Tricyclic triazolo compounds as dgk inhibitors

Patent metadata

Field	Value
Publication number	US-2023399342-A1
Application number	US-202318330623-A
Country	US
Kind code	A1
Filing date	Jun 7, 2023
Priority date	Jun 8, 2022
Publication date	Dec 14, 2023
Grant date	—

Abstract

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

First claim

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each is a single or double bond, wherein at least one is a double bond;
U is CR 3 or N;
X is CR 4 , N, NR 4 , S, or O;
Y is CR 5 , N, or NR 5 ;
Z is CR 6 , N, NR 6 , S, or O;
R 1 is Cy 1 or L-Cy 1 ;
L is NR c7 , O, C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl;
Cy 1 is a C 3-10 cycloalkyl, 5-15 membered heteroaryl, or 4-15 membered heterocycloalkyl, wherein the C 3-10 cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents;
each R 1A 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 d11 ), 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 , C(═NOR a11 )R b11 , C(═NOR d11 )OR d11 NR c11 C(═NR e11 )NR c11 R a11 NR c11 C(═NR e11 )R bl1 , NR c11 S(O)R b11 NR c11 S(O)NRCR d11 NR c11 S(O) 2 R 11 , NR c11 S(O)(═NR c11 )R 11 , NR c11 S(O) 2 NR 11 R d11 , S(O)R b11 , S(O)NR 11 R d11 , S(O) 2 R 11 , S(O) 2 NR 11 R d11 , OS(O)(═NR c11 )R 11 , and OS(O) 2 R 11 , 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 1A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1B 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 1B 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 R 1B substituents;
each R 11 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 1B substituents;
each R 11 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 1B 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 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 d612 , 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 , C(═NOR d12 )R b12 , C(═NOR d12 )OR d12 , NR 12 C(═NR e12 )NR c12 R d12 , NR 12 C(═NR e12 )R b12 , NR 12 S(O)R b12 , NR 12 S(O)NR e12 R 12 , NR 12 S(O) 2 R 12 , NR 12 S(O)(═NR e12 )R b12 , NR 12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R 12 , 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 1B are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1C 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 1C 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 1C 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 1C 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

Assignees

• Incyte Corp

Inventors

• Hummel Joshua
• Hie Liana
• Lacharity Jacob J
• Li Xiaolei
• Manns Sharada
• Qian Ding-Quan
• Wang xiaozhao
• Wei Bo
• Xu Meizhong

Classifications

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D491/147

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title