IP Library › Granted Patent US 10,947,227

Granted Patent B2

US 10,947,227 · App. 16/421,881 · Granted Mar 16, 2021

Tricyclic heterocyclic compounds as sting activators

Inventors: Liangxing Wu (Wilmington, DE); Neil Lajkiewicz (Garnet Valley, PA); Yingda Ye (Wilmington, DE); Zhenwu Li (Wilmington, DE); Wenqing Yao (Chadds Ford, PA)

Assignee: Incyte Corporation

C07D471/04

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Quick Facts

Patent No.: US 10,947,227
App. No.: 16/421,881
Granted: Mar 16, 2021
Kind: B2

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Abstract

The present application provides tricyclic heterocyclic compounds that activate the STING pathway to produce interferons, which are useful in the treatment of various diseases including infectious diseases and cancer.

Claims (294)

1. A compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein:

R U , R V , R W , and R Q are each independently selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a , SR a , C(═O)R b , C(═O)N c R d , C(═O)OR a , OC(═O)R b , OC(═O)N c R d , N c R d , NR c C(═O)R b , NR c C(═O)OR b , NR c C(═O)N c R d , C(═NR e )R b , C(═NR e )N c R d , NR c C(═NR e )N c R d , NRcS(═O) 2 R b , NR c S(═O) 2 NR c R d , S(═O) 2 R b , and S(═O) 2 N c R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 8 groups;

each R a , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;

each R b is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8 groups;

each R e is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy;

each R 8 is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a8 , SR a8 , C(═O)R b8 , C(═O)NR c8 R d8 , C(═O)OR a8 , OC(═O)R b8 , OC(═O)NR c8 R d8 , NR c8 R d8 , NR c8 C(═O)R b8 , NR c8 C(═O)OR b8 , NR c8 C(═O)NR c8 R d8 , C(═NR e )R b8 , C(═NR e )NR c8 R d8 , NR c8 C(═NR e )NR c8 R d8 , NR c8 S(═O) 2 R b8 , NR c8 S(═O) 2 NR c8 R d8 , S(═O) 2 R b8 , and S(═O) 2 NR c8 R d8 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 10 groups;

each R a8 , R c8 , and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 10 groups;

each R b8 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 10 groups;

each R 10 is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a10 , SR a10 , C(═O)R b10 , C(═O)NR c10 R d10 , C(═O)OR a10 , OC(═O)R b10 , OC(═O)NR c10 R d10 , NR c10 R d10 , NR c10 C(═O)R b10 , NR c10 C(═O)OR b10 , NR c10 C(═O)NR c10 R d10 , C(═NR e )R b10 , C(═NR e )NR c10 R d10 , NR c10 C(═NR e )NR c10 R d10 , NR c10 S(═O) 2 R b10 , NR c10 S(═O) 2 NR c10 R d10 , S(═O) 2 R b10 , or S(═O) 2 NR c10 R d10 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R a10 , R c10 and R d10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G groups;

each R b10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R G groups;

R X is selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1_6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a0 , SR a0 , C(═O)R b0 , C(═O)NR c0 R d0 , C(═O)OR a0 , OC(═O)R b0 , OC(═O)NR c0 R d0 , NR c0 R d0 , NR c0 C(═O)R b0 , NR c0 C(═O)OR b0 , NR c0 C(═O)NR c0 R d0 , C(═NR e )R b0 , C(═NR e )NR c0 R d0 , NR c0 C(═NR e )NR c0 R d0 , NR c0 S(═O) 2 R b0 , NR c0 S(═O) 2 NR c0 R d0 , S(═O) 2 R b0 , and S(═O) 2 NR c0 R d0 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R a0 , R c0 , and R d0 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G groups;

each R b0 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R G groups;

Ring moiety A is selected from C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R A groups;

Ring moiety B is selected from C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R B groups;

