (58mg, 61 μmol, 0.100 eq) under N2atmosphere. The mixture was stirred at 100 °C for 12 hrs. The reaction mixture was diluted with H2O (10.0 mL), and extracted with ethyl acetate (10.0 mL*3). The combined organic layers were washed with brine (10.0 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC. Compound A1-15d (110 mg, 335 μmol, 54.3% yield,) was obtained as yellow oil. LC-MS: (M+H)+: 328.3.1H NMR: (400 MHz, CDCl3) δ 7.53 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 6.8 Hz, 2H), 7.33 - 7.29 (m, 1H), 6.62 (q, J = 8.8 Hz, 2H), 5.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H), 2.94 (t, J = 4.8 Hz, 4H), 1.75 - 1.70 (m, 4H), 1.55 - 1.53 (m, 2H).

[0449] Step 3: To a solution of Pd / C (50.0 mg, 46.9 μmol, 10.0% purity) in MeOH (3.00 mL) was added a solution of compound A1-15d (110 mg, 335 μmol, 1.00 eq) in MeOH (2.00 mL) under N2atmosphere. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15.0 psi...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof wherein: R1is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R2aand R2bare each independently selected from: hydrogen, halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -NO2, and -CN; R3is selected from hydrogen and C1-6alkyl; Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)N(R12)2, -N(R12)C(O)O(R12), -C(O)N(R12)2, -N(R12)C(O)R12, - N(R12)S(O)2R12, -NO2, =O, =S, =NR12, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, - N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, - OC(O)R12, -C(O)N(R12)2, -NO2, =O, =S, =NR12, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, =O, =S, =NR12, and -CN; R4is independently selected at each occurrence from (iv), (v), and (vi): (iv) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; (v) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and (vi) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is CF3, each additional R4when present is selected from (a), (b), (c), and (d): (a) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN;(b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, -OC(O)R13, - C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; and (d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; wherein when one R4is -OCH3, each additional R4when present is selected from (e), (f), and (g): (e) halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)N(R13)2, -N(R13)C(O)O(R13), -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN;(f) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR14, -N(R13)(R15), -SR13, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, =O, =S, =NR13, -CN, and C1-6alkyl-OR13; and (g) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, - OC(O)R13, -C(O)N(R13)2, -NO2, =O, =S, =NR13, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, =O, =S, =NR13, and -CN; R5is selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -NO2, =O, =S, =NR16, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR16, - SR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, -C(O)N(R16)2, - N(R16)C(O)R16, -NO2, =O, =S, =NR16, and -CN; R11, R12, R13, and R16at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, C1-6alkyl, C1-6haloalkyl, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R14is selected from: hydrogen; C1alkyl and C3-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; C2alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; R15is selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl,-NH2,-NO2, =O, and -CN; C2-6alkyl each optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle; and n is selected from 0, 1, and 2.

2. The compound or salt of claim 1, wherein R1is selected from hydrogen and C1-3alkyl.

3. The compound or salt of claim 2, wherein R1is hydrogen.

4. The compound or salt of any one of claims 1 to 3, wherein R2aand R2bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl.

5. The compound or salt of claim 4, wherein R2aand R2bare each hydrogen.

6. The compound or salt of any one of claims 1 to 5, wherein R3is selected from hydrogen and C1-3alkyl.

7. The compound or salt of claim 6, wherein R3is hydrogen.

8. The compound or salt of any one of claims 1 to 7, wherein Ring A is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10- membered heterocycleare each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

9. The compound or salt of claim 8, wherein Ring A is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

10. The compound or salt of claim 9, wherein Ring A is C3-10carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are eachoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

11. The compound or salt of claim 10, wherein Ring A is selected from C3-8monocyclic carbocycle and C6-10bicyclic carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

12. The compound or salt of claim 11, wherein Ring A is selected from C3-8monocyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are eachoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

13. The compound or salt of claim 12, wherein Ring A is selected from cyclopropyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

14. The compound or salt of claim 13, wherein Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are eachoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

15. The compound or salt of claim 14, wherein Ring A is cyclopropyl optionally substituted with one or more substituents independently selected from: -CH3,16. The compound or salt of claim 15, wherein Ring A is selected from:

17. The compound or salt of claim 13, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

18. The compound or salt of claim 17, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN.

19. The compound or salt of claim 18, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from: fluoro, -NH2, -CH3, -CF3,20. The compound or salt of claim 17, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, - C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

