Enhancer of zeste homolog 2 inhibitors

Patent metadata

Field	Value
Publication number	US-2016130261-A1
Application number	US-201414898178-A
Country	US
Kind code	A1
Filing date	Jul 9, 2014
Priority date	Jul 10, 2013
Publication date	May 12, 2016
Grant date	—

Abstract

This invention relates to novel compounds according to Formula (I) which are inhibitors of Enhancer of Zeste Homolog 2 (EZH2), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of cancers.

First claim

1 . A compound according to Formula (I):

wherein:
A is NH;
X is O, N, S, CR 6 , or NR 7 ;
Y is O, N, S, CR 6 , or NR 7 ;
Z is CR 5 or NR 8 ; wherein when X is O, S, or NR 7 , Y is N or CR 6 and Z is CR 5 ; when Y is O, S, or NR 7 , X is N or CR 6 and Z is CR 5 ; and when Z is NR 8 , Y is N or CR 6 and X is N or CR 6 ;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, (C 1 -C4)alkoxy, (C 1 -C 8 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-, halo(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl, hydroxy(C 1 -C 4 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 4 )alkyl-, R a O(O)CNH(C 1 -C 4 )alkyl-, (C6-C 10 )bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl-, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, halogen, cyano, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —C(O)NR a NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 NR a R b , nitro, —NR a R b , —NR a C(O)R b , —NR a C(O)NR a R b , —NR a C(O)OR a , —NR a SO 2 R b , —NR a SO 2 NR a R b , —NR a NR a R b , —NR a NR a C(O)R b , —NR a NR a C(O)NR a R b , —NR a NR a C(O)OR a , —OR a , —OC(O)R a , and —OC(O)NR a R b , wherein each (C3-C8)cycloalkyl, (C 6 -C 10 )bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by hydroxyl, halogen, nitro, (C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )alkoxy, —NR a R b or —CO 2 R a ;
R 4 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkyl, hydroxyl, halogen, cyano, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, —NR a R b , halo(C 1 -C 3 )alkyl, and hydroxy(C 1 -C 3 )alkyl;
R 5 is selected from the group consisting of (C 4 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkoxy, (C 4 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 2 )alkyl-, (C 3 -C 8 )cycloalkyloxy-, heterocycloalkyl, heterocycloalkyl(C 1 -C 2 )alkyl-, heterocycloalkyloxy-, aryl, heteroaryl, and —NR a R b , wherein said (C 4 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkoxy, (C 4 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 2 )alkyl-, (C 3 -C 8 )cycloalkyloxy-, heterocycloalkyl, heterocycloalkyl(C 1 -C 2 )alkyl-, heterocycloalkyloxy-, aryl, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by halogen, —OR a , —NR a R b , —NHCO 2 R a , nitro, (C 1 -C 3 )alkyl, R a R b N(C 1 -C 3 )alkyl-, R a O(C 1 -C 3 )alkyl-, (C 3 -C 8 )cycloalkyl, cyano, —CO 2 R a , —C(O)NR a R b , —SO 2 NR a R b , heterocycloalkyl, aryl, or heteroaryl, wherein said (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted 1 or 2 times, independently, by halogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, —CO 2 (C 1 -C 4 )alkyl, —NRaR b , —NHCO 2 R a , hydroxyl, oxo, (C 1 -C 4 )alkoxy, or (C 1 -C4)alkoxy(C 1 -C 4 )alkyl-; or any 2 optional substituents on said (C 2 -C 8 )alkenyl taken together with the carbon atom(s) to which they are attached represent a 5-8 membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted 1 or 2 times, independently, by (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, —CO 2 (C 1 -C 4 )alkyl, —NRaR b , —NHCO 2 R a , hydroxyl, oxo, (C 1 -C 4 )alkoxy, or (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-;
