IP Library › Granted Patent US 9,751,879
Granted Patent B2
US 9,751,879 · App. 15/219,611 · Granted Sep 5, 2017

Tricyclic compounds as anticancer agents

Inventors: Derek J. Norris (Pennington, NJ); George V. Delucca (Pennington, NJ); Ashvinikumar V. Gavai (Princeton Junction, NJ); Claude A. Quesnelle (Skillman, NJ); Patrice Gill (Levittown, PA); Daniel O'Malley (New Hope, PA); Wayne Vaccaro (Yardley, PA); Francis Y. Lee (Yardley, PA); Mikkel V. DeBenedetto (Middletown, CT); Andrew P. Degnan (Rocky Hill, CT); Haiquan Fang (Madison, CT); Matthew D. Hill (Wallingford, CT); Hong Huang (Durham, CT); William D. Schmitz (Cheshire, CT); John E. Starrett, Jr. (Waterford, CT); Wen-Ching Han (Newtown, PA); John S. Tokarski (Princeton, NJ); Sunil Kumar Mandal (Bangalore, IN)
Assignee: Bristol-Myers Squibb Company
C07D471/04A61K31/437
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Quick Facts
Patent No.
US 9,751,879
App. No.
15/219,611
Granted
Sep 5, 2017
Kind
B2
Abstract

The present invention is directed to tricyclic compounds, pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

Claims (125)

1. A compound of the formula

wherein:

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl, hydroxyalkyl, CN, CF 3 , CH 2 F, CHF 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted heterocyclo, —OR 4 , —CONR 3 R 4 , —NR 3 R 4 , NR 3 R 4 (C 1 -C 6 )alkyl-, —NR 6 OCOR 3 , —NR 6 COR 3 , NR 6 COR 3 (C 1 -C 6 )alkyl-, —NR 6 CO 2 R 3 , NR 6 CO 2 R 3 (C 1 -C 6 )alkyl-, —NR 6 CONR 3 R 4 , —SO 2 NR 3 R 4 , SO 2 (C 1 -C 6 )alkyl-, —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 or NR 6 SO 2 R 4 (C 1 -C 6 )alkyl-;

X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;

R 1 is, independently at each occurrence, one or more hydrogen, halogen, —CN, —OR 4 , —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NR 6 SO 2 — optionally substituted (C 1 -C 6 )alkyl, —NR 6 SO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NR 6 SO 2 — or optionally substituted heterocyclo-NR 6 SO 2 —;

R 2 is hydrogen, halogen, —CN, OH, —CONR 3 R 4 , —NR 6 COOR 4 , —NR 6 CONR 3 R 4 , —NR 6 COR 4 , —NR 6 SO 2 R 5 , —SO 2 NR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted aryl-SO 2 , optionally substituted heteroaryl or optionally substituted heterocyclo;

R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,

R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;

R 5 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl;

R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

R 7 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, —OR 4 , CN or halogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. A compound according to claim 1 of formula (II)

wherein:

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl, hydroxyalkyl, CN, CF 3 , CH 2 F, CHF 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted heterocyclo, —OR 4 , —CONR 3 R 4 , —NR 3 R 4 , NR 3 R 4 (C 1 -C 6 )alkyl-, —NR 6 OCOR 3 , —NR 6 COR 3 , NR 6 COR 3 (C 1 -C 6 )alkyl-, —NR 6 CO 2 R 3 , NR 6 CO 2 R 3 (C 1 -C 6 )alkyl-, —NR 6 CONR 3 R 4 , —SO 2 NR 3 R 4 , SO 2 (C 1 -C 6 )alkyl-, —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 or NR 6 SO 2 R 4 (C 1 -C 6 )alkyl-;

X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;

R 1 is, independently at each occurrence, one or more hydrogen, halogen, —CN, —OR 4 , —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NR 6 SO 2 — optionally substituted (C 1 -C 6 )alkyl, —NR 6 SO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl -NR 6 SO 2 — or optionally substituted heterocyclo-NR 6 SO 2 —;