21. The compound or salt of claim 20, wherein Ring A is phenyl optionally substituted with one or more substituents independently selected from:

22. The compound or salt of claim 17, wherein Ring A is selected from,.

23. The compound or salt of claim 11, wherein Ring A is C6-10bicyclic carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

24. The compound or salt of claim 9, wherein Ring A is 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle,wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

25. The compound or salt of claim 24, wherein Ring A is selected from 3- to 8-membered monocyclic heterocycle and 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

26. The compound or salt of claim 25, wherein Ring A is 3- to 8-membered monocyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are eachoptionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

27. The compound or salt of claim 26, wherein Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

28. The compound or salt of 27, wherein Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, and - CN; and 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; andC3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -C(O)N(R12)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

29. The compound or salt of claim 28, wherein Ring A is selected from pyrrolyl, pyrrolidinyl, pyridinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: fluoro, -CH3, -CF3, -NH2, -CH3,30. The compound or salt of claim 29, wherein Ring A is selected from:,31. The compound or salt of claim 25, wherein Ring A is 6- to 10-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from:halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

32. The compound or salt of claim 31, wherein Ring A is 6- to 10-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

33. The compound or salt of claim 32, wherein Ring A is selected from benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from:halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

34. The compound or salt of claim 33, wherein Ring A is selected from benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

35. The compound or salt of claim 34, wherein Ring A is selected from,36. The compound or salt of claim 9, wherein Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -N(R12)S(O)2R12, -NO2, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -N(R12)C(O)R12, -NO2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -OC(O)R12, -C(O)N(R12)2, -NO2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

37. The compound or salt of claim 36, wherein Ring A is selected from cyclopropyl, pyrrolyl, pyrrolidinyl, phenyl, pyridinyl, piperidinyl, benzo[d]imidazolyl, 2-3,dihydroindenyl, and indazolyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, -C(O)N(R12)2, -N(R12)S(O)2R12, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR12, -N(R12)2, and -CN; and C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR12, -N(R12)2, and -CN.

38. The compound or salt of claim 37, wherein Ring A is selected from:

39. The compound or salt of any one of claims 1 to 38, wherein R12is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, =O, C3-10carbocycle, and 3- to 6-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

40. The compound or salt of any one of claims 1 to 39, wherein n is selected from 1 and 2.

41. The compound or salt of claim 40, wherein R4is independently selected at each occurrence from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN and C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; wherein when one R4is CF3, each additional R4when present is selected from: halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN; and wherein when one R4is -OCH3, each additional R4when present is selected from:halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, and -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

42. The compound or salt of claim 41, wherein R4is independently selected at each occurrence from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)OR13, -OC(O)R13, -C(O)N(R13)2, - N(R13)C(O)R13, -NO2, and -CN.

43. The compound or salt of claim 42, wherein R4is independently selected at each occurrence from:

44. The compound or salt of claim 41, wherein R4is independently selected at each occurrence from C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN and C3-10carbocycle and 3- to 10-memberedheterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

45. The compound or salt of claim 44, wherein R4is independently selected at each occurrence from:

46. The compound or salt of claim 41, wherein R4is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, and -CN; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

47. The compound or salt of claim 46, wherein R4is independently selected at each occurrence from48. The compound or salt of claim 41, wherein one R4is -CF3, each additional R4is selected from: halogen, -OR13, -N(R13)2, -OC(O)R13, -N(R13)C(O)R13, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR13, -N(R13)2, -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2-CN, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

49. The compound or salt of claim 48, wherein one R4is -CF3, each additional R4is selected from halogen, -OR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

50. The compound or salt of claim 49, wherein one R4is -CF3, each additional R4is.

51. The compound or salt of claim 41, wherein one R4is -OCH3, each additional R4is selected from: halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R13)(R15), -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR13, -N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, and -CN.

52. The compound or salt of claim 51, wherein one R4is -OCH3, each additional R4is selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, - N(R13)(R15), C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR13, -N(R13)2, =O, C1-6alkyl, C1-6haloalkyl, and C1-6alkyl-OR13.

53. The compound or salt of claim 52, wherein one R4is -OCH3, each additional R4is selected from: chloro, fluoro, -CH3,54. The compound or salt of claim 51, wherein one R4is -OCH3, each additional R4is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -CN, C1-6alkyl, and C1-6haloalkyl.

