IP Library › Granted Patent US 9,725,449
Granted Patent B2
US 9,725,449 · App. 15/150,492 · Granted Aug 8, 2017

Tricyclic compounds as anticancer agents

Inventors: Derek J. Norris (Pennington, NJ); Wayne Vaccaro (Yardley, PA); Mikkel V. DeBenedetto (Middletown, CT); Andrew P. Degnan (Rocky Hill, CT); George V. Delucca (Pennington, NJ); Jeffrey A. Deskus (Marlborough, CT); Wen-Ching Han (Newtown, PA); Godwin Kwame Kumi (Rocky Hill, CT); William D. Schmitz (Cheshire, CT); John E. Starrett, Jr. (Waterford, CT); Matthew D. Hill (Wallingford, CT); Hong Huang (Durham, CT)
Assignee: Bristol-Myers Squibb Company
C07D471/14A61K31/439A61K31/4375A61K31/444A61K31/4545A61K31/496A61K31/519A61K31/5377A61K31/541A61K31/554A61K31/675A61K31/683C07D519/00C07F9/6561
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Quick Facts
Patent No.
US 9,725,449
App. No.
15/150,492
Granted
Aug 8, 2017
Kind
B2
Abstract

The present invention is directed to tricyclic compounds of the formula wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

Claims (180)

1. The compound of the formula

wherein

U 1 , U 2 , U 3 and U 4 are independently —N— or —CH—, provided that at least one of them is —N—;

W 1 , W 2 and W 3 are independently —N— or —CH—, provided that at least one of them is —N—;

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

p is 0, 1 or 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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. A compound according to claim 1

wherein:

U 1 , U 2 , U 3 and U 4 are independently —N— or —CH—, provided that at least one of them is —N—;

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

p is 0, 1 or 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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

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

wherein:

U 1 , U 2 , U 3 and U 4 are independently —N— or —CH—, provided that at least one of them is —N—;

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. A compound according to claim 1 of the formula

wherein

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

6. A compound according to claim 1 of the formula

wherein:

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

7. A compound according to claim 6 wherein

A is

8. A compound according to claim 1 of the formula

wherein:

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

9. A compound according to claim 8 wherein

A is

10. A compound according to claim 1 of the formula

wherein:

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 5 )cycloalkyl (C 1 -C 6 )alkoxy, optionally substituted heterocyclyl-CO—, optionally substituted 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

11. A compound according to claim 10 wherein

A is

12. A compound according to claim 1 of the formula

wherein:

A is

R is independently one or more hydrogen, CD 3 , halogen, haloalkyl hydroxyalkyl, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl;

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, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl or halo;

Z is hydrogen, halogen, —OH, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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 4-10 membered mono or azabicyclo heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) p , 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 —, wherein the optional substituents in each case are independently alkyl, cycloalkyl, aryl, 5-7 membered heterocyclyl comprising carbon atoms, and 1-4 heteroatoms selected from N and O; halo, haloalkyl, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, arylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, —SO 2 NH 2 , nitro, cyano or carboxy;

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 , (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 ) alkoxy, aryl, (C 1 -C 6 )alkyl-SO 2 —, aryl-SO 2 or heterocyclo;

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

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

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

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

the term heterocyclo, heterocycle or heterocyclyl in each occurrence meaning a 4-10 membered mono or azabicyclo ring comprising carbon atoms and 1-4 heteroatoms selected from N, O, P(═O) and S(O) 2 ,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

13. A compound according to claim 12 wherein

A is

14. A compound according to claim 1 selected from the following:

5-(dimethyl-1H-1,2,3-triazol-5-yl)-10-methanesulfonyl-13-methoxy-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

5-(dimethyl-1H-1,2,3-triazol-5-yl)-8-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-13-methoxy-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

5-(dimethyl-1H-1,2,3-triazol-5-yl)-8-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-13-methoxy-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

5-(dimethyl-1H-1,2,3-triazol-5-yl)-13-ethoxy-10-methanesulfonyl-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

