IP Library › Granted Patent US 11,767,323
Granted Patent B2
US 11,767,323 · App. 17/365,686 · Granted Sep 26, 2023

Tricyclic pyridone compounds as JAK2 V617F inhibitors

Inventors: Kai Liu (Chadds Ford, PA); Onur Atasoylu (Wilmington, DE); Yu Bai (Claymont, DE); Andrew W. Buesking (Wilmington, DE); Leah C. Konkol (Newark, DE); Cheng-Tsung Lai (Wilmington, DE); Song Mei (Wilmington, DE); Jun Pan (Media, PA); Liangxing Wu (Wilmington, DE); Wenqing Yao (Chadds Ford, PA)
Assignee: Incyte Corporation
C07D471/14C07D519/00
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Quick Facts
Patent No.
US 11,767,323
App. No.
17/365,686
Granted
Sep 26, 2023
Kind
B2
Abstract

The present application provides tricyclic pyridone compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.

Claims (198)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

R 2 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a2 , SR a2 , NHOR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)NR 2 (OR a2 ), C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR e2 C(═NR e2 )R b2 , NR c2 S(O)R b2 , NR c2 S(O)NR c2 R d2 , NR e2 S(O) 2 R b2 , NR c2 S(O)(═NR e2 )R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , S(O) 2 NR c2 R d2 , OS(O)(═NR e2 )R b2 , and OS(O) 2 R b2 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2A substituents;

each R a2 , R e2 , and R d21 s independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a2 , R c2 and R d2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2A substituents;

or, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;

each R b2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2A substituents;

each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 2A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a21 , SR a21 , NHOR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)NR c21 (OR a21 ) C(O)OR a21 , OC(O)R b21 , OC(O)NR c21 R d21 , NR c21 R d21 , NR c21 R d21 , NR e21 C(O)R b21 , NR 21 C(O)OR a21 NR c21 C(O)NR c21 R d21 , C(═NR e21 )R b21 , C(═NR e21 )NR c21 R d21 , NR c21 C(═NR e21 )NR c21 R d21 , NR c21 C(═NR e21 )R b21 , NR c21 S(O)R b21 , NR c21 S(O)NR c21 R d21 , NR c21 S(O) 2 R b21 , NR c21 S(O)(═NR e21 )R b21 , NR c21 S(O) 2 NR e21 R d21 , S(O)R b21 , S(O)NR c21 R d21 , S(O) 2 R b21 , S(O) 2 NR c2 R d21 , OS(O)(═NR e21 )R b21 , and OS(O) 2 R b21 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2B substituents;

each R a21 , R c21 , and R d21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a21 , R c21 and R d21 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2B substituents;

or, any R c21 and R d21 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 2B substituents;

each R b21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b21 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2B substituents;

each R e21 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 2B is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a22 , SR a22 , NHOR a22 , C(O)R b22 , C(O)NR c22 R d22 , C(O)NR c22 (OR a22 ), C(O)OR a22 , OC(O)R b22 , OC(O)NR c22 R d22 , NR c22 R d22 , NR c22 NR d22 , NR c22 C(O)R b22 , NR c22 C(O)OR a22 , NR c22 C(O)NR c22 R d22 , C(═NR e22 )R b22 , C(═NR e22 )NR c22 R d2 , NR 22 C(═NR e22 )NR c22 R d22 , NR c22 C(═NR e22 )R b22 , NR c22 S(O)R b22 , NR c22 S(O)NR c22 R d22 , NR c22 S(O) 2 R b22 , NR c22 S(O)(═NR e22 )R b22 , NR c22 S(O) 2 NR c22 R d22 , S(O)R b22 , S(O)NR c22 R d22 , S(O) 2 R b22 , S(O) 2 NR c22 R d22 , OS(O)(═NR e22 )R b22 , and OS(O) 2 R b22 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2B are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2C substituents;

each R a22 , R c22 , and R d22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a22 , R c22 and R d22 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2C substituents;

or, any R c22 and R d22 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 2C substituents;