L is selected from —R—R—, —R—R—R—, -Cy-, —R-Cy-, -Cy-R—, —R-Cy-R—, —R—R-Cy-, -Cy-R—R—, and -Cy-R-Cy-;

each R is independently M, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 alkylene-M, M-C 1-6 alkylene, C 1-6 alkylene-M-C 1-6 alkylene, M-C 1-6 alkylene-M, C 2-6 alkenylene-M, M-C 2-6 alkenylene, C 2-6 alkenylene-M-C 2-6 alkenylene, M-C 2-6 alkenylene-M, C 2-6 alkynylene-M, M-C 2-6 alkynylene, C 2-6 alkynylene-M-C 2-6 alkynylene, or M-C 2-6 alkynylene-M, wherein each of said C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene is optionally substituted by 1, 2, 3, or 4 groups independently selected R G groups;

each Cy is independently selected from C 3-14 cycloalkyl, phenyl, 4-14 membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR L —, —C(O)O—, —OC(O)—, —OC(O)NR L —, —NR L —NR L C(O)—, —NR L C(O)O—, —NR L C(O)NR L —, —NR L S(O) 2 —, —S(O) 2 —, —S(O) 2 NR L —, or —NR L S(O) 2 NR L —; provided that when M is attached to a nitrogen atom, then M is selected from —C(O)—, —C(O)NR L —, —C(O)O—, —S(O) 2 —, or —S(O) 2 NR L —;

each R L is independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, and C 1-3 haloalkyl;

each R A is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a1 , SR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , OC(═O)R a1 , OC(═O)NR b1 R d1 , NR c1 R d1 , NR c1 C(═O)R b1 , NR c1 C(═O)OR b1 , NR c1 C(═O)NR c1 R d1 , C(═NR e )R b1 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )NR c1 R d1 , NR c1 S(═O) 2 R b2 , NR c1 S(═O) 2 NR c1 R d1 , S(═O) 2 R b1 , and S(═O) 2 NR c1 R d1 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R A1 groups;

each R B is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a2 , SR a2 , C(═O)R b2 , C(═O)NR c2 R d2 , C(═O)OR a2 , OC(═O)R b2 , OC(═O)NR c2 R d2 , NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , NR c2 C(═O)NR c2 R d2 , C(═NR e )R b2 , C(═NR e )NR c2 R d2 , NR c2 C(═NR e )NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(═O) 2 R b2 , and S(═O) 2 NR c2 R d2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R B1 groups;

each R a1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R A1 groups;

each R b1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R A1 groups;

each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R B1 groups;

each R b2 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R B1 groups;

each R A1 and R B1 is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a12 , SR a12 , C(═O)R b12 , C(═O)NR b12 R c12 , C(═O)OR a12 , OC(═O)R b12 , OC(═O)NR c12 R d12 , NR c12 R d12 , NR c12 C(═O)R b12 , NR c12 C(═O)OR b12 , NR c12 C(═O)NR c12 R d12 , C(═NR e )R b12 , C(═NR e )NR c12 R d12 , NR c12 C(═NR e )NR c12 R d12 , NR c12 S(═O) 2 R b12 , NR c12 S(═O) 2 NR c12 R d12 , S(═O) 2 R b12 , and S(═O) 2 NR c12 R d12 wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R a12 , R c12 ,and R d12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G groups;

each R b12 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R G groups;

R 3 is H, C 1-4 alkyl or C 1-4 haloalkyl;

R 4 is H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a4 , SR a4 , C(═O)R 4 , C(═O)NR c4 R d4 , C(═O)OR a4 , OC(═O)R 4 , OC(═O)NR c4 R d4 , NR c4 R d4 , NR 4 C(═O)R b4 , NR c4 C(═O)OR b4 , NR c4 C(═O)NR c4 R d4 , C(═NR e )R b4 , C(═NR e )NR c4 R d4 , NR c4 C(═NR e )NR c4 R d4 , NR c4 S(═O) 2 R b4 , NR c4 S(═O) 2 NR c4 R d4 , S(═O) 2 R b4 , or S(═O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4a groups;

