Phosphine oxide alkyl amide substituted heteroaryl compounds as modulators of IL-12, IL-23 and/or IFN alpha responses

Patent metadata

Field	Value
Publication number	US-10294256-B2
Application number	US-201715838434-A
Country	US
Kind code	B2
Filing date	Dec 12, 2017
Priority date	Dec 13, 2016
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

Compounds having the following formula I:

or a stereoisomer or pharmaceutically-acceptable salt thereof, where all substituents are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

First claim

What is claimed is:

1. A compound having the following formula I:

wherein:
X is —N— or —CH—;
Y is —N— or —CH—;
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
R 3 is P(O)—(C 1-4 alkyl) 2 ;
or a pharmaceutically-acceptable salt thereof.

2. The compound according to claim 1 , of the formula

wherein:
X is —N— or —CH—;
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
R 3 is P(O)—(C 1-4 alkyl) 2 ;
or a pharmaceutically-acceptable salt thereof.

3. The compound according to claim 2 , of the formula

wherein:
X is —N— or —CH—;
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
R 3 is P(O)—(C 1-4 alkyl) 2 ;
or a pharmaceutically-acceptable salt thereof.

4. The compound according to claim 3 , of the formula

wherein:
X is —N— or —CH—;
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
or a pharmaceutically-acceptable salt thereof.

5. The compound according to claim 4
wherein:
R 1 is CD 3 or C 1-3 alkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
or a pharmaceutically-acceptable salt thereof.

6. The compound according to claim 5
wherein:
R 1 is CD 3 ;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
or a pharmaceutically-acceptable salt thereof.

7. The compound according to claim 1 , of the formula

wherein:
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
R 3 is P(O)—(C 1-4 alkyl) 2 ;
or a pharmaceutically-acceptable salt thereof.

8. The compound according to claim 1 , of the formula

wherein:
R 1 is CD 3 , C 1-3 alkyl or C 3-6 cycloalkyl;
R 2 is CO—C 3-6 cycloalkyl, C 5-8 aryl or a 5-7 membered heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, substituted with 0-4 R 2a ;
R 2a is independently, at each occurrence, hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 5-8 aryl or a 5-7 heterocyclyl having carbon atoms and 1-4 heteroatoms independently selected from N, O, and S, said aryl or heterocyclyl substituted with 0-2 R a ;
R a is hydrogen, halogen or C 1-4 alkyl;
R 3 is P(O)—(C 1-4 alkyl) 2 ;
or a pharmaceutically-acceptable salt thereof.

9. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

10. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1 , wherein the disease is an inflammatory or autoimmune disease selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's Disease, Siögren's syndrome or scleroderma.

Assignees

• Bristol Myers Squibb Co

Inventors

• Yang Michael G
• Xiao Zili
• Duncia John V
• Weinstein David S

Classifications

• C07F9/650905

  having the nitrogen atoms in the positions 1 and 2 · CPC title

• C07D237/24

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title