Substituted pyrimidine Bmi-1 inhibitors

Patent metadata

Field	Value
Publication number	US-10370371-B2
Application number	US-201314914909-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Aug 30, 2013
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

Amine substituted 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
X is N or N substituted with an oxygen atom substituent to form an N-oxide;
R 1 is bicyclic heteroaryl selected from the group consisting of 1H-indolyl, 2H-indazolyl, 1H-benzimidazolyl, pyrazolo[1,5-a ]pyridinyl, pyrazolo[1,5-c]pyrimidinyl, 1H-imidazo[4,5-b ]pyridinyl, 1H-imidazo[4,5-c ]pyridinyl, imidazo[1,2-a]pyrazinyl, 7H-purinyl and quinolinyl, wherein the heteroatom is N, wherein the bicyclic heteroaryl is 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;
R 2 is cyano, hydroxyl, nitro, C 1-8 alkoxy, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, hydroxyl-amino, hydroxyl-C 1-8 alkyl-amino, C 1-8 alkoxy-C 1-8 alkyl-amino, C 1-8 alkyl-thio, C 1-8 alkyl-carbonyl, C 1-8 alkyl-carbonyl-amino, amino-carbonyl, C 1-8 alkyl-amino-carbonyl, (C 1-8 alkyl) 2 -amino-carbonyl, amino-carbonyl-amino, C 1-8 alkyl-amino-carbonyl-amino, (C 1-8 alkyl) 2 -amino-carbonyl-amino, C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-amino, amino-sulfonyl, C 1-8 alkyl-amino-sulfonyl, (C 1-8 alkyl) 2 -amino-sulfonyl, amino-sulfonyl-amino, C 1-8 alkyl-amino-sulfonyl-amino, (C 1-8 alkyl) 2 -amino-sulfonyl-amino, P(O)(R 7 ) 2 -amino or heteroaryl, wherein heteroaryl is optionally substituted with one, two, three or four C 1-8 alkyl substituents;
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 C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl, each 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 alky-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, 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 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 7 is independently hydroxyl or (C 1-8 alkoxy) n , wherein n represents an integer from 1 to 5; and,
R 8 is independently hydrogen or C 1-8 alkyl;
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

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

3. A compound or a form thereof selected from the group consisting of:
N 2 -[4-(trifluoromethyl)phenyl]-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N 2 -[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
4-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine
6-(2-methyl-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
4-chloro-N-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine
N 2 -[4-(difluoromethoxy)-3-fluorophenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N 2 -[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N 2 -[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2,4-diamine
N 2 -[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N 2 -[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
2-{[6-(2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol
2-{[2-{[3-fluoro-4-(trifluoromethyl)phenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol
2-{[2-{[4-(difluoromethoxy)-3-fluorophenyl]amino}-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-4-yl]amino}ethanol
4-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine
4-chloro-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-2-amine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
2-{[6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]amino}ethanol
N 4 -hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N 2 -[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(quinolin-4-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N 2 -[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
4-chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-am

Assignees

• Ptc Therapeutics Inc

Inventors

• Du Wu
• Baiazitov Ramil
• Lee Chang-Sun
• Moon Young-Choon
• Paget Steven D
• Ren Hongyu
• Sydorenko Nadiya
• Wilde Richard Gerald

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D403/04 Primary

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

• C07D401/04

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

• C07D239/48 Primary

  Two nitrogen atoms · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title