R 5 is H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a5 , SR a5 , C(═O)R 5 , C(═O)NR c5 R d5 ,C(═O)OR a5 , OC(═O)R b5 , OC(═O)NR c5 R d5 , NR 5c R 5d , NR c5 C(═O)R b5 , NR c5 C(═O)OR b5 , NR c5 C(═O)NR c5 R d5 , C(═NR e )R b5 , C(═NR e )NR c5 R d5 NR c5 C(═NR e )NR c5 R d5 , NR c5 S(═O) 2 R b5 , NR c5 S(═O) 2 NR c5 R d5 , S(═O) 2 R b5 , or S(═O) 2 NR c5 R d5 ,wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 5a groups;

R 6 is H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a6 SR a6 , C(═O)R 6 , C(═O)NR c6 R d6 , C(═O)OR a6 , OC(═O)R b6 , OC(═O)NR c6 R d6 , NR c6 R d6 , NR c6 C(═O)R b6 , NR c6 C(═O)OR b6 , NR c6 C(═O)NR c6 R d6 , C(═NR e )R b6 , C(═NR e )NR c6 R d6 , NR 6 C(═NR e )NR c6 R d6 , NR c6 S(═O) 2 R b6 , NR 6 S(═O) 2 NR c6 R d6 , S(═O) 2 R b6 , or S(═O) 2 NR c6 R d6 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 6a groups;

R 7 is H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a7 , SR a7 , C(═O)R b7 , C(═O)NR c7 R d7 , C(═O)OR a7 , OC(═O)R a7 , OC(═O)NR c7 R d7 , NR c7 R d7 , NR c7 C(═O)R b7 , NR c7 C(═O)OR b7 , NR c7 C(═O)NR c7 R d7 , C(═NR e )R b7 , C(═NR e )NR c7 R d7 , NR c7 C(═NR e )NR c7 R d7 , NR c7 S(═O) 2 R b7 , NR c7 S(═O) 2 NR c7 R d7 , S(═O) 2 R b7 , or S(═O) 2 NR c7 R d7 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 7a groups;

each R a4 , R c4 , and R d4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4a groups;

each R b4 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 4a groups;

each R a5 , R c5 , and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4a groups;

each R b5 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 5a groups;

each R a6 , R c6 , and R d6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6a groups;

each R b6 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynylC 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 6a groups;

each R a7 , R c7 , and R d7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7a groups;

each R b7 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 7a groups;

each R 4a , R 5a , R 6a , and R 7a are independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a9 , SR a9 , C(═O)R 9 , C(═O)NR c9 R d9 , C(═O)OR a9 , OC(═O)R b9 , OC(═O)NR c9 R d9 , NR c9 R d9 , NR c9 C(═O)R b9 , NR c9 C(═O)OR b9 , NR b9 C(═O)NR c9 R d9 , C(═NR e )R b9 , C(═NR e )NR c9 R d9 , NR c9 C(═NR e )NR c9 R d9 , NR c9 S(═O) 2 R b9 , NR c9 S(═O) 2 NR c9 R d9 , S(═O) 2 R b9 , and S(═O) 2 NR c9 R d9 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 8 groups;

each R a9 , R c9 , and R d9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 37 cycloalkyl-C 14 alkyl, phenyl-C 14 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups;

each R b9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 11 groups;

each R 11 is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a11 SR a11 , C(═O)R b11 , C(═O)NR c11 R d11 , C(═O)OR a11 , OC(═O)R b11 , OC(═O)NR c11 R d11 , NR c11 R d11 , NR c11 C(═O)R b11 , NR c11 C(═O)OR b11 , NR c11 C(═O)NR c11 R d11 , C(═NR e )R b11 , C(═NR e )NR c11 R d11 , NR c11 C(═NR e )NR c11 R d11 , NR c11 S(═O) 2 R b11 , NR c11 S(═O) 2 NR c11 R d11 , S(═O) 2 R b11 , and S(═O) 2 NR c11 R d11 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R a11 , R c11 , and R d11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G groups;

each R b11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R G groups; and

each R G is independently selected from OH, NO 2 , CN, halo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonylamino, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino,

wherein each heteroaryl has 1-4 heteroatom ring members each independently selected from N, O, S and B; and