10-methanesulfonyl-13-( 2 H 3 )methoxy-5-[5-( 2 H 3 )methyl-3-methyl-1,2-oxazol-4-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-13-( 2 H 3 )methoxy-5-[5-( 2 H 3 )methyl-3-methyl-1,2-oxazol-4-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-ethoxy-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-(cyclopropylmethoxy)-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(S)-(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(S)-(4,4-difluorocyclohexyl)(3-fluoropyridin-2-yl)methyl]-10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-(cyclopropylmethoxy)-8-[(S)-(2-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-ethoxy-8-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-(cyclopropylmethoxy)-8-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

10-methanesulfonyl-13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[oxan-4-yl(2,4,6-trifluorophenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

8-[(4,4-difluorocyclohexyl)(phenyl)methyl]-5-(dimethyl-1H-1,2,3-triazol-5-yl)-10-methanesulfonyl-13-methoxy-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

13-(cyclopropylmethoxy)-8-[(S)-(4,4-difluorocyclohexyl)(phenyl)methyl]-10-methanesulfonyl-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

N-[5-(dimethyl-1,2-oxazol-4-yl)-10-methanesulfonyl-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaen-13-yl]cyclopropanesulfonamide,

13-(cyclopropylmethoxy)-5-(dimethyl-1H-1,2,3-triazol-5-yl)-10-methanesulfonyl-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaene,

10-methanesulfonyl-13-methoxy-5-(4-methoxy-1-methyl-1H-1,2,3-triazol-5-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaene

[5-(dimethyl-1H-1,2,3-triazol-5-yl)-13-methoxy-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2,4,6,10,12-hexaen-10-yl]methanol,

2-{13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaen-10-yl}propan-2-ol,

{13-methoxy-5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2,4,6,10,12-hexaen-10-yl}methanol,

2-[5-(dimethyl-1H-1,2,3-triazol-5-yl)-13-methoxy-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2,4,6,10,12-hexaen-10-yl]propan-2-ol,

2-[5-(dimethyl-1,2-oxazol-4-yl)-8-[(4-fluorophenyl)(oxan-4-yl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl]propan-2-ol,

2-[5-(dimethyl-1,2-oxazol-4-yl)-13-methoxy-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2,4,6,10,12-hexaen-10-yl]propan-2-ol,

2-{5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl}propan-2-ol,

2-{5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2,4,6,10,12-hexaen-10-yl}propan-2-ol,

2-[5-(dimethyl-1H-1,2,3-triazol-5-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl]propan-2-ol,

2-{5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,10-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl}propan-2-ol,

2-[5-(dimethyl-1H-1,2,3-triazol-5-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,10-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl]propan-2-ol,

2-[5-(dimethyl-1,2-oxazol-4-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl]propan-2-ol,

2-[5-(4-ethyl-1-methyl-1H-1,2,3-triazol-5-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl]propan-2-ol,

4-{5-[4-( 2 H 3 )methyl-1-methyl-1H-1,2,3-triazol-5-yl]-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,10-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(9),2(7),3,5,10,12-hexaen-11-yl}-1λ 6 ,4-thiomorpholine-1,1-dione, or

2-{8-[(S)-(4-fluorophenyl)(oxan-4-yl)methyl]-5-[5-( 2 H 3 )methyl-3-methyl-1,2-oxazol-4-yl]-3,8,12-triazatricyclo[7.4.0.0 2 , 7 ]trideca-1(13),2(7),3,5,9,11-hexaen-11-yl}propan-2-ol,

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

15. 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.

16. 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.

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

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 12, 2016
From: NORRIS, DEREK J.; VACCARO, WAYNE; DEBENEDETTO, MIKKEL V.; DEGNAN, ANDREW P.; DELUCCA, GEORGE V.; DESKUS, JEFFREY A.; HAN, WEN-CHING; KUMI, GODWIN KWAME; SCHMITZ, WILLIAM D.; STARRETT, JOHN E., JR.; HILL, MATTHEW D.; HUANG, HONG
To: BRISTOL-MYERS SQUIBB COMPANY
Reel/Frame 039132/0050 →
Continuity (2)
Provisional Application 62159991 · May 12, 2015
Related Publication 20160333013A1 · Nov 17, 2016