Inhibitors of lysine methyl transferase

Patent metadata

Field	Value
Publication number	US-9822103-B2
Application number	US-201415037066-A
Country	US
Kind code	B2
Filing date	Nov 18, 2014
Priority date	Nov 22, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

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.

First claim

We claim:

1. A compound of formula (I)

wherein
the dotted line represents an optional double bond;
Z is O, CH 2 or a direct bond;
R 1 is hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 2 is hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 3 is hydrogen, halogen, —CN, —CONR 12 R 13 , optionally substituted C 6 -C 10 mono or bicyclic aryl, optionally substituted C 6 -C 10 mono or bicyclic heteroaryl, optionally substituted C 1 -C 6 alkyl C 6 aryl or optionally substituted C 1 -C 6 alkyl C 5 -C 8 heteroaryl, wherein the optional substituents are halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CONR 12 R 13 or heterocyclo;
R 4 , R 5 , R 6 , R 7 and R 8 are independently one or more hydrogen, flourine, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo; or
R 6 and R 7 may be taken together to form a fused C 3 -C 8 cycloalkyl group, or
R 4 and R 6 may be taken together to form a spiro C 4 -C 8 cycloalkyl group; or
R 7 and R 8 may be taken together to form a spiro C 3 -C 8 cycloalkyl group;
R 9 , R 10 and R 11 are independently hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or
R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo group;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1

wherein
R 1 is hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 2 is hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 3 is hydrogen, halogen, —CN, —CONR 12 R 13 , optionally substituted C 6 -C 10 mono or bicyclic aryl, optionally substituted C 6 -C 10 mono or bicyclic heteroaryl, optionally substituted C 1 -C 6 alkyl C 6 aryl or optionally substituted C 1 -C 6 alkyl C 5 -C 8 heteroaryl, wherein the optional substituents are halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CONR 12 R 13 or heterocyclo;
R 4 , R 5 , R 6 , R 7 and R 8 are independently one or more hydrogen, flourine, CF 3 or optionally substituted C 1 -C 6 alkyl; or
R 6 and R 7 may be taken together to form a fused C 3 -C 8 cycloalkyl group, or
R 4 and R 6 may be taken together to form a spiro C 4 -C 8 cycloalkyl group; or
R 7 and R 8 may be taken together to form a spiro C 3 -C 8 cycloalkyl group;
R 9 , R 10 and R 11 are independently hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or
R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo group;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. A compound of Formula (II)

wherein
Z is O, CH 2 or a direct bond;
R 1 is hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 2 is hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 3 is hydrogen, halogen, —CN, —CONR 12 R 13 , optionally substituted C 6 -C 10 mono or bicyclic aryl, optionally substituted C 6 -C 10 mono or bicyclic heteroaryl, optionally substituted C 1 -C 6 alkyl C 6 aryl or optionally substituted C 1 -C 6 alkyl C 5 -C 8 heteroaryl, wherein the optional substituents are halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CONR 12 R 13 or heterocyclo;
R 4 , R 5 , R 6 , R 7 and R 8 are independently one or more hydrogen, fluorine, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo; or
R 6 and R 7 may be taken together to form a fused C 3 -C 8 cycloalkyl group, or
R 7 and R 8 may be taken together to form a spiro C 3 -C 8 cycloalkyl group;
R 9 , R 10 and R 11 are independently hydrogen, halogen, CF 3 , optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl or optionally substituted heterocyclo;
R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or
R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo group;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. The compound according to claim 3 of the formula

wherein
Z is O, CH 2 or a direct bond;
R 1 is hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 2 is hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 3 is hydrogen, halogen, —CN, —CONR 12 R 13 , optionally substituted C 6 -C 10 mono or bicyclic aryl, optionally substituted C 6 -C 10 mono or bicyclic heteroaryl, optionally substituted C 1 -C 6 alkyl C 6 aryl or optionally substituted C 1 -C 6 alkyl C 5 -C 8 heteroaryl, wherein the optional substituents are halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CONR 12 R 13 or heterocyclo;
R 4 , R 5 , R 6 , R 7 and R 8 are independently one or more hydrogen, fluorine, CF 3 or optionally substituted C 1 -C 6 alkyl; or
R 6 and R 7 may be taken together to form a fused C 3 -C 8 cycloalkyl group, or
R 7 and R 8 may be taken together to form a spiro C 3 -C 8 cycloalkyl group;
R 9 , R 10 and R 11 are independently hydrogen, halogen, CF 3 or optionally substituted C 1 -C 6 alkyl;
R 12 and R 13 are independently hydrogen, C 1 -C 6 alkyl, or
R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo group;

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. The compound which is
7-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxamide,
7-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxamide,
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxamide,
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl

Assignees

• Bristol Myers Squibb Co

Inventors

• Seitz Steven P
• Markwalder Jay A
• Purandare Ashok Vinayak

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title