wherein each heterocycloalkyl has 1-4 heteroatom ring members each independently selected from N, O, S and B.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R U is H, halo, CN, C 1-6 alkyl, OR a , C(═O)R b , C(═O)NR c R d , S(═O) 2 R b , or S(═O) 2 NR c R d .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R W is H, halo, CN, C 1-6 alkyl, OR a , C(═O)R b , C(═O)NR c R d , S(═O) 2 R b , or S(═O) 2 NR c R d .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R a , R c , and R d is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;

each R b is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 8 groups; and

each R 8 is independently selected from OH, NO 2 , CN, halo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R V is H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C(═O)NR c R d , wherein R c and R d are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Q is H or OR a , wherein R a is selected from H, C 1-6 alkyl, and 4-7 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl is optionally OH or C 1-3 alkoxy.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R X is selected from H, D, halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R X is H or C 1-6 alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a4 , SR a4 , C(═O)R b4 , C(═O)NR c4 R d4 , C(═O)OR a4 , OC(═O)R b4 , OC(═O)NR c4 R d4 , NR c4 R d4 , NR c4 C(═O)R b4 , NR c4 C(═O)OR b4 , NR c4 C(═O)NR c4 R d4 , NR c4 S(═O) 2 R b4 , NR c4 S(═O) 2 NR c4 R d4 , S(═O) 2 R b4 , or S(═O) 2 NR c4 R d4 , wherein said C 1-6 alkyl C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4a groups.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R a4 , R c4 , and R d4 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 4a groups; and

each R b4 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 4a groups.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is 5 membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R A groups.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R A groups.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring moiety B is 5 membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R B groups.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring moiety B is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R B groups.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is selected from —R—R— and —R—R—R—.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R is independently C 1-6 alkylene or C 2-6 alkenylene.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —CH 2 —CH═CHCH 2 —.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R U is H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C(═O)NR c R d ;

R V is H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C(═O)NR c R d ;

R W is H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C(═O)NR c R d ;

R Q is H, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C(═O)NR c R d ;

each R c and R d is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

R X is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkyl;

R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl;

R 3 is H;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R A groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R B groups;

each R A is independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;

each R B is independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl; and

L 1 is —CH 2 —CH═CH—CH 2 —.

22. A compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R U , R V , and R W are each independently selected from H, D, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

R Q is selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, —C 1-6 alkylene-R 80 , —C 1-6 alkylene-R 90 , —C 1-6 alkylene-OR 80 , —C 1-6 alkylene-NHR 80 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a , OR f , SR a , C(═O)R b , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , NR c R d , NR c C(═O)R b , NR c C(═O)OR b , NR c C(═O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NRcC(═NR e )NR c R d , NRcS(═O) 2 R b , NR c S(═O) 2 NR c R d , S(═O) 2 R b , and S(═O) 2 NR c R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 8 groups;

R a , R c , and R d are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 8 groups;

R b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R 8 groups;

each R e is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy;

R f is selected from C 1-6 alkyl and C 1-6 haloalkyl, which are each optionally substituted with 1 substituent selected from R 80 , —OR 80 , R 90 , and —NHR 80 ;

each R a8 , R c8 , and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3 cycloalkyl-C 4 alkyl, phenyl-C 4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 10 groups;

each R a10 , R c10 ,and R d10 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G groups;

each R b10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 37 cycloalkyl-C 14 alkyl, phenyl-C 14 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R G groups;

R 80 is a linear peptide chain having 2-6 amino acids;

R 90 is a linear chain of formula —(O—C 2-4 alkylene) z -R G , wherein z is 1, 2, 3, 4, 5, or 6;

Y is N or CR Y ;

Z is N or CR Z ;

R X , R Y , and R Z are each independently selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl;

Ring moiety A is 5-membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R A groups;

Ring moiety B is 5-membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R B groups;

