Heterocyclic compounds as immunomodulators

Patent metadata

Field	Value
Publication number	US-12466822-B2
Application number	US-202117483959-A
Country	US
Kind code	B2
Filing date	Sep 24, 2021
Priority date	Dec 22, 2016
Publication date	Nov 11, 2025
Grant date	Nov 11, 2025

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

First claim

What is claimed is:

1 . A compound of Formula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

ring A is selected from:

wherein each subscript r is an integer of 1, 2, or 3;
L is —C(O)NR 13 —, wherein the carbonyl group is attached to ring A;
X is N or CR 17 ;
R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl or —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl and C 1-4 alkoxy of R 2 is optionally substituted with 1 or 2 substituents independently selected from C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, —C(O)NH 2 , NH 2 , —NHC 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;
R 3 is methyl, halo, CN or C 1-4 haloalkyl;
R 4 is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl or —N(C 1-4 alkyl) 2 ;
R 5 is C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl or —N(C 1-4 alkyl) 2 ;
R 6 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NHR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR a )R a , C(═NR a )NR a R a , NR a C(═NR a )NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 6 is optionally substituted with 1, 2, 3, 4 or 5 R b substituents;
R 7 is H, halo, CN, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy of R 7 are each optionally substituted with CN;
or two R 6 substituents attached to the same ring carbon atom taken together with the ring carbon atom to which they are attached form spiro C 3-6 cycloalkyl or spiro 4- to 7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 independently selected R f substituents;
R 8 and R 9 are each independently selected from H, halo, CN, OH, —COOH, C 1-4 alkyl, C 1-4 alkoxy, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R 8 or R 9 are each optionally substituted with 1, 2 or 3 independently selected R 9 substituents;
or R 8 and R 9 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 4-, 5-, 6- or 7-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 R q substituents;
or R 8 and R 10 taken together with the atoms to which they are attached form 4-, 5-, 6- or 7-membered heterocycloalkyl, having zero to one additional heteroatoms as ring members selected from O, N or S, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl formed by R 8 and R 10 are each optionally substituted with 1 or 2 R q substituents;
R 10 and R 11 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, —C(O)R g , —C(O)OR g , —C(O)NR g R g , —SO 2 R g and —SO 2 NR g R g , wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 10 or R 11 are each optionally substituted with 1, 2, or 3 independently selected R d substituents;
or R 10 and R 11 taken together with the nitrogen atom to which they are attached form 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycloalkyl, wherein the 4-11 membered heterocycloalkyl is each optionally substituted with 1, 2 or 3 R f substituents;
R 12 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl or —N(C 1-4 alkyl) 2 ;
each R 13 is independently H, C 1-6 haloalkyl or C 1-6 alkyl optionally substituted with a substituent selected from C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl and —N(C 1-4 alkyl) 2 ;
R 14 and R 15 are each independently selected from H, halo, CN, OH, —COOH, C 1-4 alkyl, C 1-4 alkoxy, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl of R 14 or R 15 are each optionally substituted with 1, 2, or 3 independently selected R q substituents;
or R 14 and R 15 taken together with the carbon atom to which they are attached form 3-, 4-, 5- or 6-membered cycloalkyl or 3-, 4-, 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 R q substituents;
R 17 is H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, halo, OH, —COOH, NH 2 , —NHC 1-4 alkyl or —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl and C 1-4 alkoxy are each optionally substituted with 1 or 2 substituents independently selected from CN, halo and —C(O)NH 2 ;
each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 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 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 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 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R a are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents;
each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , C(═NR e )NR e R e , NR e C(═NR e )NR e R e , NR e C(═NOH)NR e R e , NR e C(═NCN)N

Assignees

• Incyte Corp

Inventors

• Wu Liangxing
• Lajkiewicz Neil
• He Chunhong
• Xiao Kaijiong
• Zhu Wenyu
• Li Zhenwu
• Qi Chao
• Konkol Leah C
• Yao Wenqing

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title