Substituted reverse pyrimidine Bmi-1 inhibitors

Patent metadata

Field	Value
Publication number	US-10428050-B2
Application number	US-201314443911-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Nov 21, 2012
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

Amine substituted reverse pyrimidine 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 substituted on a carbon atom ring member with one, two, three or four R 5 substituents, or on a nitrogen atom ring member with an oxygen atom substituent to form an N-oxide;
X is N or N substituted with an oxygen atom substituent to form an N-oxide;
R 2 is amino;
R 3 is hydrogen, cyano, halo, C 1-8 alkyl, amino, C 1-8 alkyl-amino or (C 1-8 alkyl) 2 -amino;
R 4 is phenyl, optionally substituted with one, two, three or four R 6 substituents;
R 5 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, oxo, C 1-8 alkyl, cyano-C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-C 1-8 alkyl, halo-C 1-8 alkoxy, C 2-8 alkenyl, C 1-8 alkoxy-C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy-C 2-8 alkynyl, carboxyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, hydroxyl-C 1-8 alkyl-amino, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl-amino, C 1-8 alkyl-thio, C 1-8 alkyl-carbonyl, C 1-8 alkyl-carbonyl-amino, C 1-8 alkyl-carbonyl-oxy, C 1-8 alkyl-carbonyl-oxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-C 1-8 alkyl, C 1-8 alkoxy-carbonyl-amino, C 1-8 alkyl-sulfonyl, C 3-14 cycloalkyl, aryl, aryl-C 1-8 alkyl, aryl-amino, aryl-C 1-8 alkyl-amino, heteroaryl, heteroaryl-C 1-8 alkyl and heterocyclyl, wherein C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl and the aryl and heteroaryl portions of aryl-C 1-8 alkyl, aryl-amino, aryl-C 1-8 alky-amino and heteroaryl-C 1-8 alkyl are each 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 6 is independently selected from the group consisting of cyano, halo, 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 1-8 alkoxy-C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy-C 2-8 alkynyl, carboxyl, formyl, formyl-oxy, C 1-8 alkyl-carbonyl, halo-C 1-8 alkyl-carbonyl, C 1-8 alkyl-thio, halo-C 1-8 alkyl-thio, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, C 1-8 alkyl-carbonyl, C 1-8 alkyl-carbonyl-oxy, C 1-8 alkyl-carbonyl-oxy-C 1-8 alkyl, C 1-8 alkoxy-carbonyl, halo-C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-C 1-8 alkyl, C 1-8 alkoxy-carbonyl-amino, C 1-8 alkoxy-carbonyl-amino-C 1-8 alkyl, amino-carbonyl, C 1-8 alkyl-amino-carbonyl, (C 1-8 alkyl) 2 -amino-carbonyl, C 1-8 alkyl-carbonyl-amino, C 1-8 alkyl-carbonyl-amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl-amino, C 1-8 alkyl-amino-C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino, hydroxyl-C 1-8 alkyl-amino, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl, hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl-amino, imino-C 1-8 alkyl, hydroxyl-imino-C 1-8 alkyl, C 1-8 alkoxy-imino-C 1-8 alkyl, C 1-8 alkyl-sulfonyl, halo-C 1-8 alkyl-sulfonyl, amino-sulfonyl, C 1-8 alkyl-amino-sulfonyl, (C 1-8 alkyl) 2 -amino-sulfonyl, B(OR 8 ) 2 , C 3-14 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein C 3-14 cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one, two, three or four halo or C 1-8 alkyl substituents;
R 8 is independently hydrogen or C 1-8 alkyl;
wherein the form of the compound is selected from the group consisting of a free acid, free base, salt, ester, hydrate, solvate, chelate, clathrate, isotopologue, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

2. The compound of claim 1 , or form thereof, wherein R 1 is substituted bicyclic heteroaryl or bicyclic heterocyclyl selected from the group consisting of 1H-indolyl, 2H-indazolyl, 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.

3. The compound of claim 2 , or form thereof, wherein R 1 is substituted bicyclic heteroaryl selected from the group consisting of 1H-indolyl, 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl and imidazo[1,2-a]pyrimidinyl.

4. A compound or form thereof, selected from the group consisting of:
2-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
N-[4-(difluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-4,6-diamine,
2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
N-[4-(trifluoromethoxy)phenyl]-2-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-4,6-diamine,
2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-4,6-diamine,
N-[4-(trifluoromethyl)phenyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-4,6-diamine,
2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
N-[4-(difluoromethoxy)phenyl]-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine,
2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)-N-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-4,6-diamine,
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine,
N-[4-(difluoromethoxy)-3-fluorophenyl]-2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine,
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-4,6-diamine,
N-[4-(trifluoromethyl)phenyl]-2-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine,
N-[3-fluoro-4-(trifluoromethyl)phenyl]-2-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-4,6-diamine,
2-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
[3-(4-amino-6-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl]methanol,
2-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(2,6-dimethyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(6-ethyl-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(6-ethenyl-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(2-cyclopropyl-6-fluoro-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine,
2-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-4,6

Assignees

• Ptc Therapeutics Inc

Inventors

• Lee Chang-Sun
• Baiazitov Ramil
• Cao Liangxian
• Davis Thomas W
• Du Wu
• Liu Ronggang
• Moon Young-Choon
• Paget Steven D
• Ren Hongyu
• Sydorenko Nadiya
• Wilde Richard Gerald

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/04

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

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D403/12 Primary

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