Cyclic dinucleotides as anticancer agents

Patent metadata

Field	Value
Publication number	US-11339185-B2
Application number	US-201916683667-A
Country	US
Kind code	B2
Filing date	Nov 14, 2019
Priority date	Feb 13, 2018
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

The present invention is directed to compounds of the formulae I, II and III as shown belowwherein 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 formula III

wherein
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 each 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, C 1-3 alkyl or C 3-6 cycloalkyl;
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 ;
or two R 5 groups may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
or R 5 and R 6 may be taken together to form a 5-6 membered carbocyclic or heterocyclic group;
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 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, halogen or methyl;
Y is CR a or N;
m is 0, 1, 2 or 3;
n is 0 or 1;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2. The compound according to claim 1 of the formula

wherein
X is independently O or S;
R 1 and R 2 are each 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, C 1-3 alkyl or C 3-6 cycloalkyl;
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 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 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, halogen or methyl;
Y is CR a or N;
m is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The compound according to claim 2 of the formula

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

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

5. 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.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of diseases or conditions that may be alleviated by the induction of an immune response via the STING pathway.

8. A compound or a pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the disease or condition is cancer.

9. 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.

10. A method for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound, according to claim 1 , or a pharmaceutically acceptable salt thereof,
in combination with the administration of a therapeutically effective amount of one or more immuno-oncology agents.

11. The method of claim 10 , wherein the immune-oncology agent is a PD-L1 antagonist.

Assignees

• Bristol Myers Squibb Co

Inventors

• Fink Brian E
• Dodd Dharmpal S
• Walker Steven J
• Chen Libing
• Zhao Yufen
• Ruan Zheming
• Qin Lan-Ying
• Park Peter Kinam
• Kamau Muthoni G
• Harikrishnan Lalgudi S

Classifications

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/7084

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

• C07H21/00

  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

• A61K2039/505

  comprising antibodies · CPC title