Hydro-1h-pyrrolo[1,2-a]pyrazine compounds for the treatment of autoimmune disease

Patent metadata

Field	Value
Publication number	US-2023219959-A1
Application number	US-202017777260-A
Country	US
Kind code	A1
Filing date	Nov 17, 2020
Priority date	Nov 19, 2019
Publication date	Jul 13, 2023
Grant date	—

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R3 and n are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

First claim

1 . A compound of formula (I),

wherein
R 1 is

wherein R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen, nitro or cyano; R 4a is C 1-6 alkyl or C 3-7 cycloalkyl; R 5 , R 5a and R 5b are independently selected from H and deuterium; R 6 is H or halogen;
R 2 is C 1-6 alkyl;
R 3 is a 5-7 membered monocyclic aryl or heteroaryl, a 7-12 membered bicyclic heterocyclyl, heterocyclyl-heterocyclyl, heterocyclylamino, C 1-6 alkyl (heterocyclyl)amino or heterocyclyloxy;
or a pharmaceutically acceptable salt thereof.

2 . A compound according to claim 1 , wherein
R 1 is wherein R 4 is cyano; R 5 is H or deuterium; R 2 is C 1-6 alkyl; R 3 is (5,6,7,8-tetrahydro-2,6-naphthyridinyl)piperazinyl; (amino(C 1-6 alkoxy)pyrrolidinyl)-3,4-dihydro-1H-2,6-naphthyridinyl; (amino(C 1-6 alkoxy)pyrrolidinyl)-7,8-dihydro-5H-1,6-naphthyridinyl; (C 1-6 alkyl) 2 aminopiperidinyl; (C 1-6 alkyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl)azetidinyl; (C 1-6 alkyl-5,6,7,8-tetrahydro-1,6-naphthyridinyl)amino; (C 1-6 alkyl-5,6,7,8-tetrahydro-2,6-naphthyridinyl)amino; (C 1- 6 alkyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl)amino; (C 1-6 alkyl-7,8-dihydro-SH-1,6-naphthyridinyl)amino; 2,9-diazaspiro[5.5]undecanyl; 3,8-diazabicyclo[3.2.1]octanyl; 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinylamino; 5,6,7,8-tetrahydro-1,6-naphthyridinyloxy; 5,6,7,8-tetrahydro-1,7-naphthyridinylamino; 5,6,7,8-tetrahydro-2,6-naphthyridinylamino; 5,6,7,8 -tetrahydropyrido [4,3-d]pyrimidinylamino; amino(C 1- 6 alkyl)azetidinyl; amino(C 1-6 alkyl)piperidinyl; amino(C 1-6 alkyl)pyrrolidinyl; C 1- 6 alkyl(5,6,7,8-tetrahydro-1,6-naphthyridinyl)amino; piperazinyl; piperazinyl-3,4-dihydro-1H-isoquinolinyl or piperazinyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazinyl; or a pharmaceutically acceptable salt thereof.

3 . A compound of formula (Ia),

wherein
R 1 is

wherein R 4 is cyano; R 5 is H or deuterium;
R 2 is C 1-6 alkyl;
R 3 is (5,6,7,8-tetrahydro-2,6-naphthyridinyl)piperazinyl; (amino(C 1-6 alkoxy)pyrrolidinyl)-3,4-dihydro-1H-2,6-naphthyridinyl; (amino(C 1-6 alkoxy)pyrrolidinyl)-7,8-dihydro-5H-1,6-naphthyridinyl; (C 1-6 alkyl) 2 aminopiperidinyl; (C 1-6 alkyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl)azetidinyl; (C 1-6 alkyl-5,6,7,8-tetrahydro-1,6-naphthyridinyl)amino; (C 1-6 alkyl-5,6,7,8-tetrahydro-2,6-naphthyridinyl)amino; (C 1- 6 alkyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl)amino; (C 1-6 alkyl-7,8-dihydro-SH-1,6-naphthyridinyl)amino; 2,9-diazaspiro[5.5]undecanyl; 3,8-diazabicyclo[3.2.1]octanyl; 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl; 5,6,7,8-tetrahydro-1,6-naphthyridinylamino; 5,6,7,8-tetrahydro-1,6-naphthyridinyloxy; 5,6,7,8-tetrahydro-1,7-naphthyridinylamino; 5,6,7,8-tetrahydro-2,6-naphthyridinylamino; 5,6,7,8 -tetrahydropyrido [4,3-d]pyrimidinylamino; amino(C 1- 6 alkyl)azetidinyl; amino(C 1-6 alkyl)piperidinyl; amino(C 1-6 alkyl)pyrrolidinyl; C 1- 6 alkyl(5,6,7,8-tetrahydro-1,6-naphthyridinyl)amino; piperazinyl; piperazinyl-3,4-dihydro-1H-isoquinolinyl or piperazinyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazinyl;
or a pharmaceutically acceptable salt thereof.

