Inhibitors of lysine methyl transferase

• US 9,738,630 B2
• Filed: 11/18/2014
• Issued: 08/22/2017
• Est. Priority Date: 11/19/2013
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Kim, Kyoung S., Zhang, Liping, Purandare, Ashok Vinayak, Seitz, Steven P.
• Primary Examiner(s): O DELL, DAVID K
• Application Number:
  US15/037,081
• Publication Number:
  US 20160297806A1
• Time in Patent Office: 1,008 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

There are disclosed compounds that are inhibitors of EZH2, pharmaceutical compositions containing said compounds and methods of treating hyperproliferative, inflammatory, infectious, and immunoregulatory disorders and diseases, utilizing the compounds of the invention.

Claims

1. The compound which is

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N-((1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((7-fluoro-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

N-((6,7-Dimethoxy-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((6-methoxy-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-1-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

tert-Butyl 4-(5-(1-(sec-butyl)-3-methyl-4-(((1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)carbamoyl)-1H-indo-6-yl)pyridin-2-yl)piperazine-1-carboxylate,

1-(sec-Butyl)-3-methyl-N-((1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide,

N-((6,8-Difluoro-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((8-fluoro-1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N-((1-methyl-3-oxo-7-(trifluoromethyl)-2,3-dihydroisoquinolin-4-yl)methyl)-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((1-ethyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((1-ethyl-7-fluoro-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

N-((1,7-Dimethyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′

-(morpholinomethyl)-[1,1′

-biphenyl]-3-carboxamide,

2,2-Dimethyl-N-((1-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)methyl)-7-(6-(piperazin-1-yl)pyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamide, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.