Immunomodulator compounds

Patent metadata

Field	Value
Publication number	US-10639284-B2
Application number	US-201715633569-A
Country	US
Kind code	B2
Filing date	Jun 26, 2017
Priority date	Jun 27, 2016
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (II):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

What is claimed is:

1. A compound of Formula (II)

or a pharmaceutically acceptable salt thereof; wherein:
R 1 is selected from the group consisting of halogen, C 5-8 cycloalkyl, C 6-10 aryl, wherein the C 6-10 aryl is optionally substituted with 1 to 5 R x substituents;
each R x is independently selected from the group consisting of halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a , —O—X 1 —CO 2 R a , —O—X 1 —CONR a R b ,
—X 1 —OR a , —X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , and —S(O) 2 NR a R b , wherein each X 1 is a C 1-4 alkylene; each R a and R b is independently selected from hydrogen, C 1-4 alkyl, and C 1-8 haloalkyl; each R c is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 1-8 haloalkyl;

each R 2a , R 2b and R 2c is independently selected from the group consisting of H, halogen, —CN, —R d , —CO 2 R e , —CONR e R f , —C(O)R e , —OC(O)NR e R f , —NR f C(O)R e , —NR f C(O) 2 R d , —NR e —C(O)NR e R f , —NR e R f , —OR e , —O—X 2 —OR e , —O—X 2 —NR e R f , —O—X 2 —CO 2 R e , —O—X 2 —CONR e R f , —X 2 —OR e , —X 2 —NR e R f , —X 2 —CO 2 R e , —X 2 —CONR e R f , —SF 5 , —S(O) 2 NR e R f , and C 6-10 aryl, wherein each X 2 is a C 1-4 alkylene; each R e and R f is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R d is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;
R 3 is —NR g R h ;
R g is selected from the group consisting of H, C 1-8 haloalkyl and C 1-8 alkyl;
R h is selected from —C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl-COOH, C 1-8 alkyl-OH, C 1-8 alkyl-CONH 2 , C 1-8 alkyl-SO 2 NH 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-CONOH, C 1-8 alkyl-NR h1 R h2 , —C(O)—C 1-8 alkyl, —C(O)—C 1-8 alkyl-OH, —C(O)—C 1-8 alkyl-COOH, C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOH, —C 3-10 cycloalkyl-OH, —C 1-8 alkyl-C 3-10 cycloalkyl, C 10 carbocyclyl, —C 1-8 alkyl-C 6-10 aryl, —C 1-8 alkyl-(C═O)—C 6-10 aryl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkenyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 1-8 alkynyl, —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-COOH, and —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-OH optionally substituted with CO 2 H;
wherein
R h1 and R h2 are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 hydroxyalkyl;
the C 1-8 alkyl portions of R h are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO 2 NH 2 , CONH 2 , CONOH, COO—C 1-8 alkyl, PO 3 H 2 optionally substituted with 1 to 2 C 1-3 alkyl substituents,
the C 10 carbocyclyl, and the C 6-10 aryl portions of R h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) 2 , COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 , COO—C 1-8 alkyl, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-CONOH, C 1-4 alkyl-PO 3 H 2 , C 1-4 alkyl-COOH, and phenyl and
the C 3-10 cycloalkyl portions of R h are optionally substituted with 1 to 4 R w substituents;

each R w substituent is independently selected from C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-COOH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-CONOH, C 1-4 alkyl-PO 3 H, OH, COO—C 1-8 alkyl, COOH, SO 2 NH 2 , CONH 2 , CONOH, PO 3 H 2 and oxo;
R 4 is selected from the group consisting of pyridinyl and —O—C 1-4 alkyl-pyridinyl wherein the pyridinyl is optionally substituted with 1 to 5 R z ,
each R z is independently selected from the group consisting of halogen, —CN, —R m , —CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 3 —OR n , —O—X 3 —NR n R p , —O—X 3 —CO 2 R n , —O—X 3 —CONR n R p , —X 3 —OR n , —X 3 —NR n R p , —X 3 —CO 2 R n , —X 3 —CONR n R p , —SF 5 , —S(O) 2 R n R p , and —S(O) 2 NR n R p ,
wherein each X 3 is a C 1-4 alkylene; each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;
n is 0, 1, 2 or 3;
each R 5 is independently selected from the group consisting of halogen, —CN, —R q , —CO 2 R r , —CONR r R s , —C(O)R r , —OC(O)NR r R s , —NR r C(O)R s , —NR r C(O) 2 R q , —NR r —C(O)NR r R s , —NR r R s , —OR r , —O—X 4 —OR r , —O—X 4 —NR r R s , —O—X 4 —CO 2 R r , —O—X 4 —CONR r R s , —X 4 —OR r , —X 4 —NR r R s , —X 4 —CO 2 R 2 , —X 4 —CONR r R s , —SF 5 , —S(O) 2 NR r R s , wherein each X 4 is a C 1-4 alkylene; each R r and R s is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R q is independently selected from the group consisting of C 1-8 alkyl, and C 1-8 haloalkyl;
R 6a is selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; and
m is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having the formula (IIa)

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having the formula (IIb)

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl, wherein the phenyl is optionally substituted with 1 to 5 R x substituents.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with 1 or 2 R x wherein each R x is independently selected from halogen, C 1-8 alkyl, O—C 1-8 alkyl, O—C 1-8 haloalkyl, —NR a R b , and CN.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with F.

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

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H and R 2a is selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-3 haloalkyl, —CN, —OMe and OEt.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H and R 2a is halogen.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H and R 2a is Cl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 is independently selected from the group consisting of halogen, —CN, −R q , —NR r R g , and —OR r , wherein each R r and R s is independently selected from hydrogen, C 1-8 alkyl and C 1-8 haloalkyl and each R q is independently selected from the group consisting of C 1-8 alkyl and C 1-8 haloalkyl.

Assignees

• Chemocentryx Inc

Inventors

• Lange Christopher
• Malathong Viengkham
• Mcmurtrie Darren J
• Punna Sreenivas
• Singh Rajinder
• Yang Ju
• Zhang Penglie

Classifications

• C07D213/30

  Oxygen atoms · CPC title

• C07D213/85 Primary

  in position 3 · CPC title

• A61K31/36

  Compounds containing methylenedioxyphenyl groups, e.g. sesamin · CPC title

• C07D409/12

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

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title