each R b22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b22 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2C substituents;

each R e22 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 2C is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a23 , SR a23 , NHOR a23 , C(O)R b23 , C(O)NR c23 R d23 , C(O)NR 23 (OR a23 ), C(O)OR a23 , OC(O)R b23 , OC(O)NR c23 R d23 , NR c23 R d23 , NR c23 NR c23 R d23 , NR c23 C(O)R b23 , NR c23 C(O)OR a23 , NR c23 C(O)NR c23 R 23 , C(═NR e23 )R b23 , C(═NR e23 )R 23 R d23 , NR c23 C(═NR e23 )NR c23 R d23 , NR c23 C(═NR e23 )R b23 , NR c23 S(O)R b23 , NR c23 S(O)NR c23 R 23 , NR e23 S(O) 2 R b23 , NR e23 S(O)(═NR e23 )R b23 , NR c23 S(O) 2 NR c23 R d23 , S(O)R b23 , S(O)NR c23 R d23 , S(O) 2 R b23 , S(O) 2 NR c23 R d23 , OS(O)(═NR e23 )R b23 , and OS(O) 2 R b23 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R 2C are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a23 , R c23 , and R d23 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R a23 , R e23 and R d23 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c23 and R d23 attached to the same N atom, together with the N atom to which they are attached, form a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b23 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R b23 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R e23 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

R 3 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a3 , SR a3 , NHOR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)NR c3 (OR a3 ), C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(═NR e3 )R b3 , C(═NR e3 )NR c3 R d3 , NR c3 C(NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )R b3 , NR c3 S(O)R b3 , NR c3 S(O)NR c3 R d3 , NR c3 S(O) 2 R b3 , NR c3 S(O)(═NR e3 )R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , S(O) 2 NR c3 R d3 , OS(O)(═NR e3 )R b3 , and OS(O) 2 R b3 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3A substituents;

each R a3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a3 , R c3 and R d3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3A substituents;

or, any R c3 and R d3 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 3A substituents;

each R b3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3A substituents;

each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 3A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a31 , SR a31 , NHOR a31 , C(O)R b31 , C(O)NR c31 R d31 , C(O)NR c31 (OR a31 ), C(O)OR a31 , OC(O)R b31 , OC(O)NR c31 R d31 , NR b31 R d31 , NR c3 NR c31 R d31 , NR c31 C(O)R b31 , NR c31 C(O)OR a31 , NR c31 C(O)NR c31 R d31 , C(═NR e31 )R b31 , C(═NR e31 )NR c31 R d31 , NR c31 C(═NR e31 NR c31 R d31 , NR c31 C(═NR e31 )R b31 , NR c31 S(O)R b31 , NR c31 S(O)NR b31 R d31 , NR c31 S(O) 2 R b31 , NR c31 S(O)(═NR e31 )R b31 NR c31 S(O) 2 NR c31 R d31 , S(O)R b31 , S(O)NR c31 R d31 , S(O) 2 R b31 , S(O) 2 NR c31 R d31 , OS(O)(═NR e31 )R b31 , and OS(O) 2 R b31 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 3A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3B substituents;

each R a31 , R c31 , and R d31 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a3 , R c31 and R d31 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3B substituents;

or, any R c31 and R d31 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 3B substituents;

each R b31 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b31 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3B substituents;

each R e31 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 3B is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a32 , SR a32 , NHOR a32 C(O)R b32 , C(O)NR c32 R d32 , C(O)NR 32 (OR a32 ), C(O)OR a32 , OC(O)R b32 , OC(O)NR c32 R d32 NR c32 R d32 , NR c32 NR c32 R d32 , NR b32 C(O)R b32 , NR 62 C(O)OR a32 , NR 32 C(O)NR c32 R d32 , C(═NR e32 )R b32 , C(═NR e32 )NR c32 R d32 , NR c32 C(═NR e32 NR c32 R d32 , NR e32 C(═NR e32 )R b32 , NR e32 S(O)R b32 , NR e32 S(O)NR e32 R d32 , NR e32 S(O) 2 R b32 , NR c32 S(O)(═NR e32 )R b32 , NR c32 S(O) 2 NR c32 R d32 , S(O)R b32 , S(O)NR c32 R d32 , S(O) 2 R b32 , S(O) 2 NR e32 R d32 , OS(O)(═NR e32 )R b32 , and OS(O) 2 R b32 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 3B are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3C substituents;

