5 or 8-substituted imidazo[1, 5-a] pyridines as indoleamine and/or tryptophane 2, 3-dioxygenases

Patent metadata

Field	Value
Publication number	US-10280163-B2
Application number	US-201615564666-A
Country	US
Kind code	B2
Filing date	Apr 8, 2016
Priority date	Apr 10, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

Disclosed herein are 5 or 8-substituted imidazo[1,5-a]pyridines and pharmaceutical compositions comprising at least one such 5 or 8-substituted imidazo[1,5-a]pyridines, processes for the preparation thereof, and the use thereof in therapy. Disclosed herein are certain 5 or 8-substituted imidazo[1,5-a]pyridines that can be useful for inhibiting indoleamine 2,3-dioxygenase and/or tryptophane 2,3-dioxygenase and for treating diseases or disorders mediated thereby.

First claim

The invention claimed is:

1. A compound having the structure of Formula (IA):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
n is 0, 1, 2, 3, or 4;
R a and R b are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 1 is hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl;
R 2 and R 3 are each independently hydrogen, halogen, OR 7 , NR 7 R 8 , COR 7 , SO 2 R 7 , C(═O)OR 7 , C(═O)NR 7 R 8 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with at least one substituent R 9 ;
R 4 , R 5 and R 6 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —OR 7 , or —SR 7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, and heteroaryl are each independently optionally substituted with at least one substituted R 9 ,
provided that at least one of R 4 and R 5 is not hydrogen;
R C is C 3-10 cycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with at least one substituent R 9 ;
R 7 and R 8 are each independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one substituent R 9 ; or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring which optionally comprises a further hetero atom selected from nitrogen, oxygen and sulfur atom, and is optionally substituted with at least one substituent R 9 ;
R 9 is hydrogen, halogen, C 1-4 haloalkyl, C 1-4 alkyl, C 2-8 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —C 1-4 alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, or —NR′SO 2 aryl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl group are each independently optionally substituted by one, two or three substituents selected from halo, hydroxyl, C 1-4 alkyl and C 1-4 haloalkyl; and
R′, R″, and R′″ are each independently H, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or more halogen, C 1-4 haloalkyl and C 1-4 alkyl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a ring selected from heterocyclyl optionally substituted by halogen, C 1-4 haloalkyl and C 1-4 alkyl and heteroaryl rings optionally substituted by halogen, C 1-4 haloalkyl and C 1-4 alkyl.

2. The compound of claim 1 having the structure of Formula (IA):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
n is 0, 1, 2, 3, or 4;
R a and R b are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 1 is hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl;
R 2 and R 3 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with at least one substituent R 9 ;
R 4 , R 5 and R 6 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, or —OR 7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, and heteroaryl are each independently optionally substituted with at least one substituted R 9 ,
provided that at least one of R 4 and R 5 is not hydrogen;
R C is C 3-10 cycloalkyl optionally substituted with at least one substituent R 9 ;
R 7 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one substituent R 9 ;
R 9 is hydrogen, halogen, C 1-4 haloalkyl, C 1-4 alkyl, C 2-8 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —C 1-4 alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, NR′SO 2 R″, or —NR′SO 2 aryl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl group are each independently optionally substituted by one, two or three substituents selected from halo, hydroxyl, C 1-4 alkyl and C 1-4 haloalkyl; and
R′ and R″ are each independently selected from H, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted by one or more halogen, C 1-4 haloalkyl and C 1-4 alkyl.

3. The compound of claim 1 , wherein n is 0, 1 or 2.

4. The compound of claim 1 , wherein R a and R b are hydrogen.

5. The compound of claim 1 , wherein R 1 is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl.

6. The compound of claim 1 , wherein R 2 and R 3 are each independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.

7. The compound of claim 1 , wherein R 4 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl or heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.

8. The compound of claim 7 , wherein R 4 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, phenyl optionally substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl, heteroaryl optionally substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl, or —OC 1-6 alkyl.

9. The compound of claim 7 , wherein R 4 is F, Cl, Br, I, methyl, isopropyl, propenyl, ethynyl, cyclopropyl, CF 3 , phenyl, dimethylisoxazolyl or methoxy.

10. The compound of claim 1 , wherein R 4 is not hydrogen, and R 5 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl or heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.

11. The compound of claim 10 , wherein R 5 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl or —OC 1-6 alkyl.

12. The compound according to claim 7 , wherein R 6 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl or heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.

13. The compound according to claim 10 , wherei

Assignees

• Beigene Ltd

Inventors

• Wang Hexiang
• Zhang Guoliang
• Guo Yunhang
• Ren Bo
• Wang Zhiwei
• Zhou Changyou

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/18

  for HIV · CPC title