Cyclic dinucleotides as anticancer agents

Patent metadata

Field	Value
Publication number	US-11427610-B2
Application number	US-201816849091-A
Country	US
Kind code	B2
Filing date	Oct 16, 2018
Priority date	Oct 16, 2017
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

The present invention is directed to compounds of the formulawherein 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.

First claim

We claim:

1. A compound of the formula

wherein
each X is independently O or S;
X 1 , X 2 , X 3 and X 4 are each independently O or NH;
R 1 and R 2 are independently

with the proviso that one of R 1 and R 2 must be

Z 1 is N or CR a ;
Z 2 is NR b ;
R a is H, halogen, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R b is H, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , —C(O)R a1 , —C(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R a1 is H or C 1-3 alkyl substituted with 0-6 R 5 ;
R 3 and R 4 are independently H, CH 3 , halogen, NH 2 or OH;
R 3a and R 4a are independently H, CH 3 , halogen, NH 2 or OH; or
R 3 and R 3a or R 4 and R 4a may independently be taken together to form a 3-4 membered carbocycle; or
R 3 and R 3a or R 4 and R 4a may independently be taken together to form a C═CH 2 substituent;
R 5 is H, halogen, C 1-3 alkyl substituted with 0-6 R a , C 3-6 cycloalkyl substituted with 0-6 R a , aryl substituted with 0-6 R a or heteroaryl substituted with 0-6 R a , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 5a is H or C 1-3 alkyl substituted with 0-6 R 5 ;
R 6 is H, halogen, C 1-3 alkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 8 is H, halogen, C 1-3 alkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 9 is H, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , aryl substituted with 0-6 R 5 or heteroaryl substituted with 0-6 R 5 ;
Y is CR 5 or N;
m is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1 wherein

wherein
each X is independently O or S;
X 1 , X 2 , X 3 and X 4 are each independently O or NH;
R 1 and R 2 are independently

with the proviso that one of R 1 and R 2 must be

Z 1 is N or CR a ;
Z 2 is NR b ;
R a is H, halogen, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R b is H, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , —C(O)R a1 , —C(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R a1 is H or C 1-3 alkyl substituted with 0-6 R 5 ;
R 3 is H, CH 3 , and halogen, NH 2 or OH;
R 3a is H, CH 3 , halogen, NH 2 or OH; or
R 3 and R 3a may be taken together to form a 3-4 membered carbocycle; or
R 3 and R 3a may be taken together to form a C═CH 2 substituent;
R 5 is H, halogen, C 1-3 alkyl substituted with 0-6 R a , C 3-6 cycloalkyl substituted with 0-6 R a , aryl substituted with 0-6 R a or heteroaryl substituted with 0-6 R a , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 5a is H or C 1-3 alkyl substituted with 0-6 R 5 ;
R 6 is H, halogen, C 1-3 alkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 8 is H, halogen, C 1-3 alkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R 9 is H, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , aryl substituted with 0-6 R 5 or heteroaryl substituted with 0-6 R 5 ;
Y is CR 5 or N;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The compound according to claim 1 of the formula

wherein
X is S;
X 1 , X 2 , X 3 and X 4 are each independently O or NH;
R 1 and R 2 are independently

with the proviso that one of R 1 and R 2 must be

Z 1 is N or CR a ;
Z 2 is NR b ;
R a is H, halogen, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R a1 , —NR a1 R a1 , —NR a1 C(O)R a1 , —NR a1 COOR a1 , —NR a1 C(O)NR a1 R a1 , —NR a1 S(O) 2 R a1 , —NR a1 S(O) 2 NR a1 R a1 , —S(O)R a1 , —S(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R b is H, C 1-6 alkyl substituted with 0-6 R 5 , C 3-6 cycloalkyl substituted with 0-6 R 5 , —C(O)R a1 , —C(O)NR a1 R a1 , —S(O) 2 R a1 or S(O) 2 NR a1 R a1 ;
R a1 is H or C 1-3 alkyl substituted with 0-6 R 5 ;
R 3 is H, CH 3 , and halogen, NH 2 or OH;
R 3a is H, CH 3 , halogen, NH 2 or OH; or
R 3 and R 3a may be taken together to form a 3-4 membered carbocycle; or
R 3 and R 3a may be taken together to form a C═CH 2 substituent;
R 5 is H, halogen, C 1-3 alkyl substituted with 0-6 R a , C 3-6 cycloalkyl subs

Assignees

• Bristol Myers Squibb Co

Inventors

• Fink Brian E
• Zhao Yufen
• Chen Libing
• Huang Audris

Classifications

• C07K16/18

  against material from animals or humans · CPC title

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title