R 2 is hydrogen, halogen, —CN, OH, —CONR 3 R 4 , —NR 6 COOR 4 , —NR 6 CONR 3 R 4 , —NR 6 COR 4 , —NR 6 SO 2 R 5 , —SO 2 NR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted aryl-SO 2 , optionally substituted heteroaryl or optionally substituted heterocyclo;

R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,

R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;

R 5 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl;

R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

R 7 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, —OR 4 , CN or halogen;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. A compound according to claim 2 of formula (II)

wherein:

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl, hydroxyalkyl, CN, CF 3 , CH 2 F, CHF 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted heterocyclo, —OR 4 , —CONR 3 R 4 , —NR 3 R 4 , NR 3 R 4 (C 1 -C 6 )alkyl-, —NR 6 OCOR 3 , —NR 6 COR 3 , NR 6 COR 3 (C 1 -C 6 )alkyl-, —NR 6 CO 2 R 3 , NR 6 CO 2 R 3 (C 1 -C 6 )alkyl-, —NR 6 CONR 3 R 4 , —SO 2 NR 3 R 4 , SO 2 (C 1 -C 6 )alkyl-, —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 or NR 6 SO 2 R 4 (C 1 -C 6 )alkyl-;

X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;

R 1 is, independently at each occurrence, one or more hydrogen, halogen, —CN, —OR 4 , —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NR 6 SO 2 — optionally substituted (C 1 -C 6 )alkyl, —NR 6 SO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NR 6 SO 2 — or optionally substituted heterocyclo-NR 6 SO 2 —;

R 2 is hydrogen, halogen, —CN, OH, optionally substituted (C 1 -C 6 )alkyl, optionally Substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,

R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;

R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. A compound according to claim 3 of the formula

wherein

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl, hydroxyalkyl, CN, CF 3 , CH 2 F, CHF 2 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted heterocyclo, —OR 4 , —CONR 3 R 4 , —NR 3 R 4 , NR 3 R 4 (C 1 -C 6 )alkyl-, —NR 6 OCOR 3 , —NR 6 COR 3 , NR 6 COR 3 (C 1 -C 6 )alkyl-, —NR 6 CO 2 R 3 , NR 6 CO 2 R 3 (C 1 -C 6 )alkyl-, —NR 6 CONR 3 R 4 , —SO 2 NR 3 R 4 , SO 2 (C 1 -C 6 )alkyl-, —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 or NR 6 SO 2 R 4 (C 1 -C 6 )alkyl-;

X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;

R 1 is, independently at each occurrence, one or more hydrogen, halogen, —CN, —OR 4 , —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NR 6 SO 2 — optionally substituted (C 1 -C 6 )alkyl, —NR 6 SO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NR 6 SO 2 — or optionally substituted heterocyclo-NR 6 SO 2 —;

R 2 is hydrogen, halogen, —CN, OH, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,

R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;

R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

5. A compound according to claim 4 of the formula

wherein:

A is

X and Y are independently selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —NR 3 R 4 , —CONR 3 R 4 , —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 or —NR 6 SO 2 R 4 ;

R 1 is, independently at each occurrence, one or more hydrogen, halogen, —CN, —OR 4 , —NR 3 R 4 , —CONR 3 R 4 , —COOH, —OCONR 3 R 4 , —NR 6 OCOR 3 , —NR 6 CONR 3 R 4 , —NR 6 SO 2 NR 3 R 4 , —NR 6 SO 2 R 4 , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl-CO—, optionally substituted (C 3 -C 8 )cycloalkyl-SO 2 —, optionally substituted aryl (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted heterocyclyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, —NR 6 SO 2 — optionally substituted (C 1 -C 6 )alkyl, —NR 6 SO 2 -optionally substituted heterocyclo, optionally substituted (C 1 -C 6 )alkyl-NR 6 SO 2 — or optionally substituted heterocyclo-NR 6 SO 2 —;

R 2 is hydrogen, halogen, —CN, OH, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 1 -C 6 ) alkoxy, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclo;

R 3 is hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, optionally substituted aryloxy(C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkyl-SO 2 —, optionally substituted heterocyclyl, optionally substituted heterocyclyl(C 1 -C 6 )alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl(C 1 -C 6 )alkyl,

R 4 is hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 8 )cycloalkyl;

or R 3 and R 4 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted (C 4 -C 8 ) heteroaryl or (C 4 -C 8 ) heterocyclic ring;

R 6 is hydrogen or optionally substituted (C 1 -C 6 )alkyl;

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

6. A compound selected from the following:

2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-(1,1,1,7,7,7-hexafluoroheptan-4-yl)-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,

2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,

2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(1S)-4,4,4-trifluoro-1-phenylbutyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,

2-[3-(dimethyl-1,2-oxazol-4-yl)-5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,

2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-5-[(4-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-ol,

2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl]propan-2-ol,

2-{3-[4-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazole,

5-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-7-methanesulfonyl-5H-pyrido[3,2-b]indol-3-yl}-4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazole,

2-{5-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,

2-{3-[5-( 2 H 3 )methyl-3-methyl-1,2-oxazol-4-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl}propan-2-ol

2-{3-[4-( 2 H 3 )methoxy-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl}propan-2-ol,

2-[3-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl]propan-2-ol,

(1R)-1-cyclopropyl-1-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl]ethan-1-ol,

2-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

(1S)-1-cyclopropyl-1-{6-fluoro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,

(1R)-1-cyclopropyl-1-{6-fluoro-3- [4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan -4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,

2-{5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol -5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{8-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{6-fluoro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{5-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{8-fluoro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

(1R)-1-cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,

2-{6-fluoro-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{6-chloro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-[(R)-(4,4-difluorocyclohexyl)({9-fluoro-7-methanesulfonyl-3-[4-( 2 H 3 )methyl-1-methyl -1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-5-yl})methyl]-3-fluoropyridine,

(1S)-1-cyclopropyl-1-{6-fluoro-5-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}ethan-1-ol,

2-{8-fluoro-5-[(5-methyl-1,2-oxazol-3-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{5-[(5-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{5-[(3-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{5-[(4-chloropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{5-[(4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methyl]-6-fluoro-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{6-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{3-[4-( 2 H 3 )methoxy-1-( 2 H 3 )methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol,

2-{3-[4-methoxy-1-( 2 H 3 )methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl}propan-2-ol,

5-{7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-methoxy-1-methyl-1H-1,2,3-triazole,

2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl]propan-2-amine,

N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl]propan-2-yl}acetamide,

N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl]propan-2-yl }methanesulfonamide,

methyl N-{2-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl]propan-2-yl }carbamate,

5-{6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,

5-{9-fluoro-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazole,

5-{6-methanesulfonyl-9-methoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,

N-[3-(dimethyl-1H-1,2,3-triazol-5-yl)-6-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-9-yl]cyclopropanesulfonamide,

5-{9-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-1,4-dimethyl-1H-1,2,3-triazole,

5-{9-methanesulfonyl-6,7-dimethoxy-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b ]indol-3-yl}-4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazole,

5-{9-fluoro-7-methanesulfonyl-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}-4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazole, or

2-{3-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b]indol-7-yl }propan-2-ol,

and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof

7. A compound according to claim 1 wherein the IC50 in the FRET BRD4 assay disclosed is less than 1500 nM.

8. A compound according to claim 1 wherein the IC50 in the FRET BRD4 assay disclosed is less than 25 nM.

9. A compound according to claim 1 wherein the IC50 in the FRET BRD4 assay disclosed is less than 5 nM.

10. A pharmaceutical composition which comprises a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. A combination pharmaceutical product comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents.

12. A method for inhibiting a bromodomain which comprises contacting the bromodomain with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. A method of treating cancer comprising administering a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer is small cell ling caner, non-small cell lung cancer, colorectal cancer, multiple myeloma or AML.

Continuity (3)
Continuation 14580355 · Dec 23, 2014
Provisional Application 61920500 · Dec 24, 2013
Related Publication 20160326173A1 · Nov 10, 2016