55. The compound or salt of claim 54, wherein one R4is -OCH3, each additional R4is selected from cyclopropyl, cyclobutyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

56. The compound or salt of claim 55, wherein one R4is -OCH3, each additional R4is selected from:

57. The compound or salt of any one of claims 1 to 56, wherein R13is independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl, and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle.

58. The compound or salt of any one of claims 1 to 57, wherein R14is selected from: hydrogen, C1alkyl, C1haloalkyl, C3-6alkyl, and C3-6haloalkyl; C2alkyl substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, C3-6carbocycle, and 3- to 6-membered heterocycle.

59. The compound or salt of any one of claims 1 to 58, wherein R15is selected from hydrogen and C2-6haloalkyl.

60. The compound or salt of any one of claims 1 to 59, wherein R5is selected from: C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -N(R16)2, -C(O)R16, -C(O)OR16, -OC(O)R16, - C(O)N(R16)2, -N(R16)C(O)R16, -NO2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

61. The compound or salt of claim 60, wherein R5is selected from C1-6alkyl, C1-6haloalkyl, C3-6carbocycle and 3- to 6-membered heterocycle.

62. The compound or salt of claim 61, wherein R5is selected from -CH3, -CHF2, and cyclopropyl.

63. The compound or salt of any one of claims 1 to 62, wherein R16is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

64. The compound or salt of any one of claims 1 to 63, wherein the compound of Formula (I) is a compound or salt selected from Table 1.

65. A compound represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof wherein: X is selected from C(R30) and N; Y is selected from C(R30) and N; wherein at least one of X or Y is N; R21is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R22aand R22bare each independently selected from: hydrogen, halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR31, -SR31, -N(R31)2, -C(O)R31, -NO2,and -CN; R23is selected from hydrogen and C1-6alkyl;Ring B is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -OC(O)N(R32)2, -N(R32)C(O)O(R32), -C(O)N(R32)2, -N(R32)C(O)R32, - N(R32)S(O)2R32, -NO2, =O, =S, =NR32, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, - OC(O)R32, -C(O)N(R32)2, -N(R32)C(O)R32, -NO2, =O, =S, =NR32, and - CN; C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, - C(O)N(R32)2, -NO2, =O, =S, =NR32, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR32, - SR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, - N(R32)C(O)R32, -NO2, =O, =S, =NR32, and -CN; R24is independently selected at each occurrence from (a), (b), (c), and (d): (a) halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -OC(O)N(R33)2, -N(R33)C(O)O(R33), -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, and -CN; (b) C1alkyl optionally substituted with one or more substituents independently selected from: -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, -OC(O)R33, - C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituentsindependently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (c) C2-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, -SR33, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR33, - SR33, -N(R33)2, -C(O)R33, -C(O)OR33, -OC(O)R33, -C(O)N(R33)2, - N(R33)C(O)R33, -NO2, =O, =S, =NR33, and -CN; and (d) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -NO2, =O, =S, =NR33, CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -SR33, -N(R33)2, -C(O)R33, -C(O)OR33, - OC(O)R33, -C(O)N(R33)2, -N(R33)C(O)R33, -NO2, =O, =S, =NR33, and - CN; and R30is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R31, R32, and R33at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; andm is selected from 1 and 2.

66. The compound or salt of claim 65, wherein R21is selected from hydrogen and C1-3alkyl.

67. The compound or salt of claim 66, wherein R21is hydrogen.

68. The compound or salt of any one of claims 65 to 67, wherein R22aand R22bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl.

69. The compound or salt of claim 68, wherein R22aand R22bare each hydrogen.

70. The compound or salt of any one of claims 65 to 69, wherein R23is selected from hydrogen and C1-3alkyl.

71. The compound or salt of claim 70, wherein R23is hydrogen.

72. The compound or salt of any one of claims 65 to 71, wherein X is C(H) and Y is N.

73. The compound or salt of any one of claims 65 to 71, wherein X is N and Y is C(H).

74. The compound or salt of any one of claims 65 to 73, wherein Ring B is selected from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR32, -N(R32)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -C(O)R32, -C(O)OR32, -OC(O)R32, -C(O)N(R32)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN.