each R a32 , R 32 , and R d32 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a32 , R c32 and R d32 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3C substituents;

or, any R c32 and R d32 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 3C substituents;

each R b32 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b32 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3C substituents;

each R e32 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 3C is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a33 , SR a33 , NHOR a33 , C(O)R b33 , C(O)NR c33 R d33 , C(O)NR c33 (OR a33 ), C(O)OR a33 , OC(O)R b33 , OC(O)NR c33 R d33 , NR c33 R d33 , NR c33 NR c33 R d33 , NR c33 C(O)R b33 , NR c33 C(O)OR a33 , NR c33 C(O)NR c33 R d33 , C(═NR e33 )R b33 , C(═NR e33 )NR c33 R d33 , NR c33 C(═NR e33 )NR c33 R d33 , NR b33 C(═NR e33 )R b33 , NR c33 S(O)R b33 , NR c33 S(O)NR b33 R d33 , NR c33 S(O) 2 R b33 , NR c33 S(O)(═NR e33 )R b33 , NR c33 S(O) 2 NR c33 R d33 , S(O)R b33 , S(O)NR c33 R d33 , S(O) 2 R b33 , S(O) 2 NR c33 R d33 , OS(O)(═NR e33 )R b33 , and OS(O) 2 R b33 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R 3C are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a33 , R c33 , and R d33 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R a33 , R c33 and R d33 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c33 and R d33 attached to the same N atom, together with the N atom to which they are attached, form a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b33 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R b33 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R e33 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

R 4 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(═NR e4 )R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )R b4 , NR c4 S(O)R b4 , NR c4 S(O)NR c4 R d4 , NR c4 S(O) 2 R b4 , NR c4 S(O)(═NR e4 )R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , S(O) 2 NR c4 R d4 , OS(O)(═NR e4 )R b4 , and OS(O) 2 R b4 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4A substituents;

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 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a4 , R c4 and R d4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4A substituents;

or, any R c4 and R d4 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 4A substituents;

each R b4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4A substituents;

each R e4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 4A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)NR c41 (OR a41 ), C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 , NR c41 NR c41 R d41 , NR c41 C(O)R b41 , NR c41 C(O)OR a41 , NR c41 C(O)NR c41 R d41 , C(═NR e41 )R b41 , C(═NR e41 )NR c41 R d41 , NR c41 C(═NR e41 )NR c41 R d41 , NR c41 C(═NR e41 )R b41 , NR c41 S(O)R b41 , NR c41 S(O)NR c4 R d41 , NR c41 S(O) 2 R 41 , NR c41 S(O)(═NR e41 )R 41 , NR c41 S(O) 2 NR c41 R d41 , S(O)R b41 , S(O)NR c41 R d41 , S(O) 2 R b41 , S(O) 2 NR c41 R d41 , OS(O)(═NR e 41)R 41 , and OS(O) 2 R b41 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 4A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4B substituents;

each R a41 , R c41 , and R d41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a41 , R c41 and R d41 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4B substituents;

or, any R c41 and R d41 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents;

each R b41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b41 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4B substituents;

each R e41 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 4B is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a42 , SR a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)NR c42 (OR a42 ), C(O)OR a42 , OC(O)R b42 , OC(O)NR c42 R d42 , NR c42 R d42 , NR c42 NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , C(═NR e42 )R b42 , C(═NR e42 )NR c42 R d42 , NR 42 C(═NR e42 )NR c42 R d42 , NR c42 C(═NR e42 )R b42 , NR c42 S(O)R b42 , NR c42 S(O)NR e42 R d42 , NR c42 S(O) 2 R b42 , NR c42 S(O)(═NR e42 )R b42 , NR c42 S(O) 2 NR c42 R d42 , S(O)R b42 , S(O)NR c42 R d42 , S(O) 2 R b42 , S(O) 2 NR c42 R d42 , OS(O)(═NR e42 )R b42 , and OS(O) 2 R b42 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 4B are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4C substituents;