L 1 is selected from —R—R— and —R—R—R—;

provided that when M is attached to a nitrogen atom, then M is selected from —C(O)—, —C(O)NR L —, —C(O)O—, —S(O) 2 —, or —S(O) 2 NR L ;

each R L is independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, and C 1-3 haloalkyl;

each R A is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R B is independently selected from halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-4 cycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

R 5 , R 6 , and R 7 are each independently selected from H, D, OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

R 4 is H, D, halo, CN, NO 2 , C 1-6 alkyl, —C 1-6 alkylene-R 80 , —C 1-6 alkylene-R 90 , —C 1-6 alkylene-OR 80 , —C 1-6 alkylene-NHR 80 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a4 , OR f4 , SR a4 , C(═O)R b4 , C(═O)NR c4 R d4 , C(═O)OR a4 , OC(═O)R b4 , OC(═O)NR c4 R d4 , NR c4 R d4 , NR c4 C(═O)R b4 , NR c4 C(═O)OR b4 , NR c4 C(═O)NR c4 R d4 , C(═NR e )R b4 , C(═NR)NR c4 R d4 , NR c4 C(═NR e )NR c4 R d4 , NR c4 S(═O) 2 R c4 , NR c4 S(═O) 2 NR c4 R d4 , S(═O) 2 R b4 , or S(═O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4a groups;

R f4 is selected from C 1-6 alkyl and C 1-6 haloalkyl, which are each optionally substituted with 1 substituent selected from R 80 , R 90 , —OR 80 , and —NHR 80 ;

each R 4a is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a9 , SR a9 , C(═O)R b9 , C(═O)NR c9 R d9 , C(═O)OR a9 , OC(═O)R b9 , OC(═O)NR c9 R d9 , NR c9 R d9 , NR c9 C(═O)R b9 , NR c9 C(═O)OR b9 , NR c9 C(═O)NR c9 R d9 , C(═NR e )R b9 , C(═NR e )NR c9 R d9 , NR c9 C(═NR e )NR c9 R d9 , NR 9 S(═O) 2 R 9 , NR 9 S(═O) 2 NR c9 R d9 , S(═O) 2 R 9 , and S(═O) 2 NR c9 R d9 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 11 groups;

each R a9 , R c9 , and R d9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 groups;

R f4 is selected from C 1-6 alkyl and C 1-6 haloalkyl, which are each optionally substituted with 1 substituent selected from R 80 , —OR 80 , and —NHR 80 ;

each R 11 is independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a11 , SR a11 , C(═O)R b11 , C(═O)NR c11 R d11 , C(═O)OR a11 , OC(═O)R b11 , OC(═O)NR c11 R d11 , NR c11 R d11 , NR c11 C(═O)R b11 , NR c11 C(═O)ORl, NR c11 C(═O)NR c11 R d11 , C(═NR e )R b11 , C(═NR e )NR c11 R d11 NR c11 C(═NR e )NR c11 R d11 , NR c11 S(═O) 2 R b11 , NR c11 S(═O) 2 NR c11 R d11 , S(═O) 2 R b11 , and S(═O) 2 NR c11 R d11 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R G groups;

each R G is independently selected from H, D, OH, NO 2 , CN, halo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonylamino, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino,

wherein each heteroaryl has 1-4 heteroatom ring members each independently selected from N, O, S and B; and

wherein each heterocycloalkyl has 1-4 heteroatom ring members each independently selected from N, O, S and B.

23. The compound of claim 22 , wherein:

R Q is selected from H, C 1-6 alkyl, OR a , and OR f , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R 8 groups;

R a is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 4-7 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl and 4-7 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1 or 2 independently selected R 8 groups;

R f is C 1-6 alkyl which is substituted with 1 substituent selected from R 90 and —NHR 80 ;

each R 8 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a8 , C(═O)OR a8 , OC(═O)R b8 , OC(═O)NR c8 R d8 , NR c8 R d8 , NR c8 C(═O)R b8 , NHC(═O)NHR a8 , NR c8 S(═O) 2 R b8 , and NR c8 C(═O)OR b8 ;

each R a8 , R c8 , and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 10 groups;

each R b8 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 10 groups;

each R 10 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a10 , NR c10 R d10 , and C(═O)OR a10 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R G groups;

each R a10 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

R 80 is a linear peptide chain having 2-4 amino acids; and

R 90 is a linear chain of formula —(O—C 2-4 alkylene) z -R G , wherein z is 1, 2, 3, or 4.