75. The compound or salt of claim 74, wherein Ring B is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

76. The compound or salt of claim 75, wherein Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR32, -N(R32)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-6carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR32, -N(R32)2, -CN, C1-6alkyl, and C1-6haloalkyl.

77. The compound or salt of claim 76, wherein Ring B is selected from phenyl and piperidinyl, each of which is optionally substituted with fluoro -CH3, -CF3,78. The compound or salt of claim 77, wherein Ring B is selected from:

79. The compound or salt of any one of claims 65 to 78, wherein R32is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

80. The compound or salt of any one of claims 65 to 79, wherein m is 1.

81. The compound or salt of any one of claims 65 to 79, wherein m is 2.

82. The compound or salt of any one of claims 65 to 81, wherein R24is independently selected at each occurrence from: halogen, -OR33, -N(R33)2, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

83. The compound or salt of claim 82, wherein R24is independently selected at each occurrence from: halogen, -OR33, and -CN; C1alkyl optionally substituted with one or more substituents independently selected from C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl; and C2-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.

84. The compound or salt of claim 83, wherein R24is selected from chloro,85. The compound or salt of any one of claims 65 to 79, wherein R24is independently selected at each occurrence from C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR33, -N(R33)2, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR33, -N(R33)2, and -CN.

86. The compound or salt of claim 85, wherein R24is independently selected at each occurrence from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

87. The compound or salt of claim 86, wherein R24is selected from88. The compound or salt of any one of claims 65 to 87, wherein R33is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-10carbocycle and 3- to 10-membered heterocycleoptionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl.

89. The compound or salt of any one of claims 65 to 88, wherein the compound of Formula (II) is a compound or salt selected from Table 2.

90. A compound represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof wherein: R41is selected from hydrogen and C1-6alkyl; R42aand R42bare each independently selected from: hydrogen, halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, -CN; and C1-6alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR51, -SR51, -N(R51)2, -C(O)R51, -NO2, and -CN; R43is selected from hydrogen and C1-6alkyl; Ring C is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from (i), (ii), and (iii): (i) halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -OC(O)N(R52)2, -N(R52)C(O)O(R52),-C(O)N(R52)2, -N(R52)C(O)R52, - N(R52)S(O)2R52, -NO2, =O, =S, =NR52, and -CN; (ii) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, - OC(O)R52, -C(O)N(R52)2, -N(R52)C(O)R52, -NO2, =O, =S, =NR52, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR52, - SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, - C(O)N(R52)2, -NO2, =O, =S, =NR52, -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR52, -SR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, - N(R52)C(O)R52, -NO2, =O, =S, =NR52, and -CN; Ring D is a 7- to 12-membered heterocycle; p is selected from 0, 1, 2, and 3; R44is independently selected at each occurrence from (a), (b), and (c): (a) halogen, -OR53, -SR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - OC(O)N(R53)2, -N(R53)C(O)O(R53),-C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =S, =NR53, and -CN; (b) C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -N(R53)(R54), -SR53, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and - CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, C1-6haloalkyl, -OR53, - SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; and (c) C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, - OC(O)R53, -C(O)N(R53)2, -NO2, =O, =S, =NR53, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR53, -SR53, -N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -N(R53)C(O)R53, -NO2, =O, =S, =NR53, and -CN; wherein when Ring D is 2,7-naphthyridinyl or isoquinolinyl, p is selected from 1, 2, and 3; R51, R52, and R53at each occurrence are independently selected from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and R54at each occurrence is independently selected from: hydrogen; C1alkyl substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; C2-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O- C1-6haloalkyl, C1-6alkyl, C1-6haloalkyl, -NH2, -NO2, =O, and -CN.

91. The compound or salt of claim 90, wherein R41is selected from hydrogen and C1-3alkyl.

92. The compound or salt of claim 91, wherein R41is hydrogen.

93. The compound or salt of any one of claims 90 to 92, wherein R42aand R42bare each independently selected from hydrogen, halogen, C1-3alkyl, and C1-3haloalkyl.

94. The compound or salt of claim 93, wherein R42aand R42bare each hydrogen.

95. The compound or salt of any one of claims 90 to 94, wherein R43is selected from hydrogen and C1-3alkyl.

96. The compound or salt of claim 95, wherein R43is hydrogen.

97. The compound or salt of any one of claims 90 to 96, wherein Ring C is selected from C3-10- carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -CN, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR52, -N(R52)2, and -CN; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, -C(O)R52, -C(O)OR52, -OC(O)R52, -C(O)N(R52)2, -NO2, -CN, and C1-6alkyl, wherein when the C1-6alkyl is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN.

