Substituted triazine BMI-1 inhibitors

Patent metadata

Field	Value
Publication number	US-9975878-B2
Application number	US-201315038039-A
Country	US
Kind code	B2
Filing date	Nov 21, 2013
Priority date	Nov 21, 2013
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

Amine substituted triazine 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 (IIa):

or a form thereof, wherein
R 1 is 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, wherein R 1 is 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 4 is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl, each optionally substituted with one, two, three or four R 7 substituents;
R 5 is cyano, halo, hydroxyl, nitro, C 1-8 alkyl, hydroxyl-C 1-8 alkyl, 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 9 ) 2 -amino or heteroaryl, wherein heteroaryl is optionally substituted with one, two, three or four C 1-8 alkyl substituents;
R 6 is independently selected from the group consisting of cyano, halo, nitro, oxo, hydroxyl, 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 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 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 10 ) 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 9 is independently hydroxyl or (C 1-8 alkoxy) n , wherein n represents an integer from 1 to 5; 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, polymorph, isotopologue, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.

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

3. A compound or a form thereof selected from the group consisting of:
N-(3-fluoro-4-methoxyphenyl)-6-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-1,3,5-triazine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4-diamine
N-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-[3-fluoro-4-(trifluoromethyl)phenyl]-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-(1H-indol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-(1-benzofuran-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
N-[4-(difluoromethoxy)-3-fluorophenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-[4-(difluoromethoxy)phenyl]-6-(5,6-difluoro-2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
6-(5,6-dichloro-2-methyl-1H-benzimidazol-1-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
N-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N′-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
6-(2-methyl-1H-benzimidazol-1-yl)-N-(quinolin-6-yl)-1,3,5-triazine-2,4-diamine
N-(1,3-benzoxazol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-hydroxy-6-(2-methyl-1H-benzimidazol-1-yl)-N′-(quinolin-6-yl)-1,3,5-triazine-2,4-diamine
6-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
N-(1,3-benzodioxol-5-yl)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
2-{[4-(1,3-benzodioxol-5-ylamino)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazin-2-yl]amino}ethanol
6-(2-methyl-1H-benzimidazol-1-yl)-N-(quinolin-3-yl)-1,3,5-triazine-2,4-diamine
2-{[4-(2-methyl-1H-benzimidazol-1-yl)-6-(quinolin-3-ylamino)-1,3,5-triazin-2-yl]amino}ethanol
N-(isoquinolin-3-yl)-6-(2-methyl-1H-benzimidazol-1-yl)-1,3,5-triazine-2,4-diamine
N-[4-(difluoromethoxy)phenyl]-6-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-1,3,5-triazine-2,4-diamine
6-(6-fluoro-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
6-[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]-N-[4-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4-diamine
6-(6-fluoro-2-methyl-1H-benzimid

Assignees

• Ptc Therapeutics Inc

Inventors

• Koyama Hiroo
• Baiazitov Ramil
• Du Wu
• Lee Chang-Sun
• Moon Young-Choon
• Paget Steven D
• Ren Hongyu
• Sydorenko Nadiya

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/04 Primary

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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title