US 10,370,371 B2Granted

Substituted pyrimidine Bmi-1 inhibitors

AssigneePTC Therapeutics, Inc.

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

Life of this patent

Estimating the term…

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.

Claims7

Dependent claims

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;
R1 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 R5 substituents or on a nitrogen atom ring member with an oxygen atom substituent to form an N-oxide;
R2 is cyano, hydroxyl, nitro, C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, hydroxyl-amino, hydroxyl-C1-8alkyl-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkyl-thio, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-amino, amino-carbonyl, C1-8alkyl-amino-carbonyl, (C1-8alkyl)2-amino-carbonyl, amino-carbonyl-amino, C1-8alkyl-amino-carbonyl-amino, (C1-8alkyl)2-amino-carbonyl-amino, C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-amino, amino-sulfonyl, C1-8alkyl-amino-sulfonyl, (C1-8alkyl)2-amino-sulfonyl, amino-sulfonyl-amino, C1-8alkyl-amino-sulfonyl-amino, (C1-8alkyl)2-amino-sulfonyl-amino, P(O)(R7)2-amino or heteroaryl, wherein heteroaryl is optionally substituted with one, two, three or four C1-8alkyl substituents;
R3is hydrogen, cyano, halo, C1-8alkyl, amino, C1-8alkyl-amino or (C1-8alkyl)2-amino;
R4 is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl, each optionally substituted with one, two, three or four R6 substituents;
R5 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, oxo, C1-8alkyl, cyano-C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, C1-8alkyl-thio, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkyl-sulfonyl, C3-14cycloalkyl, aryl, aryl-C1-8alkyl, aryl-amino, aryl-C1-8alky-amino, heteroaryl, heteroaryl-C1-8alkyl and heterocyclyl, wherein C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl and the aryl and heteroaryl portions of aryl-C1-8alkyl, aryl-amino, aryl-C1-8alky-amino and heteroaryl-C1-8alkyl are each optionally substituted with one, two, three or four halo, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxyl-C1-8alkoxy or carboxyl substituents;
R6 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, formyl, formyl-oxy, C1-8alkyl-carbonyl, halo-C1-8alkyl-carbonyl, C1-8alkyl-thio, halo-C1-8alkyl-thio, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, halo-C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkoxy-carbonyl-amino-C1-8alkyl, amino-carbonyl, C1-8alkyl-amino-carbonyl, (C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, imino-C1-8alkyl, hydroxyl-imino-C1-8alkyl, C1-8alkoxy-imino-C1-8alkyl, C1-8alkyl-sulfonyl, halo-C1-8alkyl-sulfonyl, amino-sulfonyl, C1-8alkyl-amino-sulfonyl, (C1-8alkyl)2-amino-sulfonyl, B(OR8)2, C3-14cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein C3-14cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one, two, three or four halo or C1-8alkyl substituents;
R7 is independently hydroxyl or (C1-8alkoxy)n, wherein n represents an integer from 1 to 5;
and,
R8 is independently hydrogen or C1-8alkyl;
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

9 more elements

A compound or a form thereof selected from the group consisting of:

N2-[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)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[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)-N2-[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
N2-[4-(difluoromethoxy)-3-fluorophenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[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)-N2-[4-(difluoromethoxy)-3-fluorophenyl]pyrimidine-2,4-diamine
N2-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[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)-N2-[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
N4-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N2-[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)-N2-[3-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(quinolin-4-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
4-chloro-N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-amine
6-(6-chloro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-chloro-2-ethyl-1H-imidazo [4,5-b]pyridin-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
4-chloro-6-(2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine
6-(2-methyl-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
4-chloro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-2-amine
6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
6-(6-bromo-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
-6-(2,6-dimethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
6-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-chloro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-ol
6-(5-chloro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(5,7-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(4-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2,6-dimethyl-1H-benzimidazol-1-yl)-N2-[3-methyl-4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2,6-dimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-5-fluoro-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
5-fluoro-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-5-fluoro-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(4,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
5-fluoro-6-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5,6-difluoro-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidine-4-carbonitrile
6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-6-fluoro-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-6-fluoro-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
6-[2-(methoxymethyl)-1H-benzimidazol-1-yl]-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-5,6-difluoro-1H-benzimidazol-1-yl) pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(methoxymethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[6-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[5-fluoro-2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
6-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-[2-(propan-2-yl)-1H-benzimidazol-1-yl]pyrimidine-2,4-diamine
6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4-diamine
6-(5-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
6-(6-chloro-2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-[6-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine
6-(5-chloro-2-ethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-chloro-2-ethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(trifluoromethyl)phenyl]-6-[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidine-2,4-diamine
[6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl]phosphoramidic acid
6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)pyrimidine-2,4-diamine
6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-ethyl-5-fluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)-3 -fluorophenyl]-6-(5-fluoro-2-methyl-1H -benzimidazol-1-yl)p yrimidine-2,4-diamine
6-(2-cyclopropyl-5-methoxypyrazolo [1,5-a]p yridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-4-oxido-1H-imidazo[4,5-b]pyridin-1-yl-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(5-fluoro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide
6-(2-ethyl-5-fluoropyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide
4-chloro-6-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine
6-(5-methoxy-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine 3-oxide
6-(2-cyclopropyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide
3-(6-amino-2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)-2,5,6-trimethylpyrazolo[1,5-c]pyrimidin-7(6H)-one
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine 3-oxide
6-(5-amino-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
6-(5-chloro-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(5-chloro-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(difluoromethoxy)phenyl]pyrimidine-2,4-diamine
6-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N2-(3-methylphenyl)pyrimidine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-bromophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N2-(4-nitrophenyl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(dimethylamino)phenyl]-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
4-{[4-amino-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(3-fluorophenyl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(3-methylphenyl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(3-methoxyphenyl)pyrimidine-2,4-diamine
N2-(3-chlorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-fluoro-4-methoxyphenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-phenylpyrimidine-2,4-diamine
N2-[4-(dimethylamino)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
4-{[4-amino-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile
6-(2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethoxy)phenyl[pyrimidine-2,4-diamine
N2-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-fluoro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-chloro-4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-(2-methylphenyl)pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(1,3-benzodioxol-5-yl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-1H-benzimidazol-1-yl)-N2-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamine
N2-(3-chloro-4-methoxyphenyl)-6-(2-ethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(6-methoxypyridin-3-yl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-phenylpyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4-diamine
N2-[4-(dimethylamino)phenyl]-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(3-fluorophenyl)pyrimidine-2,4-diamine
N2-(3-chlorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(3-methoxyphenyl)pyrimidine-2,4-diamine
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(3-methylphenyl)pyrimidine-2,4-diamine
4-{[4-amino-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidin-2-yl]amino}benzonitrile
6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)-N2-(3-fluoro-4-methoxyphenyl)pyrimidine-2,4-diamine
N2-(4-chloro-3-fluorophenyl)-6-(6-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chloro-3-fluorophenyl)-6-(2-ethyl-6-fluoro-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
5-fluoro-N2-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
5-fluoro-6-(2-methyl-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(4-chloro-3-fluorophenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-methylphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-fluoro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-chloro-4-methoxyphenyl)-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-[4-(difluoromethoxy)phenyl]-6-(2,5,6-trimethyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(3,5-dimethyl-1,2-oxazol-4-yl)-N2-(4-methoxyphenyl)pyrimidine-2,4-diamine
6-(3,5-dimethyl-1,2-oxazol-4-yl)-N2-(4-methylphenyl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chloro-3-fluorophenyl)-6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(3-chlorophenyl)-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(4-nitrophenyl)pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(3-methylphenyl)pyrimidine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N2-(3-methoxyphenyl)pyrimidine-2,4-diamine
5-chloro-N2-(4-methoxyphenyl)-6-(2-methyl-1H-benzimidazol-1-yl)pyrimidine-2,4-diamine
N2-(4-chlorophenyl)-6-(3,5-dimethylisoxazol-4-yl)pyrimidine-2,4-diamine;
and,
6-(5-fluoro-2-methyl-1H-benzimidazol-1-yl)-N2-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine3-oxide;
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

