Granted Patent B2

US 11,713,327 · App. 17/251,494 · Granted Aug 1, 2023

Inventors: Fabian Dey (Basel, CH); Buyu Kou (Shanghai, CN); Haixia Liu (Shanghai, CN); Hong Shen (Shanghai, CN); Xiaoqing Wang (Shanghai, CN); Weixing Zhang (Shanghai, CN); Zhisen Zhang (Shanghai, CN); Zhiwei Zhang (Shanghai, CN); Wei Zhu (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D519/00C07D413/14C07D417/14C07D471/04C07D487/04C07D498/10

Abstract

Claims (209)

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 H or deuterium; R 4b is H, deuterium or C 1-6 alkyl; R 4c is C 1-6 alkyl or C 3-7 cycloalkyl; and R 5 is H or halogen;

R 2 is:

1,2,3,4-tetrahydroisoquinolinyl which is unsubstituted or substituted by C 1-6 alkoxy, hydroxy or hydroxyC 1-6 alkyl;

2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl;

3,4-dihydro-1H-isoquinolinyl di-substituted by hydroxy and C 1-6 alkyl;

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl;

4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl;

5,6,7,8-tetrahydro-1,6-naphthyridinyl;

5,6,7,8-tetrahydro-1,7-naphthyridinyl;

5,6,7,8-tetrahydro-2,6-naphthyridinyl which is unsubstituted or substituted by C 1-6 alkyl;

5,6,7,8-tetrahydro-2,7-naphthyridinyl which is unsubstituted or substituted by C 1-6 alkyl;

5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl which is unsubstituted or substituted by C 1-6 alkyl;

5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl;

5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl;

6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl which is unsubstituted or substituted by C 1-6 alkyl;

6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl;

7,8-dihydro-5H-1,6-naphthyridinyl substituted by C 1-6 alkyl; or

isoindolinyl which is unsubstituted or substituted by hydroxyC 1-6 alkyl or C 1-6 alkyl;

R 3 is C 1-6 alkyl;

L is 1,4-diazepanyl; hydroxy-1,4-diazepanyl; piperazinyl; (hydroxyC 1-6 alkyl)piperazinyl; 1,6-diazaspiro[3.3]heptanyl; aminoazetidinyl; pyrrolidinylamino; 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl; 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl; 3,3-dimethyl-piperazinyl; 3,7-diazabicyclo[4.2.0]octanyl; or 5-oxa-2,8-diazaspiro[3.5]nonanyl; and

a and b are reference labels to which instances of L are aligned;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein:

R 1 is

wherein:

R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or cyano; R 4a is H or deuterium; R 4b is H, deuterium or C 1-6 alkyl; R 4c is C 1-6 alkyl or C 3-7 cycloalkyl; and

R 5 is halogen;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , wherein the compound of formula (I) is a compound of formula (Ia),

wherein:

R 1 is

wherein:

R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or cyano; R 4a is H or deuterium; R 4b is H, deuterium or C 1-6 alkyl; R 4c is C 1-6 alkyl or C 3-7 cycloalkyl;

R 5 is halogen; and

a and b are reference labels to which instances of L are aligned;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 , wherein:

R 4 is methyl, trifluoromethyl, methoxy or cyano; R 4b is H, deuterium or methyl; R 4c is methyl, ethyl or isopropyl; R 5 is fluoro; and

R 2 is 1-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl;

1,2,3,4-tetrahydroisoquinolin-7-yl;

1-methylisoindolin-5-yl;

2-(2-hydroxyethyl)isoindolin-5-yl;

2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl;

2-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl;

3-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl;

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-1-yl;

4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl;

4-hydroxy-1,2,3,4-tetrahydroisoquinolin-6-yl;

4-hydroxy-2-methyl-3,4-dihydro-1H-isoquinolin-6-yl;

4-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl;

5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl;

5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl;

5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl;

5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl;

5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl;

5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl;

5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl;

5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl;

5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl;

5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl;

5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl;

5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl;

5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl;

5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl;

6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl;

6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl;

6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl;

6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl;

6-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl;

6-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-yl;

7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl;

7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl;

7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl;

8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl;

isoindolin-4-yl; or

isoindolin-5-yl;

R 3 is methyl; and

L is 1,4-diazepanyl, hydroxy-1,4-diazepanyl, piperazinyl, (hydroxymethyl)piperazinyl, 1,6-diazaspiro[3.3]heptanyl, aminoazetidinyl, pyrrolidinylamino, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, 2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazinyl, 3,3-dimethyl-piperazinyl, 3,7-diazabicyclo[4.2.0]octanyl, or 5-oxa-2,8-diazaspiro[3.5]nonanyl, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 2 , wherein:

R 1 is

 wherein R 4 is cyano; and R 4b is H or deuterium;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein L is

wherein R a is H or hydroxy; R b is H or hydroxyC 1-6 alkyl; and R c is C 1-6 alkyl, and a and b align with the reference labels in (I).

7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein L is

wherein R a is H; and a and b align with the reference labels in (I).

8. A compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein L is

and a and b align with the reference labels in (I).

9. A compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 1,2,3,4-tetrahydroisoquinolinyl which is unsubstituted or substituted by hydroxy; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl which is unsubstituted or substituted by C 1-6 alkyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; or 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl which is unsubstituted or substituted by C 1-6 alkyl.

10. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 1,2,3,4-tetrahydroisoquinolin-6-yl; 4-hydroxy-1,2,3,4-tetrahydroisoquinolin-6-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl; 5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; 5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl; or 7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl.

11. A compound according to claim 1 , wherein:

R 1 is

 wherein R 4 is cyano; R 4a is H or deuterium; R 4b is H or deuterium;

R 2 is 1,2,3,4-tetrahydroisoquinolinyl which is unsubstituted or substituted by hydroxy; 5,6,7,8-tetrahydro-1,6-naphthyridinyl; 5,6,7,8-tetrahydro-2,6-naphthyridinyl which is unsubstituted or substituted by C 1-6 alkyl; 5,6,7,8-tetrahydro-2,7-naphthyridinyl; or 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl which is unsubstituted or substituted by C 1-6 alkyl; and

L is

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11 , wherein:

R 2 is 1,2,3,4-tetrahydroisoquinolin-6-yl; 4-hydroxy-1,2,3,4-tetrahydroisoquinolin-6-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl; 5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; 5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl; 5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; 5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl; or 7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl; and

R 3 is methyl; or a pharmaceutically acceptable salt thereof.

13. A compound selected from:

5-[(2R,6S)-2-methyl-6-[[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[(4-isoindolin-4-ylpiperazin-1-yl)methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[(3S)-3-(hydroxymethyl)-4-isoindolin-5-yl-piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[(3R)-3-(hydroxymethyl)-4-isoindolin-5-yl-piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[(4-isoindolin-5-ylpiperazin-1-yl)methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

7-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]-1,3-benzothiazole-4-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(1,2,3,4-tetrahydroisoquinolin-7-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)piperazin yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-(hydroxymethyl)-4-isoindolin-5-yl-piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[2-(hydroxymethyl)-4-isoindolin-5-yl-piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-[2-(2-hydroxyethyl)isoindolin-5-yl]piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(4-hydroxy-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-[1-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

8-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoxaline-5-carbonitrile;

4-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)piperazin yl]methyl]morpholin-4-yl]-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(1-methylisoindolin-5-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)pyrrolidin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-1,4-diazepan-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(6-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[(6R)-6-hydroxy-4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,4-diazepan-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[(6S)-6-hydroxy-4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,4-diazepan-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[1-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-1,6-diazaspiro[3.3] heptan-6-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[9-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-(isoindolin-5-ylamino)pyrrolidin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-1,4-diazepan-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[[1-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)azetidin-3-yl]amino]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[[1-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)azetidin-3-yl]amino]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(1,2,3,4-tetrahydroisoquinolin-6-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[8-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[(4aR,7aR)-4-(5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]methyl]-6-methylmorpholin-4-yl]quinoline-8-carbonitrile;

cis-5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazin-6-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

trans-5-[(2R,6S)-2-methyl-6-[[3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-3,7-diazabicyclo[4.2.0]octan-7-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3,3-dimethyl-4-(5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[3-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamino)pyrrolidin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(4-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[4-(4-hydroxy-2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)piperazin-1-yl]methyl]-6-methyl-morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(3-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperazin yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7R)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7S)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7S)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7R)-7-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-1,7-naphthyridin-2-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(6R)-6-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(6S)-6-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(8S)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(8R)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(55)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7S)-7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2R,6S)-2-methyl-6-[[4-[(7R)-7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(7S)-7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(7R)-7-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(6R)-6-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(6S)-6-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(8S)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(8R)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

8-[(2R,6S)-2-methyl-6-[[4-[(55)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

(2R,6S)-4-(8-methoxyquinoxalin-5-yl)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholine;

2-methyl-8-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]methyl]-4-[8-(trifluoromethyl)quinoxalin-5-yl]morpholine;

(2R,6S)-2-methyl-4-(8-methylquinoxalin-5-yl)-6-[[4-[(5R)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholine;

(2R,6S)-2-methyl-4-(8-methylquinoxalin-5-yl)-6-[[4-[(5S)-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholine;

2,3-dideuterio-8-[(2R,6S)-2-methyl-6-[[4-[(8S)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

2,3-dideuterio-8-[(2R,6S)-2-methyl-6-[[4-[(8R)-8-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

2,3-dideuterio-8-[(2R,6S)-2-methyl-6-[[4-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

2,3-dideuterio-8-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoxaline-5-carbonitrile;

2-deuterio-5-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

2-deuterio-5-[(2R,6S)-2-methyl-6-[[4-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

1-methyl-4-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]-1,8-naphthyridin-2-one;

1-isopropyl-4-[(2R,6S)-2-methyl-6-[[4-[(5R)-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl]piperazin-1-yl]methyl]morpholin-4-yl]-1,8-naphthyridin-2-one; and

1-methyl-4-[(2R,6S)-2-methyl-6-[[4-(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)piperazin-1-yl]methyl]morpholin-4-yl]-1,8-naphthyridin-2-one;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

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

16. A pharmaceutical composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

17. A method for the treatment of systemic lupus erythematosus or lupus nephritis in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of a compound as defined in claim 13 , or pharmaceutically acceptable salt thereof.

Assignments (10)

Priority Claims (3)

Continuity (1)