IP Library › Granted Patent US 12,600,723

Granted Patent B2

US 12,600,723 · App. 18/222,688 · Granted Apr 14, 2026

Tetracyclic compounds as DGK inhibitors

Inventors: Joshua Hummel (Hockessin, DE); Shicheng Shi (Princeton, NJ); Xiaozhao Wang (Moorestown, NJ)

Assignee: Incyte Corporation

C07D471/22 C07B2200/05

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Quick Facts

Patent No.: US 12,600,723
App. No.: 18/222,688
Granted: Apr 14, 2026
Kind: B2

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Abstract

The present application provides tetracyclic compounds that modulate the activity of diacylglycerol kinase (DGK), which are useful in the treatment of various diseases, including cancer.

Claims (239)

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is a single or double bond;

W is CR 7 , C(O), N, or NR 7 ;

X is CR 8 , C(O), N, or NR 8 ;

Y is CR 9 or N;

Z is CR 10 or N;

wherein no more than 2 of W, X, Y, and Z can be N or a substituted N;

n is 0, 1, or 2;

each R 2 is independently selected from halo, 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, CN, NO 2 , OR a2 , NHOR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)NR c2 (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 c2 C(═NR e2 )R b2 , NR c2 S(O)R b2 , NR c2 S(O)NR c2 R d2 , NR c2 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, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

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, 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-;

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 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group;

each R b2 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-;

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

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

R 7 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 a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)NR c7 (OR a7 ), C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C(═NR e7 )R b7 , C(═NR e7 )NR c7 R d7 , C(═NOR a7 )R b7 , C(═NOR a7 )OR a7 , NR c7 C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )R b7 , NR c7 S(O)R b7 , NR c7 S(O)NR c7 R d7 , NR c7 S(O) 2 R b7 , NR c7 S(O)(═NR e7 )R b7 , NR c7 S(O) 2 NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 S(O) 2 NR c7 R d7 , OS(O)(═NR e7 )R b7 , and OS(O) 2 R b7 , 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 7 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 7A substituents;

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 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 a7 , R c7 and R d7 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 7A substituents;

or, any R c7 and R d7 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 7A substituents;

each R b7 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 b7 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 7A substituents;

each R e7 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 7A 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 a71 , SR a71 , NHOR a71 ,C(O)R b71 , C(O)NR c71 R d71 , C(O)NR c71 (OR a71 ), C(O)OR a71 , OC(O)R b71 , OC(O)NR c71 R d71 , NR c71 R d71 , NR c71 NR c71 R d71 , NR c71 C(O)R b71 , NR c71 C(O)OR a71 , NR c71 C(O)NR c71 R d71 , C(═NR e71 )R b71 , C(═NR e71 )NR c71 R d71 , C(═NOR a71 )R b71 , C(═NOR a71 )OR a71 , NR c71 C(═NR e71 )NR c71 R d71 , NR c71 C(═NR e71 )R b71 , NR c71 S(O)R b71 , NR c71 S(O)NR c71 R d71 , NR c71 S(O) 2 R b71 , NR c71 S(O)(═NR e71 )R b71 , NR c71 S(O) 2 NR e71 R d71 , S(O)R b71 , S(O)NR c71 R d71 , S(O) 2 R b71 , S(O) 2 NR c71 R d71 , OS(O)(═NR e71 )R b71 , and OS(O) 2 R b71 , 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 7A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R a71 , R c71 , and R d71 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 a71 , R c71 and R d71 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

or, any R c71 and R d71 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R b71 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 b71 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R e71 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-;

R 8 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 a8 , SR a8 , NHOR a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)NR c8 (OR a8 ), C(O)OR a8 , OC(O)R b8 , OC(O)NR c8 R d8 , NR c8 R d8 , NR c8 NR c8 R d8 NR c8 C(O)R b8 , NR c8 C(O)OR a8 , NR c8 C(O)NR c8 R d8 , C(═NR e8 )R b8 , C(═NR e8 )NR c8 R d8 , C(═NOR a8 )R b8 , C(═NOR a8 )OR a8 , NR c8 C(═NR e8 )NR c8 R d8 , NR c8 C(═NR e8 )R b8 , NR c8 S(O)R b8 , NR c8 S(O)NR c8 R d8 , NR c8 S(O) 2 R b8 , NR c8 S(O)(═NR e8 )R b8 , NR c8 S(O) 2 NR c8 R d8 , S(O)R b8 , S(O)NR c8 R d8 , S(O) 2 R b8 , S(O) 2 NR c8 R d8 , OS(O)(═NR e8 )R b8 , and OS(O) 2 R b8 , 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 8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 8A substituents;

