Modulators of chemokine receptors

Patent metadata

Field	Value
Publication number	US-9834545-B2
Application number	US-201615353889-A
Country	US
Kind code	B2
Filing date	Nov 17, 2016
Priority date	Nov 19, 2015
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

Compounds are provided as chemokine inhibitors having the structure:

First claim

What is claimed is:

1. A compound having the Formula (A):

wherein
B is selected from the group consisting of furanyl, thiophenyl, oxazolyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with R 1a , R 1b , and R 2 which are independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl;
R 3 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, OH, —NR a R b , —C 1-4 alkoxy, and Y; wherein the C 1-8 alkyl is 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 , —NR a S(O) 2 R b and Y, wherein Y is a 4 to 8 membered cycloheteroalkyl group or a 3 to 8 membered cycloalkyl group or a 5- or 6-membered aryl or heteroaryl group any of which is optionally substituted with from 1 to four substituents selected from halogen, oxo, —CN, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 hydroxyalkyl, —C 1-6 haloalkyl, O—C 1-6 haloalkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —C 1-6 alkyl-NR a R b , —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 R a , —C 1-6 alkyl-CONR a R b , —C 1-6 alkyl-C(O)R a , —C 1-6 alkyl-OC(O)NR a R b , —C 1-6 alkyl-NR a C(O)R b , —C 1-6 alkyl-NR a C(O) 2 R c , —C 1-6 alkyl-NR a C(O)NR a R b , —C 1-6 alkyl-OR a , —C 1-6 alkyl-S(O) 2 NR a R b , —C 16 alkyl-NR a S(O) 2 R b , —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 , —CH 2 CO 2 R a ; 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 is selected from C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 haloalkyl; and wherein the 4 to 8 membered cycloheteroalkyl group and the 3 to 8 membered cycloalkyl group may additionally be optionally substituted with oxo;
R 5a and R 5b are each members independently selected from the group consisting of H, halogen, C 1-4 alkyl, —C 1-4 haloalkyl, O—C 1-4 haloalkyl, C 1-4 alkoxy, CO 2 H 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) or a 4 to 6 membered cycloheteroalkyl group or a 3 to 6 membered cycloalkyl group;
R 7 is a member selected from the group consisting of methyl, ethyl and C 1-2 haloalkyl; and
the subscript n is 1 or 2;
or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof.

2. A compound of claim 1 having the Formula (I):

wherein
B is selected from the group consisting of furanyl, oxazolyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with R 1a , R 1b , and R 2 which are independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl;
R 3 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, and Y; wherein the C 1-8 alkyl is 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 , —NR a S(O) 2 R b and Y, wherein Y is a 5- or 6-membered aryl or heteroaryl group with from one to four substituents selected from halogen, —CN, —C 1-4 alkyl, —C 1-4 alkoxy, —C 1-4 hydroxyalkyl, —C 1-4 haloalkyl, OCF 3 , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR a C(O)R b , —CH 2 CO 2 R a ; and 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 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, CO 2 H 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); and
the subscript n is 1 or 2;
or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof.

3. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein B is selected from the group consisting of:

4. A compound of claim 3 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein B is selected from the group consisting of:

5. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein B is furanyl or oxazolyl, each of which is optionally substituted with R 1a and R 1b , which are independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy and C 1-4 haloalkyl.

6. A compound of claim 5 or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein B is furanyl substituted with R 1a which is CH 3 or Cl and optionally substituted with R 1b which is CH 3 .

7. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein R 3 is H.

8. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein each of R 5a and R 5b is independently selected from the group consisting of H, CH 3 , Cl and F.

9. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein

is selected from the group consisting of:

10. A compound of claim 9 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein

is selected from the group consisting of:

11. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein each of R 6a and R 6b is independently selected from the group consisting of H and C 1-2 alkyl.

12. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein

is independently selected from the group consisting of

13. A compound of claim 12 , or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, tautomer or rotamer thereof, wherein

Assignees

• Chemocentryx Inc

Inventors

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

Classifications

• C07D307/52

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/4439

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

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title