each R a42 , R 42 , and R d42 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a42 , R c42 and R a42 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4C substituents;

or, any R c42 and R d42 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 4C substituents;

each R b42 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b42 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4C substituents;

each R e42 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 4C is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a43 , SR a43 , NHOR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)NR c43 (OR a43 ), C(O)OR a43 , OC(O)R b43 , OC(O)NR c43 R d43 , NR c43 R d43 NR c43 NR c43 R d43 , NR c43 C(O)R b43 , NR c43 C(O)OR a43 , NR c43 C(O)NR c43 R d43 , C(═NR e43 )R b43 , C(═NR e43 )NR c43 R d43 , NR c43 C(═NR e43 )NR c43 R d43 , NR c43 C(═NR e43 )R b43 , NR c43 S(O)R b43 , NR c43 S(O)NR c43 R d43 , NR c43 S(O) 2 R b43 , NR c43 S(O)(═NR e43 )R b43 , NR c43 S(O) 2 NR c43 R d43 , S(O)R b43 , S(O)NR c43 R d43 , S(O) 2 R b43 , S(O) 2 NR c43 R d43 , OS(O)(═NR e43 )R b43 , and OS(O) 2 R b43 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R 4C are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a43 , R c43 , and R d43 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R a43 , R c43 and R d43 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c43 and R d43 attached to the same N atom, together with the N atom to which they are attached, form a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b43 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R 43 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R e43 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

R 5 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents;

each R 5A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a51 , SR a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)NR c51 (OR a51 ), C(O)OR a51 , OC(O)R b51 , OC(O)NR c51 R d51 , NR c51 R d51 , NR c51 NR c51 R d51 , NR c51 C(O)R b51 , NR c51 C(O)OR a51 , NR c51 C(O)NR c51 R d51 , C(═NR e51 )R b51 , C(═NR e51 )NR c51 R d51 , NR c51 C(═NR e51 )NR c51 R d51 , NR c51 C(═NR e51 )R b51 , NR c51 S(O)R b51 , NR c51 S(O)NR c51 R d51 , NR c51 S(O) 2 R b51 , NR c51 S(O)(═NR e51 )R b51 , NR c51 S(O) 2 NR c51 R d51 , S(O)R b51 , S(O)NR c51 R d51 , S(O) 2 R b51 , S(O) 2 NR c51 R d51 , OS(O)(═NR e51 )R b51 , and OS(O) 2 R b51 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5B substituents;

each R a51 , R c51 , and R d51 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a51 , R c51 and R d51 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5B substituents;

or, any R c51 and R d51 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents;

each R b51 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b51 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5B substituents;

each R e51 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 5B is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a52 , SR a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)NR c52 (OR a52 ), C(O)OR a52 , OC(O)R b52 , OC(O)NR c52 R d52 , NR c52 R d52 NR c52 NR c52 R d52 NR c52 C(O)R b52 , NR c52 C(O)OR a52 , NR c52 C(O)NR c52 R d52 , C(═NR e52 )R b52 , C(═NR e52 )NR c52 R d52 , NR c52 C(═NR e52 )NR c52 R d52 NR c52 C(═NR e52 )R b52 , NR c52 S(O)R b52 , NR c52 S(O)NR c52 R d52 , NR c52 S(O) 2 R b52 , NR c52 S(O)(═NR e52 )R b52 , NR c52 S(O) 2 NR c52 R d52 , S(O)R b52 , S(O)NR c52 R d52 , S(O) 2 R b52 , S(O) 2 NR c52 R d52 , OS(O)(═NR e52 )R b52 , and OS(O) 2 R b52 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5B are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5C substituents;

each R a52 , R c52 , and R d52 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a52 , R c52 and R d52 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5C substituents;