183 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/914,909Filed 21 Nov 2013 · us provisional application
Priority: 30 Aug 2013
Published: US 2016/0214978 A128 Jul 2016
Granted: 6 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents

Family

Application61/872,091Us provisional application · filed 30 Aug 2013
US 2016/0214978 A1Pre-grant publication · published 28 Jul 2016
US 10,370,371 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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;
R1 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 R5 substituents or on a nitrogen atom ring member with an oxygen atom substituent to form an N-oxide;
R2 is cyano, hydroxyl, nitro, C1-8alkoxy, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, hydroxyl-amino, hydroxyl-C1-8alkyl-amino, C1-8alkoxy-C1-8alkyl-amino, C1-8alkyl-thio, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-amino, amino-carbonyl, C1-8alkyl-amino-carbonyl, (C1-8alkyl)2-amino-carbonyl, amino-carbonyl-amino, C1-8alkyl-amino-carbonyl-amino, (C1-8alkyl)2-amino-carbonyl-amino, C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-amino, amino-sulfonyl, C1-8alkyl-amino-sulfonyl, (C1-8alkyl)2-amino-sulfonyl, amino-sulfonyl-amino, C1-8alkyl-amino-sulfonyl-amino, (C1-8alkyl)2-amino-sulfonyl-amino, P(O)(R7)2-amino or heteroaryl, wherein heteroaryl is optionally substituted with one, two, three or four C1-8alkyl substituents;
R3is hydrogen, cyano, halo, C1-8alkyl, amino, C1-8alkyl-amino or (C1-8alkyl)2-amino;
R4 is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl, each optionally substituted with one, two, three or four R6 substituents;
R5 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, oxo, C1-8alkyl, cyano-C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, C1-8alkyl-thio, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkyl-sulfonyl, C3-14cycloalkyl, aryl, aryl-C1-8alkyl, aryl-amino, aryl-C1-8alky-amino, heteroaryl, heteroaryl-C1-8alkyl and heterocyclyl, wherein C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl and the aryl and heteroaryl portions of aryl-C1-8alkyl, aryl-amino, aryl-C1-8alky-amino and heteroaryl-C1-8alkyl are each optionally substituted with one, two, three or four halo, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxyl-C1-8alkoxy or carboxyl substituents;
R6 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, formyl, formyl-oxy, C1-8alkyl-carbonyl, halo-C1-8alkyl-carbonyl, C1-8alkyl-thio, halo-C1-8alkyl-thio, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, halo-C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkoxy-carbonyl-amino-C1-8alkyl, amino-carbonyl, C1-8alkyl-amino-carbonyl, (C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, imino-C1-8alkyl, hydroxyl-imino-C1-8alkyl, C1-8alkoxy-imino-C1-8alkyl, C1-8alkyl-sulfonyl, halo-C1-8alkyl-sulfonyl, amino-sulfonyl, C1-8alkyl-amino-sulfonyl, (C1-8alkyl)2-amino-sulfonyl, B(OR8)2, C3-14cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein C3-14cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one, two, three or four halo or C1-8alkyl substituents;
R7 is independently hydroxyl or (C1-8alkoxy)n, wherein n represents an integer from 1 to 5;
and,
R8 is independently hydrogen or C1-8alkyl;
wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

9 more elements

Facts

Application

14/914,909Filed 21 Nov 2013 · us provisional application

Priority

30 Aug 2013

Published

US 2016/0214978 A128 Jul 2016

Granted

6 Aug 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents