Granted Patent B2

US 12,486,273 · App. 17/777,260 · Granted Dec 2, 2025

Inventors: Dongdong Chen (Shanghai, CN); Fabian Dey (Zurich, CH); Dong Ding (Shanghai, CN); Hongtao Xu (Shanghai, CN); Wei Zhu (Shanghai, CN); Ge Zou (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D487/04C07D519/00

Abstract

Claims (92)

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,7R,8aS)-4-methyl-7-[[(5S)-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-[[(7S)-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-[[(7R)-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-[[(5S)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-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-[[(5R)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]amino]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-4-methyl-7-(6-piperazin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-7-[2-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-7-[7-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]-3,4-dihydro-1H-2,6-naphthyridin-2-yl]-4-methyl-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-[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,8aS)-4-methyl-7-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yloxy)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-4-methyl-7-piperazin-1-yl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

2-Deuterio-5-[(4R,7S,8aS)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-7-(3-amino-3-methyl-azetidin-1-yl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-7-(4-amino-4-methyl-1-piperidyl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

2-Deuterio-5-[(4R,7S,8aS)-7-(3-amino-3-methyl-pyrrolidin-1-yl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-7-[4-(dimethylamino)-1-piperidyl]-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

2-Deuterio-5-[(4R,7S,8aS)-7-(2,9-diazaspiro[5.5]undecan-9-yl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-4-methyl-7-[3-[(5R)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl]azetidin-1-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(4R,7S,8aS)-4-methyl-7-[3-[(5R)-5-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl]azetidin-1-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-deuterio-quinoline-8-carbonitrile;

2-Deuterio-5-[(4R,7S,8aS)-4-methyl-7-(4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-1-yl)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

2-deuterio-5-[(4R,7S,8aS)-4-methyl-7-(4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-2-yl)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile; and

2-Deuterio-5-[(4R,7S,8aS)-7-(2,9-diazaspiro[5.5]undecan-9-yl)-4-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile;

or a pharmaceutically acceptable salt thereof.

12 . A process for the preparation of a compound according to claim 1 , the process comprising any one of the following steps:

a) Buchwald-Hartwig amination reaction or nucleophilic substitution between a compound of formula (V),

 and a compound of formula (VI), X—R 7 (VI);

b) reductive amination of a compound of formula (VII),

 with R 8 —CHO;

c) substitution reaction between a compound of formula (XII),

 and amine NHR 7 R 8 ;

d) Buchwald-Hartwig amination reaction or nucleophilic substitution between a compound of formula (XIII),

 and amine NHR 7 R 8 ; and

e) nucleophilic substitution between a compound of formula (XVII),

 and a compound of formula (II), X—R 1 (II);

wherein:

X is halogen;

Y is halogen or a leaving group;

R 7 is a 5-7 membered monocyclic aryl or heteroaryl, or a 7-12 membered bicyclic heterocyclyl;

R 8 is H or C 1-6 alkyl; and

R 9 is a 5-7 membered monocyclic aryl or heteroaryl, or a 7-12 membered bicyclic heterocyclyl.

13 . A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.

14 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, when manufactured according to a process of claim 12 .

15 . A method for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis, which method comprises administering a therapeutically effective amount of a compound as defined in claim 1 to a patient in need thereof.

16 . A method for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis, which method comprises administering a therapeutically effective amount of a compound as defined in claim 11 to a patient in need thereof.

17 . A pharmaceutical composition comprising a compound in accordance with claim 11 and a therapeutically inert carrier.

18 . The process of claim 12 , wherein Y is methanesulfonate.

Assignments (4)

Priority Claims (1)

Continuity (1)

References Cited (80)