Triazolopyridine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10689378-B2
Application number	US-201716311621-A
Country	US
Kind code	B2
Filing date	Jun 6, 2017
Priority date	Jun 20, 2016
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder:

wherein A, R 6 , R 7 and R 8 are as defined herein.

First claim

What is claimed is:

1. A compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein:
A is

W is independently N or CR 4 ;
Y is independently N or CR 3 ;
Z is independently N or CR 1 ;
R 1 is independently H, halogen, or NH 2 ;
R 2 is independently H, OCH 3 , or halogen;
R 3 is independently H or halogen;
R 4 is independently H, halogen, CH 3 , or OCH 3 ;
R 5 is independently H, halogen, CH 3 , OH, OCH 3 , OCH 2 F, OCHF 2 , or OCF 3 ;
R 6 and R 7 are independently selected from: H and halogen;
R 8 is independently selected from: halogen, phenyl, and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said phenyl and heteroaryl are substituted with 0-4 R 8A ;
each R 8A is independently selected from: halogen, CN, OH, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 8B ), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, R 8C , —OR 8C , —C(═O)R 8D , NR 8E R 8F , —C(C 1 -C 4 alkyl)═N(C 1 -C 4 alkoxy), —C(═O)NR 8E R 8F , —NHC(═O)R 8D , —NHC(═O)NR 8E R 8F , —S(═O)R 8D , —S(═O) 2 R 8D , —S(═O) 2 NR 8E R 8F , —NHS(═O) 2 R 8D , —NR 8E (S(═O) 2 (C 1 -C 4 alkyl)), and —CR 8C R 8E R 8G ;
R 8B is independently selected from: CN, OH, NR e R f , C 1 -C 4 alkoxy, —C(═O)NR e R f , —NHC(═O)(C 1 -C 4 alkyl), —N(→O)(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl), and a 4- to 6-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycloalkyl is substituted with 0-2 R c ;
each R 8C is independently selected from: C 3 -C 6 cycloalkyl, phenyl, and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein each moiety is substituted with 0-2 R c ;
each R 8D is independently selected from: C 1 -C 4 alkyl and R 8C ;
R 8E and R 8G are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each R 8F is independently selected from: H and C 1 -C 4 alkyl substituted with 0-1 R d ;
each R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, benzyl, and a 4- to 6-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR g , O, and S(O) p ;
R b is independently selected from: halogen, OH, C 1 -C 4 alkoxy, and

each R c is independently selected from: ═O, halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;
R d is independently selected from: OH and NR e R f ;
R e and R f are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
R g is independently selected from: H, C 1 -C 4 alkyl, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl);
each p is independently selected from 0, 1 and 2; and
m is independently selected from 0 and 1.

2. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
each R 8A is independently selected from: halogen, CN, OH, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 8B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, R 8C , —C(═O)R 8D , NR 8F R 8F , —C(═O)NR 8F R 8F , —NHC(═O)R 8D , —NHC(═O)NR 8F R 8F , —S(═O)R 8D , —S(═O) 2 R 8D , —S(═O) 2 NHR 8F , —NHS(═O) 2 R 8D , —NR 8F (S(═O) 2 (C 1 -C 4 alkyl)), —O—C 3 -C 6 cycloalkyl, and

and
each R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, benzyl,

3. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 1 is independently H, F, or Cl;
R 2 is independently H, OCH 3 , or F;
R 3 is independently H or F;
R 4 is independently H, F, CH 3 , or OCH 3 ;
R 5 is independently H, F, CH 3 , OH, OCH 3 , OCH 2 F, OCHF 2 , or OCF 3 ;
R 6 and R 7 are independently selected from: H and F; and
R a is independently selected from: H, C 1 -C 4 alkyl substituted with 0-1 R b , C 3 -C 6 cycloalkyl,

4. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 6 and R 7 are H;
R 8 is independently selected from: phenyl, and a 6-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N and NR a ; wherein said phenyl and heteroaryl are substituted with 0-3 R 8A .

5. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 8 is independently selected from:

6. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 8 is independently selected from:

7. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 8 is independently selected from:

each R 8A is independently selected from: halogen, CN, OH, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 8B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, NH 2 , —N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C(═O)(C 1 -C 4 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —NHC(═O)(C 1 -C 4 alkyl), —NHC(═O)N(C 1 -C 4 alkyl) 2 , —S(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 4 alkyl substituted with 0-1 OH), —S(═O) 2 N(C 1 -C 4 alkyl) 2 , —NHS(═O) 2 (C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(S(═O) 2 (C 1 -C 4 alkyl)), tetrazolyl,

R 8B is independently selected from: CN, OH, C 1 -C 4 alkoxy, —N(C 1 -C 4 alkyl) 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —NHC(═O)(C 1 -C 4 alkyl), —N(→O)(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl), imidazolyl,

R a is independently selected from: H and C 1 -C 4 alkyl; and
R c is independently C 1 -C 4 alkyl.

8. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 8 is independently selected from:

each R 8A is independently selected from: halogen, CN, OH, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 8B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —NHC(═O)(C 1 -C 4 alkyl), —NHC(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),

Assignees

• Novartis Ag

Inventors

• Chan Ho Man
• Fu Xingnian
• Gu Xiang-Ju Justin
• Huang Ying
• Li Ling
• Mi Yuan
• Qi Wei
• Sendzik Martin
• Sun Yongfeng
• Wang Long
• Yu Zhengtian
• Zhang Hailong
• Zhang Ji Yue
• Zhang Man
• Zhang Qiong
• Zhao Kehao

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title