or, any R e52 and R d52 attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R 5C substituents;

each R b52 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R b52 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5C substituents;

each R e52 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

each R 5C is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a53 , SR a53 , NHOR a53 , C(O)R b53 , C(O)NR c53 R d53 , C(O)NR c53 (OR a53 ), C(O)OR a53 , OC(O)R b53 , OC(O)NR c53 R d53 , NR c53 R d53 , NR c53 NR c53 R d53 , NR c53 C(O)R b53 , NR c53 C(O)OR a53 , NR c53 C(O)NR c53 R d53 , C(═NR e53 )R b53 , C(═NR e53 )NR c53 R d53 , NR c53 C(═NR e53 NR c53 R d53 , NR c53 C(═NR e53 )R b53 , NR c53 S(O)R b53 , NR c53 S(O)NR c53 R d53 , NR c53 S(O) 2 R b53 , NR c53 S(O)(═NR e53 )R 53 , NR c53 S(O) 2 NR c53 R d53 , S(O)R b53 , S(O)NR c53 R d53 , S(O) 2 R b53 , S(O) 2 NR c53 R d53 , OS(O)(═NR e53 )R b53 , and OS(O) 2 R b53 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R 5C are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a53 , R c53 , and R d53 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R a53 , R c53 and R d53 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c53 and R d53 attached to the same N atom, together with the N atom to which they are attached, form a 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b53 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R b53 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R e53 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; and

each R M is independently selected from H, OH, halo, oxo, CN, C(O)OH, NH 2 , NO 2 , SF 5 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H and C 1-6 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, methyl, and ethyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, halo, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and NR c2 R d2 , wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 8-10 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (8-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, C(O)NR c2 R d2 , and NR c2 R d2 , wherein the phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, 8-10 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (8-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, phenyl, pyrrolidinyl, piperidinyl, benzodioxolyl, dihydrobenzodioxinyl, pyrazolyl, tetrazolyl, oxa-azaspiro[4.5]decanyl, isoxazolyl, pyridinyl, CN, C(O)NR c2 R d2 , and NR c2 R d2 , wherein the phenyl, pyrrolidinyl, piperidinyl, benzodioxolyl, dihydrobenzodioxinyl, oxa-azaspiro[4.5]decanyl, isoxazolyl, and pyridinyl of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a21 , C(O)R b21 , C(O)NR c21 R d21 , C(O)OR a21 , and S(O) 2 R b21 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2A are each optionally substituted with 1, 2, 3, or 4 independently selected R 2B substituents.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, CN, NO 2 , OR a1 , C(O)R b21 , C(O)OR a21 , and S(O) 2 R b21 , wherein the C 1-6 alkyl and 5-6 membered heteroaryl of R 2A are each optionally substituted with 1, 2, 3, or 4 independently selected R 2B substituents, wherein each R a21 and R b21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and wherein the C 1-6 alkyl of R a1 and R b21 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 2B substituents.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2A is independently selected from chloro, fluoro, methyl, trifluoromethyl, methoxy, cyanomethyl, pyrazolyl, tetrazolyl, tetrazolylmethyl, CN, NO 2 , C(O)CH 3 , C(O)OH, methylsulfonyl, and methoxyethylsulfonyl, wherein the pyrazolyl and tetrazolyl of R 2A are each optionally substituted with 1 or 2 independently selected C 1-6 alkyl substituents.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, phenyl, benzodioxolyl, dihydrobenzodioxinyl, and CN, wherein the phenyl, benzodioxolyl, and dihydrobenzodioxinyl of R 2 are each optionally substituted with 1, 2, 3, or 4 R 2A substituents independently selected from chloro, fluoro, methyl, trifluoromethyl, methoxy, pyrazolyl, tetrazolyl, CN, NO 2 , and C(O)OH, wherein the pyrazolyl and tetrazolyl of R 2A are each optionally substituted with 1 or 2 independently selected C 1-6 alkyl substituents.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and OR a3 , wherein the C 6-10 aryl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl of R 3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 3A substituents.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, methyl, ethyl, methoxy, phenyl, cyclohexyl, pyrrolidino, and tetrahydropyranyl, wherein the phenyl, cyclohexyl, and pyrrolidino of R 3 are each optionally substituted with 1, 2, 3, or 4 independently selected R 3A substituents.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, methyl, ethyl, and methoxy.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and 5-10 membered heteroaryl of R 4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 4A substituents.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, C 1-6 alkyl, phenyl, and indazolyl, wherein the phenyl and indazolyl of R 4 are each optionally substituted with methyl, methoxy, cyanocyclopropyl, or C(O)N(CH 3 ) 2 .

