Substituted triazine bmi-1 inhibitors

Patent metadata

Field	Value
Publication number	US-2016297798-A1
Application number	US-201315038039-A
Country	US
Kind code	A1
Filing date	Nov 21, 2013
Priority date	Nov 21, 2013
Publication date	Oct 13, 2016
Grant date	—

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 (I):

or a form thereof, wherein
X 1 is C—R 2 or N—R 8 ; wherein, when X 1 is C—R 2 , then X 2 and X 3 are each N—R 8 ; and, wherein, when X 1 is N—R 8 , then one of X 2 and X 3 is N—R 8 and the other is C—R 5 or C—R 3 , respectively;
X 2 is C—R 5 or N—R 8 ; wherein, when X 2 is C—R 5 , then X 1 and X 3 are each N—R 8 ; and, wherein, when X 2 is N—R 8 , then one of X 1 and X 3 is N—R 8 and the other is C—R 2 or C—R 3 , respectively;
X 3 is C—R 3 or N—R 8 ; wherein, when X 3 is C—R 3 , then X 1 and X 2 are each N—R 8 ; and, wherein, when X 3 is N—R 8 , then one of X 1 and X 2 is N—R 8 and the other is C—R 2 or C—R 5 , respectively;
R 1 is heteroaryl or heterocyclyl optionally 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 C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl, each optionally substituted with one, two, three or four R 7 substituents;
X is C—R 5 or N—R 8 ;
R 5 is hydrogen, 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 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 or 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 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 or 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 absent or an oxygen atom, wherein, when present, the oxygen atom forms an N-oxide with the nitrogen atom of attachment;
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 a salt, ester, hydrate, solvate, chelate, clathrate, polymorph, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

2 . The compound of claim 1 , wherein R 1 is optionally substituted heteroaryl or heterocyclyl selected from 1H-pyrazolyl, 1H-imidazolyl, 1,2-oxazolyl, pyridinyl, 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 or quinolinyl.

3 . The compound of claim 2 , wherein R 1 is optionally substituted heteroaryl selected from 1H-benzimidazolyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl or 1H-imidazo[4,5-b]pyridinyl.

4 . A compound or a form thereof is 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-m

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

• A61K31/5377

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title