4 . A compound according to claim 2 or 3 , wherein
R 1 is

wherein R 4 is cyano; R 5 is deuterium.

5 . A compound according to claim 4 , wherein R 3 is (3-amino-4-methoxy-pyrrolidin-1-yl)-3,4-dihydro-1H-2,6-naphthyridin-2-yl; (3-amino-4-methoxy-pyrrolidin-1-yl)-7,8-dihydro-SH-1,6-naphthyridin-6-yl; (5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl; (5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl; (5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl)azetidin-1-yl; (5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino; (5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)amino; (6-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-yl)amino; (7-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino; 2,9-diazaspiro[5.5]undecan-9-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl; 3-amino-3-methyl-azetidin-1-yl; 3-amino-3-methyl-pyrrolidin-1-yl; 3-piperazin-1-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl; 4-(dimethylamino)-1-piperidinyl; 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl; 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl; 4-amino-4-methyl-1-piperidinyl; 5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino; 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yloxy; 5,6,7,8-tetrahydro-1,7-naphthyridin-2-ylamino; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylamino; 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino; 6-piperazin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl; methyl(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino or piperazin-1-yl.

6 . A compound according to claim 5 , wherein R 2 is methyl.

7 . A compound according to claim 4 , wherein R 3 is (C 1-6 alkyl) 2 aminopiperidinyl; (C 1-6 alkyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl)azetidinyl; 3,8-diazabicyclo[3.2.1]octanyl; piperazinyl or piperazinyl-7,8-dihydro-5H-pyrido[3,4-b]pyrazinyl.

8 . A compound according to claim 7 , wherein R 3 is (5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl; 3-piperazin-1-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl; 4-(dimethylamino)-1-piperidinyl or piperazin-1-yl.

9 . A compound according to claim 4 , wherein
R 1 is wherein R 4 is cyano; R 5 is deuterium; R 2 is C 1-6 alkyl; R 3 is (C 1-6 alkyl) 2 aminopiperidinyl; (C 1-6 alkyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridinyl)azetidinyl; 3,8-diazabicyclo[3.2.1]octanyl; piperazinyl or piperazinyl-7, 8-dihydro-5H-pyrido [3,4-b]pyrazinyl; or a pharmaceutically acceptable salt thereof.

10 . A compound according to claim 9 , wherein
R 1 is wherein R 4 is cyano; R 5 is deuterium; R 2 is methyl; R 3 is (5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)azetidin-1-yl; 3,8-diazabicyclo[3.2.1]octan-3-yl; 3-piperazin-1-yl-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl; 4-(dimethylamino)-1-piperidinyl or piperazin-1-yl; or a pharmaceutically acceptable salt thereof.

11 . A compound selected from:
5-[(4R,7R,8aS)-4-methyl-7-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-ylamino)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-ylamino)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a] pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-[(6-methyl-7,8-dihydro-SH-1,6-naphthyridin-2-yl)amino]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-[methyl(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)amino]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-[[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]amino]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; 5-[(4R,7R,8aS)-4-methyl-7-[[(5S)-5-methyl-6,7-

Assignees

• Hoffmann La Roche

Inventors

• Chen Dongdong
• Dey Fabian
• Ding Dong
• Xu Hongtao
• Zhu Wei
• Zou Ge

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title

• A61P17/04

  Antipruritics · CPC title