Cyclic dinucleotides as anticancer agents

Patent metadata

Field	Value
Publication number	US-10947263-B2
Application number	US-201816641679-A
Country	US
Kind code	B2
Filing date	Aug 30, 2018
Priority date	Aug 31, 2017
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

The present invention is directed to compounds of the formula (I) 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.

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 1 , —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;
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, CN, NO 2 , OH, OR, 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;
R 6 is H, halogen, C 1-3 alkyl, 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, 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 , —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 ;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1 of formula I

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;
R 3 is H, CH 3 , halogen, NH 2 or OH;
R 3a a 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, 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;
R 6 is H, halogen, C 1-3 alkyl, CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 R a1 , —COOR 1 , —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, —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, CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR a1 , —COOR a1 , —OC(O)R a1 , —OC(O)NR a1 R 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 ;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The compound according to claim 1 of formula I

wherein
X is O;
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 1 ;
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;
R 3 is H, CH 3 , 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, 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;
R 6 is H, halogen, C 1-3 alkyl, 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 1a , —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, CN, NO 2 , OH, OR a1 , SR a1 , —C(O)NR 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 ;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4. The compound according to claim 1 of the formula

Assignees

• Bristol Myers Squibb Co

Inventors

• Qin Lan-Ying
• Ruan Zheming
• Chen Libing
• Watterson Scott Hunter
• Fink Brian E

Classifications

• C07K16/2818

  against CD28 or CD152 · CPC title

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• A61K31/7084

  Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title