Benzimidazole and imadazopyridine carboximidamide compounds

Patent metadata

Field	Value
Publication number	US-9951065-B2
Application number	US-201615153527-A
Country	US
Kind code	B2
Filing date	May 12, 2016
Priority date	May 15, 2015
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present disclosure provides indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors of Formula I:

or pharmaceutically acceptable salts thereof, in which X, L, n, m, R 1 , R 2a , R 2b , R n , R m , and R t are as defined herein, as well as pharmaceutical compositions that include a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of using the same to treat conditions mediated by IDO1.

First claim

What is claimed is:

1. A compound of Formula I:

wherein
R 1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
wherein each C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —CN, —N(R 20 )(R 22 ) and C 3-6 cycloalkyl;

X is N or CR 2c ;
R 2a , R 2b , and R 2c are independently hydrogen, hydroxyl, halo, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, or C 1-6 alkyl;
R 2d and R 2e are independently hydrogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, or C 1-6 alkyl;
n and m are independently 0, 1, 2, or 3;
each R n and R m are independently hydrogen, hydroxyl, halo, C 1-6 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two R n or R m join to form a C 3-6 cycloalkyl; and
wherein each C 1-6 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —CN, —N(R 20 )(R 22 ), C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkyl, and C 3-6 cycloalkyl;

L is a bond, —NR 3 —, —C(O)—NR 3 —, —NR 3 —C(O)—, —NR 3 SO 2 —, —NR 3 SO 2 —NR 3 —, —SO 2 NR 3 —, —O—, —S—, or S(O) t —, where t is 0, 1 or 2;
each R 3 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
R t is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —C(O)R 20 , —C(O)OR 20 , —NC(O)OR 20 , —N(R 20 )(R 22 ), —C(O)N(R 20 )(R 22 ), —SO 2 R 20 , —N(R 20 )SO 2 (R 21 ), —N(R 20 )SO 2 —N(R 21 )(R 22 ), —SO 2 N(R 20 )(R 22 ), C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when R t is C 1-6 alkoxy, —NC(O)OR 20 , —N(R 20 )(R 22 ), —N(R 20 )SO 2 (R 21 ), —N(R 20 )SO 2 —N(R 21 )(R 22 ), or —SO 2 N(R 20 )(R 22 ), and m is 0, then L is a bond;
wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, —C(O)R 20 , —N(R 20 )(R 22 ), SO 2 R 20 , —N(R 20 )SO 2 (R 21 ), —N(R 20 )SO 2 —N(R 21 )(R 22 ), SO 2 N(R 20 )(R 22 ), C 3-6 cycloalkyl, —CN, C 1-6 alkoxy, C 1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
wherein said C 3-6 cycloalkyl, C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, —N(R 20 )(R 22 ), —SO 2 R 20 , —N(R 20 )SO 2 (R 22 ), —N(R 20 )SO 2 —N(R 21 )(R 22 )—, and —SO 2 N(R 20 )(R 22 ); and said C 1-6 alkyl is optionally substituted with aryl;

R 20 , R 21 , and R 22 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl;
wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;

or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

2. The compound of claim 1 , wherein the compound is represented by Formula IV:

or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

3. The compound of claim 1 wherein R 1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

4. The compound of claim 1 wherein R 1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, and wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring;
or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

5. The compound of claim 1 wherein R 1 is selected from the group consisting of

or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

6. The compound of claim 1 wherein X is N; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

7. The compound of claim 1 wherein X is CR 2c ; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

8. The compound of claim 1 wherein L is a bond; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

9. The compound of claim 1 wherein L is —NR 3 ; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

10. The compound of claim 1 wherein R t is hydrogen; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

11. The compound of claim 1 wherein R t is C 1-6 alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, —CN, and C 1-6 alkoxy; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

12. The compound of claim 1 wherein R t is C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, —CN, C 1-6 alkoxy and C 1-6 alkyl; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

13. The compound of claim 1 wherein L is —NR 3 and R t is C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, —NO 2 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, —CN, and C 1-6 alkoxy; or a pharmaceutically acceptable salt, tautomer, optical isomer, stereoisomer, or mixture thereof.

14. The compound of claim 1 wherein the group

is selected from the group consisting of:

Assignees

• Gilead Sciences Inc

Inventors

• Bartlett Mark J
• Codelli Julian Andrew
• Corkey Britton Kenneth
• Cosman Jennifer Leigh
• Elbel Kristyna
• Loyer-Drew Jennifer Alissa
• Sperandio David
• Van Veldhuizen Joshua
• Yang Hai
• Yeung Suet Chung

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/20

  for DNA viruses · CPC title