98. The compound or salt of claim 97, wherein Ring C is selected from C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

99. The compound or salt of claim 98, wherein Ring C is selected from phenyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR52, -N(R52)2, and -CN;C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-6carbocycle, and 3- to 6-membered heterocycle, wherein the C3-10carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; and C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR52, -N(R52)2, C1-6alkyl, and C1-6haloalkyl.

100. The compound or salt of claim 99, wherein Ring C is selected from phenyl and piperidinyl each of which is optionally substituted with one or more substituents independently selected from fluoro, -CH3, -CF3,101. The compound or salt of claim 100, wherein Ring C is selected from.

102. The compound or salt of any one of claims 90 to 101, wherein R52is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

103. The compound or salt of any one of claims 90 to 102, wherein Ring D is 7 to 12- membered bicyclic heterocycle, wherein when Ring D is isoquinolinyl, p is selected from 1, 2, and 3.

104. The compound or salt of claim 103, wherein Ring D is selected from 7 to 12-membered fused heterocycle, 7 to 12-membered bridged heterocycle, and 7 to 12-membered spirocyclic heterocycle.

105. The compound or salt of claim 104, wherein Ring D is selected from 7 to 12-membered fused heterocycle and 7 to 12-membered bridged heterocycle.

106. The compound or salt of claim 105, wherein Ring D is 7 to 12-membered fused heterocycle.

107. The compound or salt of claim 106, wherein Ring D is selected from quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydro[1,4]benzodioxinyl, 2,3-dihydropyrido[3,4- b][1,4]oxazinyl, 3,4 dihydrobenzo[b][1,4]oxazinyl, and chromanyl.

108. The compound or salt of any one of claims 90 to 107, wherein R44is independently selected at each occurrence from: halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, - N(R53)C(O)R53, -NO2, and -CN; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR53, -N(R53)(R54), -C(O)R53, -C(O)OR53, -OC(O)R53, - C(O)N(R53)2, -N(R53)C(O)R53, -NO2, -CN, C3-10carbocycle and 3- to 10- membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl.; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR53-N(R53)2, -C(O)R53, -C(O)OR53, -OC(O)R53, -C(O)N(R53)2, -NO2, -CN, C1-6alkyl, and C1-6haloalkyl.

109. The compound or salt of claim 108, wherein R44is independently selected at each occurrence from: halogen, -OR53, -C(O)R53; C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from: halogen, C1-6alkyl, and C1-6haloalkyl 110. The compound or salt of claim 109, wherein R44is independently selected at each occurrence from: -CH3, -CF3,111. The compound or salt of claim 108, wherein R44is independently selected at each occurrence from: C3-6carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

112. The compound or salt of claim 111, wherein R44is independently selected at each occurrence from:

113. The compound or salt of any one of claims 90 to 112, wherein R53is independently selected at each occurrence from hydrogen and C1-6alkyl optionally substituted with one more substituents independently selected from halogen, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein each C3-10carbocycle and 3- to 10-membered heterocycle are optionallysubstituted with one or more substituents independently selected from: halogen C1-6alkyl, and C1-6haloalkyl.

114. The compound or salt of any one of claims 90 to 113, wherein R54is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl.

115. The compound or salt of any one of claims 90 to 114, whereinis selected from:

116. The compound or salt of any one of claims 90 to 115, wherein the compound of Formula (III) is a compound or salt selected from Table 3.

117. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 116, and a pharmaceutically acceptable excipient.

118. A method of modulating alpha 4 beta 7 integrin in a subject in need thereof, comprising administering to the subject a compound or salt of any one of claims 1 to 116 or a pharmaceutical composition of claim 117.

119. A method of treating an inflammatory disease or condition comprising administering to a subject in need thereof a compound or salt of any one of claims 1 to 116 or a pharmaceutical composition of claim 117.

120. The method of claim 119, wherein the inflammatory disease or condition is selected from: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, graft-versus-host disease, type 1 diabetes, immune-mediated colitis, checkpoint inhibitor induced colitis, and primary sclerosing cholangitis.

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