Substituted pyridine and pyrazine BMI-1 inhibitors

Patent metadata

Field	Value
Publication number	US-10584115-B2
Application number	US-201315037514-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Nov 21, 2013
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

Amine substituted pyridine and pyrazine compounds and forms thereof that inhibit the function and reduce the level of B-cell specific Moloney murine leukemia virus integration site 1 (Bmi-1) protein and methods for their use to inhibit Bmi-1 function and reduce the level of Bmi-1 to treat a cancer mediated by Bmi-1 are described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

or a form thereof, wherein
R 1 is bicyclic heteroaryl or bicyclic heterocyclyl selected from the group consisting of 1H-indolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 1H-benzimidazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 7H-purinyl and quinolinyl, substituted on a carbon atom ring member with one, two, three or four R 6 substituents or on a nitrogen atom ring member with an oxygen atom substituent to form an N-oxide;
R 2 and R 3 are independently hydrogen, cyano, halo, C 1-8 alkyl, amino, C 1-8 alkyl-amino or (C 1-8 alkyl) 2 -amino;
R 4 is aryl substituted with one, two, three or four R 7 substituents;
X is N—R 8 ;
R 6 is independently selected from the group consisting of cyano, halo, nitro, hydroxyl, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, halo-C 1-8 alkoxy, C 2-8 alkenyl, carboxyl, C 1-8 alkyl-amino-C 1-8 alkyl, hydroxyl-C 1-8 alkyl-amino, C 1-8 alkyl-thio, C 1-8 alkyl-carbonyl, C 1-8 alkyl-carbonyl-oxy-C 1-8 alkyl, and C 3-14 cycloalkyl, wherein C 3-14 cycloalkyl is optionally substituted with one, two, three or four halo, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, hydroxyl-C 1-8 alkoxy or carboxyl substituents;
R 7 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy, halo-C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, formyl, C 1-8 alkyl-carbonyl, halo-C 1-8 alkyl-carbonyl, C 1-8 alkyl-thio, halo-C 1-8 alkyl-thio, C 1-8 alkyl-amino, C 1-8 alkoxy-carbonyl, amino-carbonyl, C 1-8 alkyl-amino-carbonyl, hydroxyl-imino-C 1-8 alkyl, C 1-8 alkyl-sulfonyl, B(OR 10 ) 2 , and C 3-14 cycloalkyl, wherein C 3-14 cycloalkyl is optionally substituted with one, two, three or four halo or C 1-8 alkyl substituents;
R 8 is absent or an oxygen atom, wherein, when present, the oxygen atom forms an N-oxide with the nitrogen atom of attachment; and,
R 10 is independently hydrogen or C 1-8 alkyl;
wherein the form of the compound is selected from the group consisting of a salt, ester, hydrate, solvate, chelate, clathrate, isotopologue, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

2. A compound or a form thereof selected from the group consisting of:
6-(1H-benzimidazol-1-yl)-N-(4-methoxyphenyl)pyrazin-2-amine
6-(1H-benzimidazol-1-yl)-N-(4-iodophenyl)pyrazin-2-amine
N-(4-methoxyphenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
N-(3-fluoro-4-methoxyphenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-fluorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-chlorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-[4-(trifluoromethoxy)phenyl]-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(3-fluoro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrazin-2-amine
6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
6-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
N-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-7-yl]pyrazin-2-amine
6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethoxy)phenyl]pyrazin-2-amine
N-(4-chlorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrazin-2-amine
N-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrazin-2-amine
N-(3-chloro-4-methoxyphenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
4-({6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-yl}amino)benzonitrile
N-[4-(difluoromethoxy)phenyl]-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-chloro-3-fluorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(3,4-difluorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(3-chloro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrazin-2-amine
N-(3,4-dichlorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-bromo-3-fluorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-bromo-3-chlorophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-(4-methoxyphenyl)-6-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]pyrazin-2-amine
N-[4-(difluoromethoxy)phenyl]-6-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]pyrazin-2-amine
6-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethoxy)phenyl]pyrazin-2-amine
6-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
N-(4-methoxyphenyl)-6-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-[4-(difluoromethoxy)phenyl]-6-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
4-({6-[6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-yl}amino)benzonitrile
6-(2-ethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
6-(2-propyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
6-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethoxy)phenyl]pyrazin-2-amine
N-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-(4-methoxyphenyl)pyrazin-2-amine
6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
N-(4-nitrophenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-{6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-yl}benzene-1,4-diamine
N-methyl-1-(6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-1H-benzimidazol-2-amine
N-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrazin-2-amine
N-[4-(trifluoromethoxy)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrazin-2-amine
6-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
[1-(6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-1H-benzimidazol-2-yl]methanol
6-[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
N-[4-(methylsulfonyl)phenyl]-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
N-[4-(methylsulfanyl)phenyl]-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrazin-2-amine
6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine
N-[4-(difluoromethoxy)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrazin-2-amine
6-(2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine
N-(4-methoxyphenyl)-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrazin-2-amine
N-(4-methylphenyl)-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrazin-2-amine
1-(6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-1H-benzimidazol-2-amine
6-(2-methoxy-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine
(1S)-1-[1-(6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-

Assignees

• Ptc Therapeutics Inc

Inventors

• Baiazitov Ramil
• Choi Soongyu
• Du Wu
• Hwang Seongwoo
• Lee Chang-Sun
• Liu Ronggang
• Moon Young-Choon
• Paget Steven D
• Ren Hongyu
• Sydorenko Nadiya
• Wilde Richard Gerald

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title