R 6 is selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, (C 1 -C 4 )alkoxy, —B(OH) 2 , (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 4 )alkyl-, (C 6 -C 10 )bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl-, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, cyano, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —C(O)NR a NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 NR a R b , nitro, —NR a R b , R a R b N(C 1 -C 4 )alkyl-, —NR a C(O)R b , —NR a C(O)NR a R b , —NR a C(O)OR a , —NR a SO 2 R b , —NR a SO 2 NR a R b , —NR a NR a R b , —NR a NR a C(O)R b , —NR a NR a C(O)NR a R b , —NR a NR a C(O)OR a , —OR a , —OC(O)R a , and —OC(O)NR a R b , wherein each cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by R c -(C 1 -C 6 )alkyl-O—, R c -(C 1 -C 6 )alkyl-S—, R c -(C 1 -C 6 )alkyl-, (C 1 -C 4 )alkyl-heterocycloalkyl-, halogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 1 -C 6 )alkyl, cyano, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 NR a R b , nitro, —NR a R b , —NR a C(O)R b , —NR a C(O)NR a R b , —NR a C(O)OR a , —NR a SO 2 R b , —NR a SO 2 NR a R b , —OR a , —OC(O)R a , —OC(O)NR a R b , heterocycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, or heteroaryl(C 1 -C 4 )alkyl;
R 7 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 4 )alkyl-, (C 6 -C 10 )bicycloalkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 4 )alkyl-, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, heteroaryl(C 1 -C 4 )alkyl, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —C(O)NRNR a R b , —SO 2 R a , —SO 2 NR a R b , and R a R b N(C 1 -C 4 )alkyl-, wherein each cycloalkyl, bicycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by R c -(C 1 -C 6 )alkyl-O—, (C 1 -C 4 )alkyl-heterocycloalkyl-, halogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, halo(C 1 -C 6 )alkyl, cyano, —C(O)R a , —CO 2 R a , —C(O)NR a R b , —S(O)R a , —SO 2 R a , —SO 2 NR a R b , nitro, —NR a R b , —NR a C(O)R b , —NR a C(O)NR a R b , —NR a C(O)OR a , —NR a SO 2 R b , —NR a SO 2 NR a R b , —OR a , —OC(O)R a , —OC(O)NR a R b , heteroc y cloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, or heteroaryl(C 1 -C 4 )alkyl;
R 8 is selected from the group consisting of (C 4 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 2 )alkyl-, aryl, and heteroaryl, wherein said (C 4 -C 8 )alkyl, (C 4 -C 8 )cycloalkyl, heterocycloalkyl, heterocycloalkyl(C 1 -C 2 )alkyl-, aryl, or heteroaryl is optionally substituted 1, 2, or 3 times, independently, by halogen, —OR a , —NR a R b , —NHCO 2 R a , nitro, (C 1 -C 3 )alkyl, R a R b N(C 1 -C 3 )alkyl-, R a O(C 1 -C 3 )alkyl-, (C 3 -C 8 )cycloalkyl, cyano, —CO 2 R a , —C(O)NR a R b , —SO 2 NR a R b , aryl, or heteroaryl;
each R c is independently —S(O)R a , —SO 2 R a , —NR a R b —NR a C(O)OR a , —NR a SO 2 R b , or —CO 2 R a ; and
R a and R b are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-, (C 3 -C 10 )cycloalkyl, heterocycloalkyl, aryl, aryl(C 1 -C 4 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, or heteroaryl, wherein any said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally substituted 1, 2, or 3 times, independently, by halogen, hydroxyl, (C 1 -C 4 )alkoxy, amino, —NH(C 1 -C 4 )alkyl, —N((C 1 -C 4 )alkyl) 2 , (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —CO 2 H, —CO 2 (C 1 -C 4 )alkyl, —CONH 2 , —CONH(C 1 -C 4 )alkyl, —CON((C 1 -C 4 )alkyl) 2 , —SO 2 (C 1 -C 4 )alkyl, —SO 2 NH 2 , —SO 2 NH(C 1 -C 4 )alkyl, or —SO 2 N((C 1 -C 4 )alkyl) 2 ;
or R a and R b taken together with the nitrogen to which they are attached represent a 5-8 membered saturated or unsaturated ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted 1, 2, or 3 times, independently, by (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, amino, —NH(C 1 -C 4 )alkyl, —N((C 1 -C 4 )alkyl) 2 , hydroxyl, oxo, (C 1 -C 4 )alkoxy, or (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-, wherein said ring is optionally fused to a (C 3 -C 8 )cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
or R a and R b taken together with the nitrogen to which they are attached represent a 6- to 10-membered bridged bicyclic ring system optionally fused to a (C 3 -C 8 )c

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Burgess Joelle Lorraine
• Knight Steven David

Classifications

• C07D409/14 Primary

  containing three or more hetero rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title