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from phenyl and pyrazolyl, wherein the phenyl and pyrazolyl of R 5 are each optionally substituted by 1 or 2 independently selected R 5A substituents.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5A is independently selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5A are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5A is independently selected from phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-6 alkyl- of R SA are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R SA is piperidinylmethyl, which is optionally substituted by 1 or 2 independently selected R 5B groups.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5B is independently selected from C(O)R b52 , C(O)NR e52 R d52 , C(O)OR a52 , NR c52 S(O)R b52 , NR c52 S(O) 2 R b52 , S(O)R b52 , S(O)NR e52 R d52 , S(O) 2 R b52 , and S(O) 2 NR e52 R d52 .

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R a52 , R b52 , R c52 , and R d52 is independently selected from H and C 1-6 alkyl.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5B is S(O) 2 R b52 , wherein each R b52 is independently selected from H and C 1-6 alkyl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5B is methylsulfonyl.

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from pyrazolyl and phenyl, wherein the pyrazolyl and phenyl are each optionally substituted by methyl or piperidinylmethyl, wherein the piperidinylmethyl is optionally substituted by methylsulfonyl.

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

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 2 is selected from H, halo, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a , wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;

each R a2 , R b2 , R c3 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a1 , C(O)R b21 , C(O)NR c21 R d21 , and C(O)OR a21 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2A are each optionally substituted with 1, 2, 3, or 4 independently selected R 2B substituents;

each R a21 , R b21 , R e21 , and R d21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R 2B is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and OR a3 ;

R a3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 5 is selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents;

each R 5A is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 5A are each optionally substituted with 1, 2, 3, or 4 independently selected R 5B substituents;

each R 5B is independently selected from C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 , NR c52 S(O)R b52 , NR c52 S(O) 2 R b52 , S(O)R b52 , S(O)NR e52 R d52 , S(O) 2 R b52 , and S(O) 2 NR e52 R d52 ; and

each R a52 , R b52 , R c52 , and R d52 is independently selected from H and C 1-6 alkyl.

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

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 2 is selected from H, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 8-10 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, (8-10 membered heterocycloalkyl)-C 1-6 alkyl-, and CN, wherein the phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 8-10 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (8-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;

each R 2A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, CN, NO 2 , OR a21 , and C(O)OR a21 , wherein the C 1-6 alkyl and 5-6 membered heteroaryl of R 2A are each optionally substituted with 1, 2, 3, or 4 independently selected R 2B substituents;

each R a21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and OR a3 ;

R a3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 5 is selected from phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, wherein the phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents;

each R 5A is independently selected from phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the phenyl-C 1-6 alkyl-, C 3-6 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-6 membered heterocycloalkyl)-C 1-6 alkyl- of R 5A are each optionally substituted with 1, 2, 3, or 4 independently selected R 51 substituents;

each R 5B is independently selected from S(O)R b52 and S(O) 2 R b52 ; and

each R b52 is independently selected from H and C 1-6 alkyl.