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 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 a8 , R c8 and R d8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 8A substituents;

or, any R c8 and R d8 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 8A substituents;

each R b8 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 b8 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 8A substituents;

each R e8 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 8A 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 a81 , SR a81 , NHOR a81 , C(O)R b81 , C(O)NR c81 R d81 , C(O)NR c81 (OR a81 ), C(O)OR a81 , OC(O)R b81 , OC(O)NR c81 R d81 , NR c81 R d81 , NR c81 NR c81 R d81 , NR c81 C(O)R b81 , NR c81 C(O)OR a81 , NR c81 C(O)NR c81 R d81 , C(═NR e81 )R b81 , C(═NR e81 )NR c81 R d81 , C(═NOR a81 )R b81 , C(═NOR a81 )OR a81 , NR c81 C(═NR e81 )NR c81 R d81 , NR c81 C(═NR e81 )R b81 , NR c81 S(O)R b81 , NR c81 S(O)NR c81 R d81 , NR c81 S(O) 2 R b81 , NR c81 S(O)(═NR e81 )R b81 , NR c81 S(O) 2 NR c81 R d81 , S(O)R b81 , S(O)NR c81 R d81 , S(O) 2 R b81 , S(O) 2 NR c81 R d81 , OS(O)(═NR e81 )R b81 , and OS(O) 2 R b81 , 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 8A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R a81 , R c81 , and R d81 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 a81 , R c81 and R d81 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

or, any R c81 and R d81 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R b81 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 b81 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R e81 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-;

R 9 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 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 a9 , SR a9 , NHOR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)NR c9 (OR a9 ), C(O)OR a9 , OC(O)R b9 , OC(O)NR c9 R d9 , NR c99 R d99 , NR c9 NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , C(═NR e9 )R b9 , C(═NR e9 )NR c9 R d9 , C(═NOR a9 )R b9 , C(═NOR a9 )OR a9 , NR c9 C(═NR e9 )NR c9 R d9 , NR c9 C(═NR e9 )R b9 , NR c9 S(O)R b9 , NR c9 S(O)NR c9 R d9 , NR c9 S(O) 2 R b9 , NR c9 S(O)(═NR e9 )R b9 , NR c9 S(O) 2 NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O) 2 R b9 , S(O) 2 NR c9 R d9 , OS(O)(═NR e9 )R b9 , and OS(O) 2 R b9 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 9 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 9A substituents;

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 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 a9 , R c9 and R d9 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 9A substituents;

or, any R c9 and R d9 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 9A substituents;

each R c99 and R d99 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 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 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 a9 , R c9 and R d9 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 9A substituents;

each R b9 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 b9 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 9A substituents;

each R e9 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 9A 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 a91 , SR a91 , NHOR a91 , C(O)R b91 , C(O)NR c91 R d91 , C(O)NR c91 (OR a91 ), C(O)OR a91 , OC(O)R b91 , OC(O)NR c91 R d91 , NR c91 R d91 , NR c91 NR c91 R d91 , NR c91 C(O)R b91 , NR c91 C(O)OR a91 , NR c91 C(O)NR c91 R d91 , C(═NR e91 )R b91 , C(═NR e91 )NR d91 R d91 , C(═NOR a91 )R b91 , C(═NOR a91 )OR a91 , NR c91 C(═NR e91 )NR c91 R d91 , NR c91 C(═NR e91 )R b91 , NR c91 S(O)R b91 , NR c91 S(O)NR c91 R d91 , NR c91 S(O) 2 R b91 , NR c91 S(O)(═NR e91 )R b91 , NR c91 S(O) 2 NR c91 R d91 , S(O)R b91 , S(O)NR c91 R d91 , S(O) 2 R b91 , S(O) 2 NR c91 R d91 , OS(O)(═NR e91 )R b91 , and OS(O) 2 R b91 , 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 9A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R a91 , R c91 , and R d91 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 a91 , R e91 and R d91 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

or, any R c91 and R d91 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R b91 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 b91 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R e91 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-;

R 10 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 a10 , SR a10 , NHOR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)NR c10 (OR a10 ), C(O)OR a10 , OC(O)R b10 , OC(O)NR c10 R d10 , NR c10 R d10 , NR c10 NR c10 R d10 , NR c10 C(O)R b10 , NR c10 C(O)OR a10 , NR c10 C(O)NR c10 R d10 , C(═NR e10 )R b10 , C(═NR e10 )NR c10 R d10 , C(═NOR a10 )R b10 , C(═NOR a10 )OR a10 , NR c10 C(═NR e10 )NR c10 R d10 , NR c10 C(═NR e10 )R b10 , NR c10 S(O)R b10 , NR c10 S(O)NR c10 R d10 , NR c10 S(O) 2 R b10 , NR c10 S(O)(═NR e10 )R b10 , NR c10 S(O) 2 NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O) 2 R b10 , S(O) 2 NR c10 R d10 , OS(O)(═NR e10 )R b10 , and OS(O) 2 R b10 , 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 10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 10A substituents;

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 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 a10 , R c10 and R d10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 10A substituents;

or, any R c10 and R d10 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 10A substituents;

each R b10 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 b10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 10A substituents;

each R e10 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 10A 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 a101 , SR a101 , NHOR a101 , C(O)R b101 , C(O)NR c101 R d101 , C(O)NR c101 (OR a101 ), C(O)OR a101 , OC(O)R b101 , OC(O)NR c101 R d101 ,NR c101 R d101 , NR c101 NR c101 R d101 , NR c101 C(O)R b101 , NR c101 C(O)OR a101 , NR c101 C(O)NR c101 R d101 , C(═NR e101 )R b101 , C(═NR e101 )NR c101 R d101 , C(═NOR a101 )R b101 , C(═NOR a101 )OR a101 , NR c101 C(═NR e101 )NR c101 R d101 , NR c101 C(═NR e101 )R b101 , NR c101 S(O)R b101 , NR c101 S(O)NR c101 R d101 , NR c101 S(O) 2 R b101 , NR c101 S(O)(═NR e101 )R b101 , NR c101 S(O) 2 NR c101 R d101 , S(O)R b101 , S(O)NR c101 R d101 , S(O) 2 R b101 , S(O) 2 NR c101 R d101 , OS(O)(═NR e101 )R b101 , and OS(O) 2 R b101 , 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 10A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R a101 , R c101 , and R d101 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 a101 , R c101 and R a101 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

or, any R c101 and R d101 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R b101 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 b101 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;

each R e101 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-;

L 1 is C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl;

Cy 1 is a C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 11 substituents;

each R 11 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 a11 , SR a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)NR c11 (OR a11 ), C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , C(═NR e11 )R b11 , C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )R b11 , NR c11 S(O)R b11 , NR c11 S(O)NR c11 R d11 , NR e11 S(O) 2 R b11 , NR c11 S(O)(═NR e11 )R b11 , NR c11 S(O) 2 NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O) 2 R b11 , S(O) 2 NR c11 R d11 , OS(O)(═NR e11 )R b11 , and OS(O) 2 R b11 , 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 11 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 11A substituents;

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 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 a11 , R c11 and R d11 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 11A substituents;

or, any R c11 and R d11 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RILA substituents;

each R b11 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 b11 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 11A substituents;

each R e11 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 11A is independently selected from halo, 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 a111 , C(O)NR c111 R d111 , C(O)OR a111 , NR c111 R d111 , S(O)NR c111 R d111 , S(O) 2 R b111 , S(O) 2 NR c111 R d111 , and OS(O) 2 R b111 , 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 11A are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a111 , R c111 , and R d111 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 a111 , R c111 and R d111 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c111 and R d111 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 or 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b111 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 b111 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

R 12 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 a12 , SR a12 , NHOR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)NR c12 (OR a12 ), C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , C(═NR e12 )R b12 , C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )R b12 , NR c12 S(O)R b12 , NR c12 S(O)NR c12 R d12 , NR c12 S(O) 2 R b12 , NR c12 S(O)(═NR e12 )R b12 , NR c12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R b12 , S(O) 2 NR c12 R d12 , OS(O)(═NR e12 )R b12 , and OS(O) 2 R b12 , 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 12 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12A substituents;

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 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 a12 , R c12 and R d12 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12A substituents;

or, any R c12 and R d12 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12A substituents;

each R b12 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 b12 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12A substituents;

each R e12 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 12A 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 a121 , SR a121 , NHOR a121 , C(O)R b121 , C(O)NR c121 R d121 , C(O)NR c121 (OR a121 ), C(O)OR a121 , OC(O)R b121 , OC(O)NR c121 R d121 , NR c121 R d121 , NR c121 NR c121 R d121 , NR c121 C(O)R b121 , NR c121 C(O)OR a121 , NR c121 C(O)NR c121 R d121 , C(═NR e121 )R b121 , C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )R b121 , NR c121 S(O)R b121 , NR c121 S(O)NR c121 R d121 , NR c121 S(O) 2 R b121 , NR c121 S(O)(═NR e121 )R b121 , NR c121 S(O) 2 NR c121 R d121 , S(O)R b121 , S(O)NR c121 R d121 , S(O) 2 R b121 , S(O) 2 NR c121 R d121 ,OS(O)(═NR e121 )R b121 , and OS(O) 2 R b121 , 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 12A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12B substituents;

each R a121 , R c121 , and R d121 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 a121 , R c121 and R d121 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12B substituents;

or, any R c121 and R d121 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 or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12B substituents;

each R b121 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 b121 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 12B substituents;

each R e121 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 12B is independently selected from halo, 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 a122 , C(O)NR c122 R d122 , C(O)OR a122 , NR c122 R d122 , S(O)NR c122 R d122 , S(O) 2 R b122 , S(O) 2 NR c122 R d122 , and OS(O) 2 R b122 , 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 12B are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a122 , R c122 , and R d122 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 a122 , R c122 and R d122 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c122 and R d122 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 or 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R b122 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 b122 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents; 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, 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-.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CR 7 , N, or NR 7 .

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH, N, or NH.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 8 or C(O).

