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

Patent metadata

Field	Value
Publication number	US-12486273-B2
Application number	US-202017777260-A
Country	US
Kind code	B2
Filing date	Nov 17, 2020
Priority date	Nov 19, 2019
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The present invention relates to compounds of formula (I), wherein R 1 to R 3 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

The invention claimed is:

1 . A compound of formula (I),

wherein:

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; and
R 6 is H or halogen;
R 2 is C 1-6 alkyl; and
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; and
R 5 is H or deuterium;

R 2 is C 1-6 alkyl; and
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-5H-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; and
R 5 is H or deuterium;

R 2 is C 1-6 alkyl; and
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-5H-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 , wherein 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-5H-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 2 , 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;
or a pharmaceutically acceptable salt thereof.

10 . A compound according to claim 9 , wherein:
R 2 is methyl; and 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-5H-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

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P17/04

  Antipruritics · CPC title

• A61P19/04

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

• A61P19/02

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