Substituted n-(methyl-d3)pyridazine-3-carboxamide or n-(methyl-d3)-nicotinamide compounds as il-12, il-23 and/or ifnalpha modulators

Patent metadata

Field	Value
Publication number	US-2023167092-A1
Application number	US-202117997288-A
Country	US
Kind code	A1
Filing date	Apr 27, 2021
Priority date	Apr 28, 2020
Publication date	Jun 1, 2023
Grant date	—

Abstract

There are disclosed compounds of the following formula I or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein all substituents are as defined herein, which are useful in the modulation of IL-12, IL-23 and/or IFN?, by acting on Tyk-2 to cause signal transduction inhibition. The compounds of the invention may be useful for treating inflammatory and autoimmune diseases or disorders.

First claim

We claim:

1 . A compound having the following formula I

wherein
Y is N or CH;
R 1 is H, CD 3 or C 1-3 alkyl;
R 2 is —C(O)R 2a ; C 1-6 alkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a ;
R 2a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl;
R 3 is a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl each group substituted with 0-2 R 3b , CO—N(R 5 R 6 ), CO-heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b ;
R 3b is independently at each occurrence, F, OH or C 1-3 alkyl;
R 4 is hydrogen, halo or C 1-4 alkyl;
R 5 and R 6 are independently at each occurrence, hydrogen or C 1-4 alkyl,
or a stereoisomer or pharmaceutically acceptable salt thereof.

2 . The compound according to claim 1 of formula II

wherein
Y is N or CH;
R 2 is —C(O)R 2a ; C 1-6 alkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a ;
R 2a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl;
R 3 is a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl each group substituted with 0-2 R 3b , CO—N(R 5 R 6 ), CO-heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b ;
R 3b is independently at each occurrence, F, OH or C 1-3 alkyl;
R 4 is hydrogen, halo or C 1-4 alkyl;
R 5 and R 6 are independently at each occurrence, hydrogen or C 1-4 alkyl,
or a stereoisomer or pharmaceutically acceptable salt thereof.

3 . The compound according to claim 2 of the formula

wherein
Y is N or CH;
R 2 is —C(O)R 2a , —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a ;
R 2a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl;
R 3 is a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl each group substituted with 0-2 R 3b , CO—N(R 5 R 6 ), CO-heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b ;
R 3b is independently at each occurrence, F, OH or C 1-3 alkyl;
R 4 is hydrogen, halo or C 1-4 alkyl;
R 5 and R 6 are independently at each occurrence, hydrogen or C 1-4 alkyl,
or a stereoisomer or pharmaceutically acceptable salt thereof.

4 . The compound according to claim 3 of the formula

wherein
Y is N or CH;
R 2 is —C(O)R 2a , —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a ;
R 2a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-3 alkyl, OCH 3 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl;
R 3 is a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl each group substituted with 0-2 R 3b , CO—N(R 5 R 6 ), CO-heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b ;
R 3b is independently at each occurrence, F, OH or C 1-3 alkyl;
R 4 is halo;
R 5 and R 6 are independently at each occurrence, hydrogen or C 1-4 alkyl,
or a stereoisomer or pharmaceutically acceptable salt thereof.

5 . The compound according to claim 4 of the formula

wherein
Y is N or CH;
R 2 is —C(O)R 2a , —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a ;
R 2a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-3 alkyl, OCH 3 , C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-6 cycloalkyl;
R 3 is a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
R 3a is independently at each occurrence, hydrogen, OH, halo, oxo (═O), CF 3 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl each group substituted with 0-2 R 3b , CO—N(R 5 R 6 ), CO-heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b or a 5-14 membered mono or bicyclic heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-2 R 3b ;
R 3b is independently at each occurrence, F, OH or C 1-3 alkyl;
R 4 is F;
R 5 and R 6 are independently at each occurrence, hydrogen or C 1-4 alkyl,
or a stereoisomer or pharmaceutically acceptable salt thereof.

6 . The compound according to claim 5 of the formula
wherein
R 3 is a 6 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a .

7 . A compound which is
4-((3-(5-cyanopyrimidin-2-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide, 4-((3-(4-cyanopyrimidin-2-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide, 6-(cyclobutanec

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Lin James
• Weinstein David S

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/12

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