Triazolopyrimidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9580437-B2
Application number	US-201514977273-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Dec 23, 2014
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

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

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined herein.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
is a single bond or a double bond;
R 1 and R 2 are independently H or halogen;
R 3 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 0-3 R 3A ;
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 3B ), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, R 3C , —OR 3C , —C(═O)R 3D , NR 3E R 3F , —C(═O)NR 3E R 3F , —NHC(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F , —NHS(═O) 2 (C 1 -C 4 alkyl), and —CR 3C R 3E R 3G ;
R 3B is independently selected from: OH, NR e R f , C 1 -C 4 alkoxy, —C(═O)NR e R f , —S(═O) 2 (C 1 -C 4 alkyl), —NHC(═O)(C 1 -C 4 alkyl), and a 5- 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 3C 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 3D is independently selected from: C 1 -C 4 alkyl and R 3C ;
R 3E and R 3G are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each R 3F is independently selected from: H and C 1 -C 4 alkyl substituted with 0-1 R d ;
R 4 is independently selected from: H, halogen and C 1 -C 4 alkyl;
R 5 is independently selected from OH and C 1 -C 4 alkyl;
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, and benzyl;
R b is independently selected from: halogen, OH and C 1 -C 4 alkoxy;
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;
each p is independently selected from 0, 1 and 2; and
m and n are, at each occurrence, independently selected from 0 and 1.

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

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), and C 3 -C 6 cycloalkyl;
R 4 is H;
m is independently selected from 0 and 1; and
n is 0.

3. A compound or a pharmaceutically acceptable salt thereof, according to claim 2 , wherein:
R 1 is independently H or F;
R 2 is H; and
R 3 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 3A .

4. A compound or a pharmaceutically acceptable salt thereof, according to claim 3 , wherein:
R 3 is independently selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl; wherein each moiety is substituted with 0-3 R 3A .

5. A compound or a pharmaceutically acceptable salt thereof, according to claim 4 , wherein:
R 3 is independently selected from:

6. A compound or a pharmaceutically acceptable salt thereof, according to claim 4 , wherein:
R 3 is independently selected from:

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

R 3B is independently selected from: OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C1-C4 alkyl),

R 3D is independently selected from: C 1 -C 4 alkyl and 1H-piperidin-4-yl; and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).

7. A compound or a pharmaceutically acceptable salt thereof, according to claim 6 , wherein:
R 3 is independently selected from:

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

R 3B is independently selected from: OH, N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),

 and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).

8. A compound or a pharmaceutically acceptable salt thereof, according to claim 7 , wherein:
each R 3A is independently selected from: F, CI, CH 3 , —CH 2 OH, CH 2 F, CHF 2 , CF 3 , CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCHF 2 , —C(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)CH 3 , —S(═O) 2 CH 3 , NH 2 , cyclopropyl,

9. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said compound is of Formula (IA-1):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently H or F; and
R 3A is independently selected from: F, CH 3 , —CH 2 OH, CH 2 F, CHF 2 , CF 3 , and —OCH 3 .

10. A compound or a pharmaceutically acceptable salt thereof, according to claim 9 , wherein:
R 1 is F.

11. A compound according to claim 1 , wherein:
R 1 is independently H or F;
R 2 is H;
R 3 is independently a 5-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selec

Assignees

• Chan Ho Man
• 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 (Jeff)
• Zhang Man
• Zhang Qiong
• Zhao Kehao
• Novartis Ag

Inventors

• Chan Ho Man
• 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 (Jeff)
• Zhang Man
• Zhang Qiong
• Zhao Kehao

Classifications

• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title