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 8 .

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 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, and OR a8 , 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 8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halo, 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-, CN, and OR a8 , wherein 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, and 4-7 membered heterocycloalkyl-of R 8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, CN, and OR a8 , wherein C 1-6 alkyl and 5-6 membered heteroaryl of R 8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents; and

each R a8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 8A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 8A is independently selected from C 1-6 alkyl and CN.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, CN, and OR a8 , wherein C 1-6 alkyl and 5-6 membered heteroaryl of R 8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents independently selected from C 1-6 alkyl and CN; and

each R a8 is independently selected from H and C 1-6 alkyl.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, fluoro, methyl, cyanomethyl, cyano, methoxy, and methylpyrazolyl.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C(O).

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 9 .

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CR 10 .

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CH.

21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y and Z are each CH.

22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

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

24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from C 1-6 alkyl.

25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is methyl.

26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

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

28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

29 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents.

30 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R 5 is optionally substituted with 1, 2, 3, or 4 independently selected R M substituents.

31 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R M is independently selected from OH, halo, oxo, CN, C(O) OH, NH 2 , NO 2 , SF 5 , C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 haloalkyl.

32 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from methyl and methoxyethyl.

33 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1-3 alkyl.

34 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L1 is CH.

35 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl or 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl of Cy 1 are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 substituents.

36 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 11 substituents.

37 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

38 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from halo.

39 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is fluorophenyl.

40 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 is phenyl or 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl of R 12 are each optionally substituted with 1, 2, 3, or 4 independently selected R 12A substituents.

41 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 is phenyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 12A substituents.

42 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 12A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

43 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 12A is independently selected from halo.

44 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 is fluorophenyl.

45 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 and R 12 are each fluorophenyl.

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

W is CR 7 , C(O), N, or NR 7 ;

X is CR 8 , C(O), N, or NR 8 ;

Y is CH;

Z is CH;

n is 0, 1, or 2;

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 5-6 membered heteroaryl or a 4-7 membered heterocycloalkyl group;

R 7 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R 8A 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 a81 , SR a81 , NHOR a81 C(O)R b81 , C(O)NR c81 R d81 , C(O)NR c81 (OR a81 ), C(O)OR a81 , OC(O)R b81 , OC(O)NR c81 R d81 , NR c81 R d81 , NR c81 NR c81 R d81 , NR c81 C(O)R b81 , NR c81 C(O)OR a81 , NR c81 C(O)NR c81 R d81 , C(═NR e81 )R b81 , C(═NR e81 )NR c81 R d81 , C(═NOR a81 )R b81 , C(═NOR a81 )OR a81 , NR c81 C(═NR e81 )NR c81 R d81 , NR c81 C(═NR e81 )R b81 , NR c81 S(O)R b81 , NR c81 S(O)NR c81 R d81 , NR c81 S(O) 2 R b81 , NR c81 S(O)(═NR e81 )R b81 , NR c81 S(O) 2 NR c81 R d81 , S(O)R b81 , S(O)NR c81 R d81 , S(O) 2 R b81 , S(O) 2 NR c81 R d81 , OS(O)(═NR e81 )R b81 , and OS(O) 2 R b81 , 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 8A are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

L 1 is C 1-3 alkyl;

Cy 1 is phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 substituents;

each R 11 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 a11 , SR a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)NR c11 (OR a11 ), C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , C(═NR e11 )R b11 , C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )R b11 , NR c11 S(O)R b11 , NR c11 S(O)NR c11 R d11 , NR c11 S(O) 2 R b11 , NR c11 S(O)(═NR e11 )R b11 , NR c11 S(O) 2 NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O) 2 R b11 , S(O) 2 NR c11 R d11 , OS(O)(═NR e11 )R b11 , and OS(O) 2 R b11 , 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 11 are each optionally substituted with 1, 2, 3, or 4 independently selected R 11A substituents;

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 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 a11 , R c11 and R a11 are each optionally substituted with 1, 2, 3, or 4 independently selected R 11A substituents;

each R 11A is independently selected from halo, 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, CN, NO 2 , OR a111 , C(O)NR c111 R d111 , C(O)OR a111 , NR c111 R d111 , S(O)NR c111 R d111 , S(O) 2 R b111 , S(O) 2 NR c111 R d111 , and OS(O) 2 R b111 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 11A are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

or, any R c111 and R a111 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 or 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

