Heterocyclic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10723705-B2
Application number	US-201615752807-A
Country	US
Kind code	B2
Filing date	Aug 12, 2016
Priority date	Aug 14, 2015
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

The present disclosure relates to heterocyclic compounds, and pharmaceutical compositions of the same, that are modulators/inhibitors of HDACs, such as HDAC8 and are useful in the treatment of HDAC-associated diseases.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, a tautomer or a stereoisomer thereof, wherein:
Y is —C(O)NHOH and ring A is fused pyrazolyl, fused imidazolyl or fused triazolyl, each of which is optionally substituted with an R 1 substituent;
ring B is fused phenyl, fused pyridyl, fused pyrimidinyl, fused pyrazinyl, fused pyridazinyl, fused triazinyl or fused cyclohexyl, each of which is optionally substituted with 1 to 4 independently selected R 2 substituents;
wherein one of the two bridgehead atoms between ring A and ring B is optionally nitrogen;
X is C 6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with from 1-3 independently selected R 3 substituents;
L is C 1-4 alkylene, optionally substituted with from 1-3 R q substituents independently selected from halo, CN, OH, C 1-4 alkyl, —OC 1-2 alkyl, C 1-2 haloalkyl, and C 1-2 haloalkoxy; or two R q substituents attached to the same carbon taken together form C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1-2 independently selected R r substituents;
G is H, CN, OH, C 1-4 alkyl, —OC 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 haloalkoxy, wherein the C 1-4 alkyl, —OC 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 haloalkoxy of G is optionally substituted with 1-2 substituents independently selected from halo, CN, OH, NH 2 , NHR 5 , NR 5 R 5 , —C(O)NR 5 R 5 , C 1-4 alkyl, —OC 1-2 alkyl, C 1-2 haloalkyl and C 1-2 haloalkoxy, wherein each R 5 is independently C 1-4 alkyl;
each R 1 is independently 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, 5-10 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-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , 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, 5-10 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 1 are each optionally substituted with 1, 2, 3, or 4 R b substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 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-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NHR c , NR c R c , NR c C(O)R c NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O)R c or S(O) 2 NR c R C ; wherein C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 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 14 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each further optionally substituted with from 1-3 R d substituents;
each R 2 and R 3 is independently 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, 5-10 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-, (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, 5-10 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 2 or R 3 are each optionally substituted with 1, 2, 3, or 4 R b substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 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-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R, NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c or S(O) 2 NR c R c ; wherein C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, 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 b are each further optionally substituted with from 1-3 R d substituents;
or two adjacent R 3 substituents on the C 6-10 aryl of X, taken together with the atoms to which they are attached, form fused C 3-6 cycloalkyl, or fused 5- or 6-membered heterocycloalkyl;
or two adjacent R 3 substituents on the 5- to 6-membered heteroaryl of X, taken together with the atoms to which they are attached, form fused phenyl, fused C 3-6 cycloalkyl, fused 5- or 6-membered heteroaryl or fused 5- or 6-membered heterocycloalkyl, wherein the fused 5- or 6-membered heteroaryl or fused 5- or 6-membered heterocycloalkyl has 1-2 heteroatoms as ring members selected from N, O and S; and wherein fused phenyl, fused C 3-6 cycloalkyl, fused 5- or 6-membered heteroaryl and fused 5- or 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 R b substituents;
each R a is independently selected from H, 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 14 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 14 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 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 are each optionally substituted with 1, 2, 3, 4, or 5 R d substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, 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 , —R 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 , S(O)R, S(O)NR e R e , S(O) 2 R

Assignees

• Incyte Corp

Inventors

• Pan Jun
• Wang xiaozhao
• Barbosa Joseph
• Yao Wenqing
• Ye Yingda

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/416

  condensed with carbocyclic ring systems, e.g. indazole · CPC title