Benzimidazolone derivatives as bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9255089-B2
Application number	US-201414227736-A
Country	US
Kind code	B2
Filing date	Mar 27, 2014
Priority date	Mar 28, 2013
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, a bromodomain-containing protein, including bromodomain-containing protein 4 (BRD4), and to compositions and formulations containing such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I)

wherein R 1a , R 1b , R 2a , R 2b , R 3 , and X are described herein.

First claim

We claim:

1. A compound of Formula (I)

wherein
R 1a and R 1b are each independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, or CH 2 —C 3 -C 6 cycloalkyl;
R 2a and R 2b are each independently H or halogen;
R 3 is
C 5 -C 10 aryl, C 5 -C 10 heteroaryl, or C 5 -C 10 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
—S(O) 2 NHR 4 ,
wherein R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or

a moiety of the formula

wherein
R 6 is H, OH, or halogen; and R 7 and R 8 are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, or C 5 -C 12 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl; and R 7 and R 8 together form a C 1 -C 6 alkylidene group having a double bond with the carbon to which each of R 6 , R 7 , and R 8 are bound wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl groups is optionally substituted with from 1 to 5 R 20 groups;

X is N-Q, or O;
Q is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, benzyl or substituted benzyl;
each R 20 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 , wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl is optionally substituted with from one to five halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 ;
each R a and R b is independently H; or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, each of which is optionally substituted with from one to five R 21 ; or R a and R b together with the atoms to which they are attached form a heterocycle, and;
each R 21 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, or halogen;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , of Formula (Ia)

wherein
R 3 is
C 5 -C 10 aryl, C 5 -C 10 heteroaryl, or C 5 -C 10 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
—S(O) 2 NHR 4 ,
wherein R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or

a moiety of the formula

wherein
R 6 is H, OH, or halogen; and R 7 and R 8 are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, or C 5 -C 12 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl; and R 7 and R 8 together form a C 1 -C 6 alkylidene group having a double bond with the carbon to which each of R 6 , R 7 , and R 8 are bound wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl groups is optionally substituted with from 1 to 5 R 20 groups;

Q is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, benzyl or substituted benzyl;
each R 20 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 , wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl is optionally substituted with from one to five halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 ;
each R a and R b is independently H; or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, each of which is optionally substituted with from one to five R 21 ; or R a and R b together with the atoms to which they are attached form a heterocycle, and;
each R 21 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, or halogen;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , of Formula (Ib)

wherein
R 3 is
C 5 -C 10 aryl, C 5 -C 10 heteroaryl, or C 5 -C 10 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
—S(O) 2 NHR 4 ,
wherein R 4 is C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or

a moiety of the formula

wherein
R 6 is H, OH, or halogen; and R 7 and R 8 are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, or C 5 -C 12 heteroarylalkyl, each of which is optionally substituted with from 1 to 5 R 20 groups; or
R 6 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl; and R 7 and R 8 together form a C 1 -C 6 alkylidene group having a double bond with the carbon to which each of R 6 , R 7 , and R 8 are bound wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, phenyl, naphthyl, or C 3 -C 12 heteroaryl groups is optionally substituted with from 1 to 5 R 20 groups;

each R 20 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl, halogen, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) 0-2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 , wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 heterocyclic, C 5 -C 12 aryl, C 5 -C 12 heteroaryl is optionally substituted wit

Assignees

• Gilead Sciences Inc

Inventors

• Aktoudianakis Evangelos
• Chin Gregory
• Corkey Britton Kenneth
• Du Jinfa
• Elbel Kristyna
• Jiang Robert H
• Kobayashi Tetsuya
• Martinez Ruben
• Metobo Samuel E
• Mish Michael R
• Shevick Sophie
• Sperandio David
• Yang Hai
• Zablocki Jeff

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title