R 12 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 a12 , SR a12 , NHOR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)NR c12 (OR a12 ), C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , C(═NR e12 )R b12 , C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )R b12 , NR c12 S(O)R b12 , NR c12 S(O)NR c12 R d12 , NR c12 S(O) 2 R b12 , NR c12 S(O)(═NR e12 )R b12 , NR c12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R b12 , S(O) 2 NR c12 R d12 , OS(O)(═NR e12 )R b12 , and OS(O),R b12 , 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 12 are each optionally substituted with 1, 2, 3, or 4 independently selected R 12A substituents;

each R 12A 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 a121 , SR a121 , NHOR a121 C(O)R b121 , C(O)NR c121 R d121 , C(O)NR c121 (OR a121 ), C(O)OR a121 , OC(O)R b121 , OC(O)NR c121 R d121 , NR c121 R d121 , NR c121 NR c121 R d121 , NR c121 C(O)R b121 , NR c121 C(O)OR a121 , NR c121 C(O)NR c121 R d121 , C(═NR e121 )R b121 , C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )R b121 , NR c121 S(O)R b121 , NR c121 S(O)NR c121 R d121 , NR c121 S(O) 2 R b121 , NR c121 S(O)(═NR e121 )R b121 , NR c121 S(O) 2 NR c121 R d121 , S(O)R b121 , S(O)NR c121 R d121 , S(O) 2 R b121 , S(O) 2 NR c121 R d121 , OS(O)(═NR e121 )R b121 , and OS(O) 2 R b121 ;

or, any R c121 and R d121 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;

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

W is CR 7 , N, or NR 7 ;

X is CR 8 or C(O);

Y is CH;

Z is CH;

n is 0, 1, or 2;

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

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

R 5 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R 5 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

R 7 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R a8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R 8A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN;

L 1 is C 1-3 alkyl;

Cy 1 is phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 substituents;

each R 11 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 a11 , SR a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)NR c11 (OR a11 ), C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 NR c11 R d11 NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , C(═NR e11 )R b11 , C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )R b11 , NR c11 S(O)R b11 , NR c11 S(O)NR c11 R d11 , NR c11 S(O) 2 R b11 , NR c11 S(O)(═NR e11 )R b11 , NR c11 S(O) 2 NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O) 2 R b11 , S(O) 2 NR c11 R d11 , OS(O)(═NR e11 )R b11 , and OS(O) 2 R b11 , 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 11 are each optionally substituted with 1, 2, 3, or 4 independently selected R 11A substituents;

each R 11A is independently selected from halo, 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, CN, NO 2 , OR a111 , C(O)NR c111 R d111 , C(O)OR a111 , NR c111 R d111 , S(O)NR c111 R d111 , S(O) 2 R b111 , S(O) 2 NR c111 R d111 , and OS(O) 2 R b111 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R 11A are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

each R a111 , R c111 , and R a111 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 a111 , R c111 and R d111 are each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents;

R 12 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 a12 , SR a12 , NHOR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)NR c12 (OR a12 ), C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , C(═NR e12 )R b12 , C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )R b12 , NR c12 S(O)R b12 , NR c12 S(O)NR c12 R d12 , NR c12 S(O) 2 R b12 , NR c12 S(O)(═NR e12 )R b12 , NR c12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 S(O) 2 R b12 , S(O) 2 NR c12 R d12 , OS(O)(═NR e12 )R b12 , and OS(O) 2 R b12 , 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 12 are each optionally substituted with 1, 2, 3, or 4 independently selected R 12A substituents;

each R 12A 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 a121 , SR a121 , NHOR a121 ,C(O)R b121 , C(O)NR c121 R d121 , C(O)NR c121 (OR a121 ), C(O)OR a121 , OC(O)R b121 , OC(O)NR c121 R d121 , NR c121 R d121 , NR c121 NR c121 R d121 , NR c121 C(O)R b121 , NR c121 C(O)OR a121 , NR c121 C(O)NR c121 R d121 , C(═NR e121 )R b121 , C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )NR c121 R d121 , NR c121 C(═NR e121 )R b121 , NR c121 S(O)R b121 , NR c121 S(O)NR c121 R d121 , NR c121 S(O) 2 R b121 , NR c121 S(O)(═NR e121 )R b121 , NR c121 S(O) 2 NR c121 R d121 , S(O)R b121 , S(O)NR c121 R d121 , S(O) 2 R b121 , S(O) 2 NR c121 R d121 , OS(O)(═NR e121 )R b121 , and OS(O) 2 R b121 ;

or, any R c121 and R d121 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;

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

51 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, or 5.

52 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, or 5.

53 . The compound of claim 1 , wherein the compound of Formula I is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, 4, or 5.

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

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-7-(2-methoxyethyl)-5,11-dimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2-carbonitrile;

(2R,4aR)-3-(bis(4-fluorophenyl)methyl)-2,6,8-trimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c]quinoline-5,7-dione;

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-fluoro-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2,5,7,11-tetramethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;

2-((8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-6,8-dioxo-5,7,8,8a,9,10,11,12-octahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridin-2-yl) acetonitrile;

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-2-methoxy-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione;

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5,7,9,10,11,12-hexahydro-6H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-6,8(8aH)-dione; and

(8aR,11R)-10-(bis(4-fluorophenyl)methyl)-5,7,11-trimethyl-5,7,9,10,11,12-hexahydro-1H-pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,5]naphthyridine-2,6,8(8aH)-trione;

or a pharmaceutically acceptable salt thereof.