24. The compound of claim 22 , wherein:

R 4 is selected from H, C 1-6 alkyl, OR a4 , and OR f4 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R 4a groups;

R a4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 4-7 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl and 4-7 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1 or 2 independently selected R 4a groups;

R f4 is C 1-6 alkyl which is substituted with 1 substituent selected from R 90 and —NHR 80 ;

each R 4a is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a9 , C(═O)OR a9 , OC(═O)R b9 , OC(═O)NR c9 R d9 , NR d9 R d9 , NR c9 C(═O)R b9 , NHC(═O)NHR d8 , NR c9 S(═O) 2 R b9 , and NR c9 C(═O)OR b9 ;

each R a9 , R c9 , and R d9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 11 groups;

each R b9 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 11 groups;

each R a11 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a11 , NR c11 R d11 , and C(═O)OR a11 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R G groups;

each R a11 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

each R c11 and R d11 independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

R 80 is a linear peptide chain having 2-4 amino acids; and

R 90 is a linear chain of formula —(O—C 2-4 alkylene) z -R G , wherein z is 1, 2, 3, or 4.

25. The compound of claim 22 , wherein:

R V is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, carbamyl, or C 1-4 alkylcarbamyl;

R U and R W are each independently selected from H, halo, CN, C 1-4 alkyl, and C 1-4 haloalkyl;

R Q is selected from H, C 1-6 alkyl, OR a , and OR f , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R 8 groups;

R f is C 1-6 alkyl which is substituted with 1 substituent selected from R 90 and —NHR 80 ; each R 8 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a8 , C(═O)OR a8 , OC(═O)R b8 , OC(═O)NR c8 R d8 , NR c8 R d8 , NR c8 C(═O)R b8 , NHC(═O)NHR d8 , NR c8 S(═O) 2 R b8 , and NR c8 C(═O)OR b8 ;

each R a10 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

R 80 is a linear peptide chain having 2-4 amino acids;

R 90 is a linear chain of formula —(O—C 2-4 alkylene) z -R G , wherein z is 1, 2, 3, or 4;

Y is N or CR Y ;

Z is N or CR Z ;

wherein at least one of Y or Z is N;

R X , R Y , and R Z are each independently selected from H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R A groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1, 2, or 3 independently selected R B groups;

L 1 is selected from —R—R— and —R—R—R—;

each R is independently C 1-3 alkylene or C 2-3 alkenylene;

each R A is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

each R B is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

R 4 is selected from H, C 1-6 alkyl, OR a4 , and OR f4 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R 4a groups;

R 6 is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, carbamyl, or C 1-4 alkylcarbamyl;

R 5 and R 7 are each independently selected from H, halo, CN, C 1-4 alkyl, and C 1-4 haloalkyl;

R f4 is C 1-6 alkyl which is substituted with 1 substituent selected from R 90 and —NHR 80 ;

each R 4a is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a9 , C(═O)OR a9 , OC(═O)R b9 , OC(═O)NR c9 R d9 , NR c9 R d9 , NR c9 C(═O)R b9 , NHC(═O)NHR d9 , NR c9 S(═O) 2 R b9 , and NR c9 C(═O)OR b9 ;

each R a11 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

each R c11 and R d11 independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

26. The compound of claim 22 , wherein:

R V is H or carbamyl;

R U and R W are each independently selected from H, halo, CN, and C 1-3 alkyl;

R Q is selected from H, C 1-6 alkyl, OR a , and OR f ;

each R 8 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a8 , C(═O)OR a8 ; OC(═O)R b8 , OC(═O)NR c8 R d8 , NR c8 R d8 , NR c8 C(═O)R b8 , NHC(═O)NHR d8 , NR c8 S(═O) 2 R 8 , and NR c8 C(═O)OR b8 ;

each R a8 , R c8 , and R d8 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R 10 groups;

each R b8 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 5-membered heteroaryl, wherein said C 1-6 alkyl and 5-membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 10 groups;

each R a10 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

Y is N or CR Y ;

