Imidazolepyridine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10676479-B2
Application number	US-201716311575-A
Country	US
Kind code	B2
Filing date	Jun 9, 2017
Priority date	Jun 20, 2016
Publication date	Jun 9, 2020
Grant date	Jun 9, 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 3 , R 4 , R 6 , and R 7 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

R 1 and R 2 are each independently H or halogen;
R 3 is selected from: halogen, phenyl, and a 5- to 6-membered heteroaryl containing 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, OH, —(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 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 containing 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 containing 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 H, halogen or C 1 -C 4 alkyl;
R 5 is OH or C 1 -C 4 alkyl;
R 6 is selected from: H, halogen, CN, C 2 -C 4 alkynyl, —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)NR 3E R 3D , —S(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F , —CONHNH 2 , phenyl substituted with 0-2 R b , a 5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heteroaryl is substituted with 0-3 R 3A ;
R 7 is H;
R 11 is H, halogen, or NH 2 ;
R 12 is H, OCH 3 , or halogen;
R 13 is H or halogen;
R 14 is H, halogen, CH 3 , or OCH 3 ;
R 15 is H, halogen, CH 3 , OH, OCH 3 , OCH 2 F, OCHF 2 , or OCF 3 ;
each R a is independently selected from: H, 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 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 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. The 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 NR 3E R 3F , —NHS(═O) 2 (C 1 -C 4 alkyl), and —O—C 3 -C 6 cycloalkyl;
R 6 is selected from: H, halogen, CN, C 2 -C 4 alkynyl, —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)NR 3E R 3D , —S(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F , —CONHNH 2 , phenyl substituted with 0-1 R b , oxazolyl, tetrazolyl, pyridyl substituted with 0-2 R b ;
each R a is independently selected from: H, 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;
and
R 4 is H.

3. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 1 is H or F;
R 2 is H; and
R 3 is selected from: phenyl, and a 5- to 6-membered heteroaryl containing carbon atoms and 1-2 heteroatoms selected from O, N and NR a ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A ;
m is independently selected from 0 and 1; and
n is 0.

4. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
A is

R 1 is H or F;
R 3 is selected from: phenyl substituted with 0-3 R 3A , pyridyl substituted with 0-2 R 3A , pyrimidinyl substituted with 0-2 R 3A , isoxazolyl substituted with 0-2 R 3A , and

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

R 3B is selected from: halogen, OH, N(C 1 -C 4 alkyl) 2

R 4 is H;
R 6 is selected from: H, halogen, CN, C 2 -C 4 alkynyl, —CO(C 1 -C 4 alkyl), —CO 2 H, —CO 2 (C 1 -C 4 alkyl), C 1 -C 4 alkyl substituted with 0-1 OH, —CONH(C 1 -C 4 alkyl substituted with 0-1 OH), —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl), —S(═O)Ph, —S(═O) 2 Ph, —CONHNH 2 , phenyl substituted with 0-1 C 1 -C 4 alkoxy, oxazolyl, tetrazolyl, pyridyl substituted with 0-2 C 1 -C 4 alkyl,

R 7 is H; and
each R a is independently selected from: H, C 1 -C 4 alkyl substituted with 0-1 OH, —CO(C 1 -C 4 alkyl), and cyclopropyl.

5. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 3 is selected from: phenyl substituted with 0-3 R 3A , pyridyl substituted with 0-2 R 3A , and pyrimidinyl substituted with 0-2 R 3A ;
each R 3A is independently selected from: F, Cl, 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,

and
R 6 is selected from: H, Cl, CN, —C(═O)N(C 1 -C 4 alkyl) 2 , and —S(═O) 2 (C 1 -C 4 alkyl).

6. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 1 is F.

7. The compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said compound is selected from
8-(2,4-dimethylpyrimidin-5-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)imidazo[1,5-c]pyrimidin-5-amine;
5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-N-methyl-8-(2-methylpyridin-3-yl)imidazo[1,5-c]pyrimidine-1-carboxamide;
8-(2,4-dimethylpyrimidin-5-yl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,5-c]pyrimidine-1-carbonitrile;
N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)met

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title