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

R 1 is selected from H and C 1-6 alkyl;

R 2 is selected from H, phenyl, benzodioxolyl, dihydrobenzodioxinyl, and CN, wherein the phenyl, benzodioxolyl, and dihydrobenzodioxinyl of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;

R 2A is independently selected from chloro, fluoro, methyl, trifluoromethyl, methoxy, pyrazolyl, tetrazolyl, CN, NO 2 , and C(O)OH, wherein the pyrazolyl and tetrazolyl of R 2A are each optionally substituted with 1 or 2 independently selected C 1-6 alkyl substituents;

R 3 is selected from H, C 1-6 alkyl, and C 1-6 alkoxy;

R 4 is selected from H and C 1-6 alkyl;

R 5 is phenyl, which is optionally substituted by piperidinylmethyl, wherein the piperidinylmethyl is optionally substituted by S(O) 2 R b52 ; and

each R b52 is independently selected from H and C 1-6 alkyl.

31. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4.

33. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, or 4; and

m is 0, 1 or 2.

34. The compound of claim 1 , which is selected from:

2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-phenyl-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridine-8-carbonitrile;

8-(1-methyl-1H-pyrazol-5-yl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-(1H-tetrazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(9-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

8-(4-(1H-tetrazol-1-yl)phenyl)-9-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-(p-tolyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

8-(4-chlorophenyl)-6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

8-(3-chlorophenyl)-6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

8-(4-methoxyphenyl)-6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(6,9-dimethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzonitrile;

4-(6-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

4-(6-ethyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

4-(9-ethyl-6-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-8-yl)benzoic acid;

9-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-(4-nitrophenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

8-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-9-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one; and

9-methoxy-6-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-phenyl-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , which is selected from:

6-Methyl-8-(3-methylisoxazol-5-yl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-9-(tetrahydro-2H-pyran-4-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-(4-Methoxycyclohexyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-9-phenyl-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-(4-methoxycyclohexyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

N-(2-hydroxyethyl)-4-(6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-9-yl)benzamide;

4-(6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-9-yl)-N-(2-methylbenzo[d]oxazol-5-yl)benzamide;

9-(4-(Methoxymethyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-9-(4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-(4-((2-Methoxyethyl)(methyl)amino)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-9-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-(4-(1,5-Dimethyl-1H-pyrazol-4-yl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

9-(4-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

6-Methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(3-methylisoxazol-5-yl)-9-(1-(methylsulfonyl)pyrrolidin-3-yl)-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(8-((3-(1H-tetrazol-5-yl)phenyl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)-N,N-dimethylbenzamide;

4-(8-((4-((1H-tetrazol-5-yl)methyl)phenyl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)-N,N-dimethylbenzamide;

N,N-dimethyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(4-methylpyridin-3-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)benzamide;

(R)-8-(1-acetylpyrrolidin-3-yl)-6-methyl-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-phenyl-3,6-dihydro-7H-pyrrolo[3,2-f][1,7]naphthyridin-7-one;

4-(8-((4-(cyanomethyl)cyclohexyl)amino)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)-N,N-dimethylbenzamide;

N,N-dimethyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8-(4-(methylsulfonyl)piperidin-1-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)benzamide;

4-(8-(4-((2-Methoxyethyl)sulfonyl)piperidin-1-yl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)-N,N-dimethylbenzamide;

N,N-dimethyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-8-(2-oxa-8-azaspiro[4.5]decan-8-yl)-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridin-1-yl)benzamide;

1-(4-Methoxyphenyl)-N,N,6-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridine-8-carboxamide;

N,N,6-trimethyl-1-(1-methyl-1H-indazol-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridine-8-carboxamide; and

1-(4-(1-cyanocyclopropyl)phenyl)-N,N,6-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-3H-pyrrolo[3,2-f][1,7]naphthyridine-8-carboxamide;

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is deuterated.

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

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 14, 2022
From: LIU, KAI; ATASOYLU, ONUR; BAI, YU; BUESKING, ANDREW W.; KONKOL, LEAH C.; LAI, CHENG-TSUNG; MEI, SONG; PAN, JUN; WU, LIANGXING; YAO, WENQING
To: INCYTE CORPORATION
Reel/Frame 059251/0643 →
Continuity (2)
Provisional Application 63047509 · Jul 2, 2020
Related Publication 20220002299A1 · Jan 6, 2022
Cited By (1)
US 12,187,725