Azetidinyl-acetamides as CXCR7 inhibitors

Patent metadata

Field	Value
Publication number	US-12448373-B2
Application number	US-202217722491-A
Country	US
Kind code	B2
Filing date	Apr 18, 2022
Priority date	Apr 19, 2021
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

Compounds having formula I,

or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.

First claim

What is claimed is:

1. A compound having formula (I):

or a pharmaceutically acceptable salt, hydrate, N-oxide, isotopically enriched or enantiomerically enriched version or a rotamer thereof, wherein
HAr is a five-membered heteroaryl ring;
Ar 1 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and pyrazinyl;
Ar 2 is aryl or heteroaryl, each of which is independently monocyclic or fused-bicyclic;
the subscript m is 0, 1 or 2;
the subscript n is 0, 1, 2 or 3;
the subscript p is 0, 1, 2 or 3;
the subscript q is 0, 1, 2, 3 or 4;
each R 1 is a member independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, —NR a R b , —OR a , —CO 2 R a , and —C(O)NR a R b ;
each R 2 is a member independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, —NR a R b , —OR a , —CO 2 R a , and —C(O)NR a R b ;
each R 3 is a member selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —CO 2 R a , —X—CO 2 R a , —C(O)NR a R b and —X—C(O)NR a R b ;
each of R 4a and R 5a , is a member independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —X—OR a , —CO 2 R a , —X—CO 2 R a , —X—NR a R b , —C(O)NR a R b and —X—C(O)NR a R b ,
each of R 4 and R 5 , is a member independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —X—OR a , —CO 2 R a , —X—CO 2 R a , —X—NR a R b , —C(O)NR a R b and —X—C(O)NR a R b ; or R 4 and R 5 are combined to form a three- to five-membered ring having 0 or 1 heteroatom ring vertex selected from O, S or N, wherein said three- to five-membered ring is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
each R 6 is a member independently selected from the group consisting of halogen, CN, —X—CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —X—NR a R b , —C(O)NR a R b , and —X—C(O)NR a R b ,
R 7 is a member selected from the group consisting of C 1-8 alkyl, C 3-8 hydroxyalkyl, C 1-4 alkoxy-C 2-4 alkyl, —C(O)NH—C 1-8 alkyl, —C(O)—C 1-8 alkyl, —S(O) 2 —C 1-8 alkyl, C 3-8 cycloalkyl, —X—C 3-8 cycloalkyl, C 6-9 spirocycloalkyl, —X—C 6-9 spirocycloalkyl, 4- to 7-membered heterocycloalkyl, —X-4- to 7-membered heterocycloalkyl, 7- to 11-membered spiroheterocycloalkyl, and —X-7- to 11-membered spiroheterocycloalkyl, wherein each R 7 is substituted with zero to four substituents independently selected from the group consisting of hydroxy, methyl, ethyl, hydroxymethyl, fluoro, chloro, methoxy, ethoxy and cyclopropyl;
each R a and R b is independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-C 1-4 alkyl;
each X is a C 1-4 alkylene linking group wherein any of the methylene portions of X are unsubstituted or substituted with one or two methyl groups.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein HAr is selected from the group consisting of isoxazole, isothiazole, imidazole, pyrazole, thiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, and 1,2,4-triazole.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein HAr is selected from the group consisting of isoxazole and thiadiazole.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is phenyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the subscript q is 1, 2, or 3; and each R 1 is a member independently selected from the group consisting of halogen, CN, C 1-4 alkyl and C 1-4 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, phenyl, indolyl, thiazolyl, pyrazolyl, indazolyl and pyrrolopyridinyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of pyrimidinyl, pyridyl and phenyl.

8. The compound of claim 1 , wherein Ar 2 is selected from the group consisting of 2-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-thiazolyl, 4-pyrazolyl, phenyl and indolyl; and each R 6 is independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl and C 1-4 alkoxy.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —Ar 2 —(R 6 ) p is selected from the group consisting of:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the subscript m is 0.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the subscript n is 0.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the subscript p is 0, 1 or 2.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the subscript q is 1 or 2.

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

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , wherein HAr is selected from the group consisting of isoxazole and thiadiazole.

17. The compound of claim 15 , having formula (Ia1) or (Ia2):

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein HAr is selected from the group consisting of isoxazole and thiadiazole.

19. The compound of claim 1 , having formula (Ib), (Ic) or (Id):

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 , having formula (Ib1), (Ic1) or (Id1):

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein HAr is selected from the group consisting of isoxazole and thiadiazole.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is a member selected from the group consisting of C 1-8 alkyl, C 3-8 hydroxyalkyl, C 1-4 alkoxy-C 2-4 alkyl, C 3-8 cycloalkyl, C 6-9 spirocycloalkyl, 4- to 7-membered heterocycloalkyl, and 7- to 11-membered spiroheterocycloalkyl, wherein each R 7 is substituted with zero to four substituents independently selected from the group consisting of hydroxy, methyl, ethyl, hydroxymethyl, fluoro, chloro, methoxy, ethoxy and cyclopropyl.

Assignees

• Chemocentryx Inc
• Amgen Inc

Inventors

• Fan Pingchen
• Lange Christopher W
• Lui Rebecca M
• Mcmurtrie Darren J
• Scamp Ryan J
• Yang Ju
• Zeng Yibin
• Zhang Penglie

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• G01N2333/7158

  for chemokines · CPC title

• C07D417/12

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

• G01N2458/00

  Labels used in chemical analysis of biological material · CPC title

• C07D413/12

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