55 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is deuterated.

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

57 . A method of inhibiting an activity of a diacylglycerol kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

58 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

59 . The method of claim 58 , wherein the cancer is non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.

60 . The method of claim 59 , wherein the melanoma is metastatic melanoma.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 21, 2023

From: HUMMEL, JOSHUA; SHI, SHICHENG; WANG, XIAOZHAO

To: INCYTE CORPORATION

Reel/Frame 064335/0171 →

Continuity (2)

Provisional Application 63390041 · Jul 18, 2022

Related Publication 20240034734A1 · Feb 1, 2024

References Cited (172)

US 6833454B1 · Koppes et al. · 2004 [cited by applicant]

US 7381401B2 · Gajewski et al. · 2008 [cited by applicant]

US 7488802B2 · Collins et al. · 2009 [cited by applicant]

US 7943743B2 · Korman et al. · 2011 [cited by applicant]

US 8008449B2 · Korman et al. · 2011 [cited by applicant]

US 8168757B2 · Finnefrock et al. · 2012 [cited by applicant]

US 8217149B2 · Irving et al. · 2012 [cited by applicant]

US 8618288B2 · Dvorak et al. · 2013 [cited by applicant]

US 10087180B2 · Ford et al. · 2018 [cited by applicant]

US 10308644B2 · Wu et al. · 2019 [cited by applicant]

US 20070161072A1 · Prescott et al. · 2007 [cited by applicant]

US 20170145025A1 · Li et al. · 2017 [cited by applicant]

US 20170174671A1 · Wu et al. · 2017 [cited by applicant]

US 20170174679A1 · Lajkiewicz et al. · 2017 [cited by applicant]

US 20170320875A1 · Li et al. · 2017 [cited by applicant]

US 20170342060A1 · Lu et al. · 2017 [cited by applicant]

US 20170362253A1 · Xiao et al. · 2017 [cited by applicant]

US 20180016260A1 · Yu et al. · 2018 [cited by applicant]

US 20180028501A1 · Lindsley et al. · 2018 [cited by applicant]

US 20180057486A1 · Wu et al. · 2018 [cited by applicant]

US 20180177784A1 · Wu et al. · 2018 [cited by applicant]

US 20180177870A1 · Liu et al. · 2018 [cited by applicant]

US 20180179179A1 · Wu et al. · 2018 [cited by applicant]

US 20180179197A1 · Wu et al. · 2018 [cited by applicant]

US 20180179201A1 · Wu et al. · 2018 [cited by applicant]

US 20180179202A1 · Wu et al. · 2018 [cited by applicant]

US 20180273519A1 · Wu et al. · 2018 [cited by applicant]

US 20190040082A1 · Xiao et al. · 2019 [cited by applicant]

US 20190062345A1 · Xiao et al. · 2019 [cited by applicant]

US 20190071439A1 · Li et al. · 2019 [cited by applicant]

US 20190127467A1 · Shah et al. · 2019 [cited by applicant]

US 20190144439A1 · Wu et al. · 2019 [cited by applicant]

US 20190202824A1 · Wu et al. · 2019 [cited by applicant]

US 20190225601A1 · Wu et al. · 2019 [cited by applicant]

US 20190300524A1 · Wu et al. · 2019 [cited by applicant]

US 20190345170A1 · Wu et al. · 2019 [cited by applicant]

US 20230399342A1 · Hummel et al. · 2023 [cited by applicant]

US 20240025900A1 · Hummel et al. · 2024 [cited by applicant]

US 20240083898A1 · Hummel et al. · 2024 [cited by applicant]

US 20240217989A1 · Xiang et al. · 2024 [cited by applicant]

US 20240270739A1 · Xiang et al. · 2024 [cited by applicant]

US 20250066363A1 · Hummel et al. · 2025 [cited by applicant]

US 20250179083A1 · Hummel et al. · 2025 [cited by applicant]

US 20250186450A1 · Ren et al. · 2025 [cited by applicant]

CN 105315293A · 2016 [cited by applicant]

CN 109180686A · 2019 [cited by applicant]

CN 110643705A · 2020 [cited by applicant]

CN 111097048A · 2020 [cited by applicant]

CN 112300194A · 2021 [cited by applicant]

CN 113061132A · 2021 [cited by applicant]

CN 115463214A · 2022 [cited by applicant]

CN 116969943A · 2023 [cited by applicant]

EP 4083038A1 · 2022 [cited by applicant]

WO WO2001002398A1 · 2001 [cited by applicant]

WO WO2002000196A2 · 2002 [cited by applicant]

WO WO2002077177A2 · 2002 [cited by applicant]

WO WO2003042402A2 · 2003 [cited by applicant]

WO WO2004021984A2 · 2004 [cited by applicant]

WO WO2005121138A2 · 2005 [cited by applicant]

WO WO2007019083A1 · 2007 [cited by applicant]

