Inhibitors of CXCR2

Patent metadata

Field	Value
Publication number	US-9809581-B2
Application number	US-201615353949-A
Country	US
Kind code	B2
Filing date	Nov 17, 2016
Priority date	Nov 19, 2015
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

Compounds are provided as inhibitors of CXCR2, having the structure:

First claim

What is claimed is:

1. A compound having formula (I):

wherein
R 1 and R 2 are each members independently selected from the group consisting of H, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl;
R 3a is a member selected from the group consisting of methyl, ethyl, propyl, isopropyl, trifluoromethyl, CH 2 CF 3 and CF 2 CF 3 ;
R 3b is a member selected from the group consisting of H and D;
R 4 is a member selected from the group consisting of H, C 1-8 alkyl, —Y and C 1-4 alkylene-Y;
wherein Y is aryl or heteroaryl, and each R 4 is optionally substituted with from one to four substituents selected from the group consisting of halogen, —CN, —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR a C(O)R b , —NR a C(O) 2 R c , —NR a C(O)NR a R b , —NR a R b , —OR a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , and —R c ,
wherein each R a and R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl, and R c is selected from C 1-4 alkyl; C 1-4 hydroxyalkyl and C 1-4 haloalkyl;

R 5a and R 5b are each members independently selected from the group consisting of H, halogen, C 1-4 alkyl, C 1-4 alkoxy and CN;
R 6a and R 6b are each members independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl; or optionally R 6a and R 6b are taken together to form oxo (═O);
X is CH or N;
or any salts, solvates, hydrates, N-oxides, tautomers or rotamers thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a is ethyl or isopropyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3b is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3b is D.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 5a and R 5b is independently selected from the group consisting of H, Cl and F.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 6a and R 6b is independently selected from the group consisting of H and C 1-4 alkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-8 alkyl, optionally substituted with -halogen, —CN, —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR a C(O)R b , —NR a C(O) 2 R c , —NR a C(O)NR a R b , —NR a R b , —OR a , —S(O) 2 NR a R b , and —NR a S(O) 2 R b .

11. The compound of claim 1 , having formula (Ia),

wherein
R 1 is selected from the group consisting of Cl and CH 3 ;
R 3b is selected from the group consisting of H and D;
R 4 is a member selected from the group consisting of H and C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with —CONR a R b , —OC(O)NR a R b , —NR a C(O)R b , —NR a C(O) 2 R c , —NR a R b , and —OR a , wherein each R a and R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl, and R c is selected from C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl;
R 5a and R 5b are each members independently selected from the group consisting of H, F, Cl and CH 3 ;
R 6a and R 6b are each members independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl; or optionally R 6a and R 6b are taken together to form oxo (═O);
or any salts, solvates, hydrates, N-oxides or rotamers thereof.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3b is H; R 4 is H or CH 3 ; R 5a is H, i or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O).

13. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 3b is D; R 4 is H or CH 3 ; R 5a is H, F or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O).

14. The compound of claim 1 , having formula (Ib),

wherein
R 1 is selected from the group consisting of Cl and CH 3 ;
R 3b is selected from the group consisting of H and D;
R 4 is a member selected from the group consisting of H and C 1-8 alkyl, wherein the C 1-8 alkyl is optionally substituted with —CONR a R b , —OC(O)NR a R b , —NR a C(O)R b , NR a C(O) 2 R c , —NR a R b , and —OR a , wherein each R a and R b is independently selected from hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl, and R c is selected from C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl;
R 5a and R 5b are each members independently selected from the group consisting of H, F; Cl and CH 3 ;
R 6a and R 6b are each members independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl; or optionally R 6a and R 6b are taken together to form oxo (═O);
or any salts, solvates, hydrates, N-oxides or rotamers thereof.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 3b is H; R 4 is H or CH 3 ; R 5a is H, F or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O).

16. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 3b is D; R 4 is H or CH 3 ; R 5a is H, F or Cl; R 5b is H, F, Cl; R 6a and R 6b are independently selected from the group consisting of H and CH 3 , or are taken together to form oxo (═O).

17. A pharmaceutical composition comprising a compound of claim 1 .

18. The pharmaceutical composition of claim 17 , further comprising one or more additional therapeutic agents.

19. The pharmaceutical composition of claim 18 wherein the one or more additional therapeutic agents are selected from the group consisting of a cytotoxic chemotherapeutic agent, an anti-cancer or anti-tumor vaccine, chimeric antigen receptor (CAR) T cell immunotherapeutic agent, and checkpoint inhibitors.

20. The pharmaceutical composition of claim 18 wherein the one or more additional therapeutic agents are selected from the group consisting of: drugs that block the activity of CTLA-4 (CD152), PD-1 (CD279), PDL-1 (CD274), TLM-3, LAG-3 (CD223), VISTA, KIR, NKG2A, BTLA, PD-1H, TIGIT, CD96, 4-1BB (CD137), 4-IBBL (CD137L), GARP, CSF-1R, A2AR, CD73, CD47, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3 dioxygenase (IDO), and agonists of OX40, GITR, 4-1BB, ICOS, STING or CD40.

21. A method of treating a CXCR2-mediated disease or condition in a subject in need thereof, said method comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17 to said subject.

22. A

Assignees

• Chemocentryx Inc

Inventors

• Chen Xi
• Dragoli Dean R
• Fan Junfa
• Kalisiak Jaroslaw
• Leleti Manmohan Reddy
• Malathong Viengkham
• Mcmahon Jeffrey
• Tanaka Hiroko
• Yang Ju
• Yu Chao
• Zhang Penglie
• Mali Venkat

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title