Z is N or CR Z ;

wherein at least one of Y or Z is N;

R X , R Y , and R Z are each independently selected from H, halo, CN, C 1-3 alkyl, and C 1-3 haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1 or 2 independently selected R A groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1 or 2 independently selected R B groups;

L is C 3-6 alkenylene;

each R A is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

each R B is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

R 4 is selected from H, C 1-6 alkyl, OR a4 , and OR f4 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R 4a groups;

R 6 is H or carbamyl;

R 5 and R 7 are each independently selected from H, halo, CN, and C 1-3 alkyl;

R f4 is C 1-6 alkyl which is substituted with 1 substituent selected from R 90 and —NHR 80 ;

each R 4a is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a9 , OC(═O)R 9 , OC(═O)NR c9 R d9 , NR c9 R d9 , NR c9 C(═O)R b9 , NHC(═O)NHR d9 , NR c9 S(═O) 2 R c9 , and NR b9 C(═O)OR b9 ;

R 80 is a linear peptide chain having 2-4 amino acids;

R 90 is a linear chain of formula —(O—C 2-4 alkylene) z -R G , wherein z is 1, 2, 3, or 4;

each R a9 , R c9 , and R d9 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R 11 groups;

each R is independently C 1-6 alkyl, which is optionally substituted with 1 or 2 independently selected R 11 groups;

each R 11 is independently selected from H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a11 , NR c11 R d11 , and C(═O)OR a11 , wherein said C 1-6 alkyl is optionally substituted by 1 or 2 independently selected R G groups;

each R a11 is independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups;

each R c11 and R d11 independently selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1 or 2 independently selected R G groups; and

each R G is independently selected from H, OH, CN, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, and carboxy.

27. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is a pyrazole ring, which is optionally substituted by 1 or 2 independently selected R A groups; Ring moiety B is a pyrazole ring, which is optionally substituted by 1 or 2 independently selected R B groups; each R A and R B is independently selected from C 1-4 alkyl; and L 1 is —CH 2 —CH═CH—CH 2 —.

28. The compound of claim 1 , selected from:

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , selected from:

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;

(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide; and

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 22 , selected from:

(E)-9-(4-(5-carbamoyl-7-(3-cyanopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(4-methylpiperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoic acid;

(E)-2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(6S,9S,12S,15S)-15-amino-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-6,9-bis(carboxymethyl)-12-(3-guanidinopropyl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-17-oic acid;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;

(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoic acid;

(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)acetic acid;

(E)-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)glycine;

(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoic acid;

(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoic acid;

(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoic acid;

(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoic acid;

(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoic acid;

(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoic acid;

(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoic acid;

(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoic acid;

(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoic acid;

(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoic acid;

(E)-3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoic acid;

(E)-3-(2-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)ethoxy)propanoic acid;

(E)-4-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidin-1-yl)butanoic acid;

(E)-2-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidine-1-carbonyloxy)acetic acid;

(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoic acid;

(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-8-(2-(2-(2-carboxyethoxy)ethoxy)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoic acid; and

(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoic acid;

or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising the compound of claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. The compound of claim 22 , selected from:

(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide;

(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide;

(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5H-pyrido[4,3-b]indole-8-carboxamide;

(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

34. A compound of claim 22 , which has the following formula:

or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising the compound of claim 34 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 17, 2019

From: WU, LIANGXING; LAJKIEWICZ, NEIL; YE, YINGDA; LI, ZHENWU; YAO, WENQING

To: INCYTE CORPORATION

Reel/Frame 050747/0985 →

Continuity (4)

Provisional Application 62841587 · May 1, 2019

Provisional Application 62730610 · Sep 13, 2018

Provisional Application 62676810 · May 25, 2018

Related Publication 20190359608A1 · Nov 28, 2019