WO WO2007109251A2 · 2007 [cited by applicant]

WO WO2008017161A1 · 2008 [cited by applicant]

WO WO2008148926A2 · 2008 [cited by applicant]

WO WO2008156712A1 · 2008 [cited by applicant]

WO WO2009017863A2 · 2009 [cited by applicant]

WO WO2007114239A1 · 2009 [cited by applicant]

WO WO2010036959A2 · 2010 [cited by applicant]

WO WO2010089411A2 · 2010 [cited by applicant]

WO WO2011066342A2 · 2011 [cited by applicant]

WO WO2011082400A2 · 2011 [cited by applicant]

WO WO2011143423A2 · 2011 [cited by applicant]

WO WO2011159877A2 · 2011 [cited by applicant]

WO WO2011161699A2 · 2011 [cited by applicant]

WO WO2012080727A2 · 2012 [cited by applicant]

WO WO2012080729A2 · 2012 [cited by applicant]

WO WO2012130780A1 · 2012 [cited by applicant]

WO WO2014096423A1 · 2014 [cited by applicant]

WO WO2015054572A1 · 2015 [cited by applicant]

WO WO2015095492A1 · 2015 [cited by applicant]

WO WO2015193167A1 · 2015 [cited by applicant]

WO WO2016044772A1 · 2016 [cited by applicant]

WO WO2018062954A1 · 2018 [cited by applicant]

WO WO2019005883A1 · 2019 [cited by applicant]

WO WO2019046795A1 · 2019 [cited by applicant]

WO WO2020006016A1 · 2020 [cited by applicant]

WO WO2020006018A1 · 2020 [cited by applicant]

WO WO2020239123 · 2020 [cited by examiner]

WO WO2020110127A1 · 2020 [cited by applicant]

WO WO2021013561A1 · 2021 [cited by applicant]

WO WO2021041588A1 · 2021 [cited by applicant]

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Arranz-Nicolás et al., “Diacylglycerol kinase a inactivation is an integral component of the costimulatory pathway that amplifies TCR signals,” Cancer Immunology Immunotherapy, Jun. 2018, 67(6):965-980. [cited by applicant]

Atzrodt et al., “The renaissance of H/D exchange,” Angewandte Chemie International Edition English, Oct. 2007, 46(41): 7744-7765. [cited by applicant]

Bennett et al., “Proposals for the classification of the myelodysplastic syndromes,” British Journal of Haematology, Jun. 1982, 51(2): 189-199. [cited by applicant]

Blom et al., “Optimizing preparative LC/MS configurations and methods for parallel synthesis purification,” Journal of Combinatorial Chemistry, Sep. 2003, 5(5):670-683. [cited by applicant]

Blom et al., “Preparative LC—MS Purification: Improved Compound-Specific Method Optimization,” Journal of Combinatorial Chemistry, Nov. 2004, 6(6):874-883. [cited by applicant]

Blom, “Two-Pump at-Column-Dilution Configuration for Preparative Liquid Chromatography—Mass Spectrometry,” Journal of Combinatorial Chemistry, Jul. 2002, 4(4):295-301. [cited by applicant]

Cai et al., “Increased diacylglycerol kinase { expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion,” BMC cancer, Mar. 19, 2014, 14:208. [cited by applicant]

Chen et al., “Diacylglycerol Kinases in T Cell Tolerance and Effector Function,” Frontiers in Cell and Development Biology, Nov. 10, 2016, 4:130. [cited by applicant]

Chen et al., “The diacylglycerol kinase a (DGKa)/Akt/NF-KB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner,” Oncogene, Apr. 2019, 38(14):2533-… [cited by applicant]

Chinchilla et al., “Recent advances in Sonogashira reactions,” Chemical Society Reviews, Oct. 2011, 40(10):5084-5121. [cited by applicant]

Cooke et al., “Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity,” Science Signaling, Apr. 2022, 15(729):eabo0264, pp. 1-26. [cited by applicant]

Cordovilla et al., “The Stille reaction, 38 years later,” ACS Catalysis, May 2015, 5(5):3040-3053. [cited by applicant]

Fu et al., “DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer,” Cancer Letters, Apr. 2022, 532:215585. [cited by applicant]

Gonzalez et al., “Roles of the immune system in cancer: from tumor initiation to metastatic progression,” Genes & Development, Oct. 2018, 32(19-20): 1267-1284. [cited by applicant]

Gu et al., “DGKL exerts greater control than DGKα over CD8+ T cell activity and tumor inhibition,” Oncoimmunology, Jan. 2021, 10(1): 1941566. [cited by applicant]

Haas et al., “Recent developments in Negishi cross-coupling reactions,” ACS Catalysis, Mar. 2016, 6(3): 1540-1552. [cited by applicant]

Harabuchi et al. “Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection,” Frontiers in Immunology, Nov. 2022, 13:1032113. [cited by applicant]

Harris et al., “World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, Nov. 1997,” Journal of… [cited by applicant]

