Diazole lactams

Patent metadata

Field	Value
Publication number	US-11759454-B2
Application number	US-202016923197-A
Country	US
Kind code	B2
Filing date	Jul 8, 2020
Priority date	Dec 7, 2012
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are diazole lactam derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a compound represented by the structure:

wherein n is 1, 2 or 3;
each A is independently selected from the group consisting of N and CH;
A 1 is N or C(R 5 );
A 2 is N or C(R 7 );
R 1 and R 2 are each independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —SO 2 R a , —NR a R b , —CONR a R b , and 3-, 4-, 5- or 6-membered heterocycloalkane wherein the heteroatoms present as ring vertices of the heterocycloalkane ring are selected from N, O and S, and wherein the alkyl, cycloalkyl, and hetereocycloalkane portions of R 1 and R 2 are optionally further substituted with 1-3 R a ;
R 3 is a member selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —NR a R b , —CONR a R b , aryl, 5- or 6-membered heteroaryl, and 3-, 4-, 5- or 6-membered heterocycloalkane wherein the heteroatoms present as ring vertices of the heteroaryl and heterocycloalkane rings are selected from N, O and S, and wherein the alkyl, cycloalkyl, aryl, heteroaryl and hetereocycloalkane portions of R 3 are optionally further substituted with 1-3 R a ;
R 4 is a member selected from the group consisting of H, —OR a , and C 1-8 alkyl optionally substituted with —OR a ;
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —NR a R b , —CONR a R b , aryl, 5- or 6-membered heteroaryl, and 3-, 4-, 5- or 6-membered heterocycloalkane wherein the heteroatoms present as ring vertices of the heteroaryl and heterocycloalkane rings are selected from N, O and S, and wherein the alkyl, cycloalkyl, aryl, heteroaryl and hetereocycloalkane portions of R 5 , R 6 , R 7 and R 8 are optionally further substituted with 1-3 R a ; and optionally, adjacent members of R 5 , R 6 , R 7 and R 8 are connected to form an additional 5- or 6-membered ring which is saturated, unsaturated or aromatic having ring vertices selected from C, O, N and S;
each R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, amino, C 1-8 alkylamino, di C 1-8 alkylamino, carboxamide, carboxy C 1-4 alkyl ester, carboxylic acid, and —SO 2 —C 1-8 alkyl;
or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide or rotamer thereof;
and a pharmaceutically acceptable excipient or carrier.

2. The pharmaceutical composition of claim 1 , where R 8 is other than H.

3. The pharmaceutical composition of claim 1 , wherein each R 1 and R 2 is independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 1-8 haloalkyl, —CO 2 R a and —SO 2 R a .

4. The pharmaceutical composition of claim 1 , wherein n is 1.

5. The pharmaceutical composition of claim 1 , wherein the ring portion having N, A 1 and A 2 as ring vertices is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to the remainder of the compound.

6. The pharmaceutical composition of claim 1 , wherein the ring portion having N, A 1 and A 2 as ring vertices is selected from the group consisting of:

wherein
R 1 and R 2 are each independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —SO 2 R a , —NR a R b , —CONR a R b , and 3-, 4-, 5- or 6-membered heterocycloalkane wherein the heteroatoms present as ring vertices of the heterocycloalkane ring are selected from N, O and S, and wherein the alkyl, cycloalkyl, and hetereocycloalkane portions of R 1 and R 2 are optionally further substituted with 1-3 R a ; and
R 7 is H or Cl, and R 8 is C 1-8 alkyl optionally substituted with 1 or 2 R a ; and
wherein the wavy line indicates the point of attachment to the remainder of the compound.

7. The pharmaceutical composition of claim 4 , wherein the compound is represented by the structure:

wherein R 1 is Cl or F.

8. The pharmaceutical composition of claim 4 , wherein the compound is represented by the structure:

wherein R 1 is Cl or F.

9. The pharmaceutical composition of claim 4 , wherein the compound is represented by the structure:

10. The pharmaceutical composition of claim 4 , wherein the compound is represented by the structure:

11. The pharmaceutical composition of claim 1 , wherein R 3 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl and C 2-8 alkenyl.

12. A method of treating asthma, psoriasis, rheumatoid arthritis, multiple myeloma, osteoporosis, or leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1 .

13. The pharmaceutical composition of claim 1 , wherein the compound is represented by the structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 1 , wherein the compound is represented by the structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 1 , wherein the compound is represented by the structure:

or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 1 , wherein the compound is represented by the structure:

or a pharmaceutically acceptable salt thereof.

Assignees

• Chemocentryx Inc

Inventors

• Chen Xi
• Fan Pingchen
• Li Yandong
• Powers Jay P
• Malathong Viengkham
• Punna Sreenivas
• Tanaka Hiroko
• Zhang Penglie
• Dragoli Dean

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title