Joshi et al.,“ Diacylglycerol kinases: regulated controllers of T cell activation, function, and development,” International Journal of Molecular Sciences, Mar. 2013, 14(4):6649-6673. [cited by applicant]

Jung et al., “CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells,” Cancer Research, Aug. 2018, 78(16):4692-4703. [cited by applicant]

Kerekes et al., “Aurora kinase inhibitors based on the imidazo [1, 2-a] pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure,” Journal of Medicinal Chemistry, Jan. 2011, 54(1):201-210. [cited by applicant]

Kotha et al., “Recent applications of the Suzuki-Miyaura cross-coupling reaction in organic synthesis, ” Tetrahedron, Nov. 2002, 58(48):9633-9695. [cited by applicant]

Krishna et al., “Regulation of lipid signaling by diacylglycerol kinases during T cell development and function,” Frontiers in Immunology, Jul. 2013, 4:178. [cited by applicant]

Mérida et al., “Diacylglycerol kinases in cancer,” Advances in Biological Regulation, Jan. 2017, 63:22-31. [cited by applicant]

Noessner, “DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy,” Frontiers in Cell and Developmental Biology, Mar. 3, 2017, 5(Article 16):7 pages. [cited by applicant]

Prinz et al., “High DGK-a and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention,” The Journal of Immunology, Jun. 15, 2012, 188(12):5990-6… [cited by applicant]

Rainero et al., “The diacylglycerol kinase a/atypical PKC/B1 integrin pathway in SDF-la mammary carcinoma invasiveness,” PloS One, Jun. 2014, 9(6): e97144. [cited by applicant]

Remington's Pharmaceutical Sciences, 17th ed., 1985, p. 1418. [cited by applicant]

Riese et al., “Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer,” Frontiers in Cell and Developmental Biology, Oct. 2016, 4:108. [cited by applicant]

Riese et al., “Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases,” Cancer Research, Jun. 2013, 73(12):3566-3577. [cited by applicant]

Ruffo et al., “Inhibition of diacylglycerol kinase a restores restimulation-induced cell death and reduces immunopathology in XLP-1,” Science Translational Medicine, Jan. 2016, 8(321):321ra7. [cited by applicant]

Sadreddini et al., “Immune checkpoint blockade opens a new way to cancer immunotherapy,” Cellular Physiology, Jun. 2019, 234:8541-8549. [cited by applicant]

Sakane et al., “New era of diacylglycerol kinase, phosphatidic acid and phosphatidic acid- binding protein,” International Journal of Molecular Sciences, Sep. 2020, 21(18):6794-6829. [cited by applicant]

Sharma et al., “Primary, adaptive, and acquired resistance to cancer immunotherapy,” Cell, Feb. 2017, 168(4):707-723. [cited by applicant]

Sharma et al., “The next decade of immune checkpoint therapy,” Cancer Discovery, Apr. 2021, 11(4):838-857. [cited by applicant]

Sitaram et al., “Beyond the cell surface: targeting intracellular negative regulators to enhance T cell anti-tumor activity,” International Journal of Molecular Sciences, Nov. 2019, 20(23):5821-5848. [cited by applicant]

Speiser et al., “Regulatory circuits of T cell function in cancer,” Nature Reviews Immunology, Oct. 2016, 16(10):599-611. [cited by applicant]

Surry et al., “Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide,” Royal Society of Chemistry, 2011, 2(1):27-50. [cited by applicant]

Swerdlow et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed., 2008, pp. 88-103. [cited by applicant]

Takeishi et al., “Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway,” Journal of Hepatology, Jul. 2012, 57(1):77-83. [cited by applicant]

Torres-Ayuso et al., “Diacylglycerol kinase a promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src,” Oncotarget, Oct. 2014, 5(20):9710-9726. [cited by applicant]

Vardiman et al., “The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes,” Blood, Jul. 2009, 114(5):937-951. [cited by applicant]

Vardiman et al., “The World Health Organization (WHO) classification of the myeloid neoplasms,” Blood, Oct. 2002, 100(7):2292-2302. [cited by applicant]

Velnati et al., “Identification of a novel DGKa inhibitor for XLP-1 therapy by virtual screening,” European Journal of Medicinal Chemistry, Feb. 2019, 164:378-390. [cited by applicant]

Wesley et al., “Diacylglycerol Kinase { (DGK() and Casitas b-Lineage Proto-Oncogene b-deficient mice have similar functional outcomes in T Cells but DGKL-deficient mice have increased T cell activation and tumor clearan… [cited by applicant]

Xu et al., “Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties,” Journal of Labelled Compounds and Radiopharmaceuticals, Jun. 2015, 58(7):308-312. [cited by applicant]

Yu et al., “DGKZ acts as a potential oncogene in osteosarcoma proliferation through its possible interaction with ERK1/2 and MYC pathway,” Frontiers in Oncology, Jan. 4, 2019, 8:655. [cited by applicant]