PYRIDINONE COMPOUNDS FOR THE TREATMENT OF AUTOIMMUNE DISEASE

Abstract

The present invention relates to compounds of formula (I), (I), wherein R1, R2, R3, R4 and A are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

Claims

1. A compound of formula (I), whereinR1 is C1-6alkyl;R2 is C1-6alkyl;R3 is C1-6alkyl or haloC1-6alkyl;R4 is piperazinyl, piperidinyl or 3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazinyl, said piperazinyl, piperidinyl or 3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazinyl being substituted by substituent selected from 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl;phenylC1-6alkyl, wherein phenyl is substituted by piperazinyl;piperazinyl;pyrazinylC1-6alkyl, wherein pyrazinyl is substituted by piperazinyl;pyridinyl, wherein pyridinyl is substituted by piperazinyl;pyridinylC1-6alkyl, wherein pyridinyl is substituted by 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl or piperazinyl;pyrimidinyl, where pyrimidinyl is substituted by 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl; andpyrimidinylC1-6alkyl, wherein pyrimidinyl is substituted by amino(C1-6alkyl)azetidinyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl; amino-1,4-oxazepan-4-yl or piperazinyl;A is CH or N;or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein A is CH.

3. A compound according to claim 1 or 2, wherein R4 is wherein R5 is selected from 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl;phenylC1-6alkyl, wherein phenyl is substituted by piperazinyl;piperazinyl;pyrazinylC1-6alkyl, wherein pyrazinyl is substituted by piperazinyl;pyridinyl, wherein pyridinyl is substituted by piperazinyl;pyridinylC1-6alkyl, wherein pyridinyl is substituted by 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl or piperazinyl;pyrimidinyl, where pyrimidinyl is substituted by 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl; andpyrimidinylC1-6alkyl, wherein pyrimidinyl is substituted by amino(C1-6alkyl)azetidinyl; 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl; amino-1,4-oxazepan-4-yl or piperazinyl.

4. A compound according to claim 3, wherein R4 is wherein R5a is 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl, ((piperazinyl)phenyl)C1-6alkyl, ((piperazinyl)pyrazinyl)C1-6alkyl, ((piperazinyl)pyridinyl)C1-6alkyl, ((5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridinyl)C1-6alkyl, ((amino(C1-6alkyl)azetidinyl)pyrimidinyl)C1-6alkyl, ((5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl)C1-6alkyl, ((amino-1,4-oxazepan-4-yl)pyrimidinyl)C1-6alkyl or ((piperazinyl)pyrimidinyl)C1-6alkyl; wherein R5b is piperazinyl; or wherein R5c is piperazinylpyridinyl or (5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl.

5. A compound according to claim 4, wherein R4 is wherein R5a is 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl, (4-piperazin-1-ylphenyl)methyl, (3-piperazin-1-ylphenyl)methyl, (5-piperazin-1-ylpyrazin-2-yl)methyl, (5-piperazin-1-yl-2-pyridinyl)methyl, (6-piperazin-1-yl-3-pyridinyl)methyl, [6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-3-pyridinyl]methyl, [2-(3-amino-3-methyl-azetidin-1-yl)pyrimidin-5-yl]methyl, [2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]methyl, [2-[6-amino-1,4-oxazepan-4-yl]pyrimidin-5-yl]methyl, (2-piperazin-1-ylpyrimidin-5-yl)methyl or (5-piperazin-1-ylpyrimidin-2-yl)methyl; wherein R5b is piperazin-1-yl; or wherein R5c is 6-piperazin-1-yl-3-pyridinyl or 2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl.

6. A compound according to claim 4 or 5, wherein R3 is C1-6alkyl.

7. A compound according to claim 6, wherein R3 is ethyl or isopropyl.

8. A compound according to claim 6, wherein R4 is wherein R5a is ((5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl)C1-6alkyl or ((amino-1,4-oxazepan-4-yl)pyrimidinyl)C1-6alkyl;or wherein R5c is (5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl.

9. A compound according to claim 8, wherein R4 is wherein R5a is [2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl] methyl or [2-(3-amino-3-methyl-azetidin-1-yl)pyrimidin-5-yl]methyl; or wherein R5c is 2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl.

10. A compound according to claim 1, wherein R1 is C1-6alkyl;R2 is C1-6alkyl;R3 is C1-6alkyl;R4 is wherein R5a is ((5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl)C1-6alkyl or ((amino-1,4-oxazepan-4-yl)pyrimidinyl)C1-6alkyl; wherein R5c is (5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidinyl;A is CH;or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10, wherein R1 is methyl;R2 is methyl;R3 is ethyl or isopropyl;R4 is wherein R5a is [2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]methyl or [2-(3-amino-3-methyl-azetidin-1-yl)pyrimidin-5-yl]methyl; or wherein R5c is 2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl;A is CH;or a pharmaceutically acceptable salt thereof.

12. A compound selected from: 5-[2-ethyl-6-[4-[[2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-ethyl-6-[4-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)-3 pyridyl]methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[6-[4-[[2-(3-amino-3-methyl-azetidin-1-yl)pyrimidin-5-yl]methyl]piperazin-1-yl]-2-ethyl-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[6-[4-[[2-[(6S)-6-amino-1,4-oxazepan-4-yl]pyrimidin-5-yl]methyl]piperazin-1-yl]-2-ethyl-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-ethyl-6-[4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[[2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]methyl] piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(5-piperazin-1-yl-2-pyridyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(5-piperazin-1-ylpyrazin-2-yl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(2-piperazin-1-ylpyrimidin-5-yl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[6-[4-[[2-(3-amino-3-methyl-azetidin-1-yl)pyrimidin-5-yl]methyl]piperazin-1-yl]-2-isopropyl-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(6-piperazin-1-yl-3-pyridyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-[(3-piperazin-1-ylphenyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-isopropyl-6-[8-(6-piperazin-1-yl-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;5-[2-(difluoromethyl)-6-[4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one ;5-[2-isopropyl-6-(4-piperazin-1-yl-1-piperidyl)-3-pyridyl]-1,3-dimethyl-pyridin-2-one; and5-[2-ethyl-6-[2-[2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-8-yl]-3-pyridyl]-1,3-dimethyl-pyridin-2-one;or a pharmaceutically acceptable salt thereof.

13. A process for the preparation of a compound according to any one of claims 1 to 12 comprising any of the following steps: a) deprotection of compound of formula (IX), with an acid to afford compound of formula (I-1),b) deprotection of compound of formula (XV), with an acid to afford compound of formula (I-2),c) deprotection of compound of formula (XVII), with an acid to afford compound of formula (I-3),wherein PG is Boc; L is piperazinyl, piperidinyl, piperazinylpiperidinyl, piperidinylpiperazinyl or 3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl; G1 is 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl, phenyl, piperazinyl, pyrazinyl, pyridinyl or pyrimidinyl; G2 is piperazinyl, 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl, amino(C1-6alkyl)azetidinyl or amino-1,4-oxazepan-4-yl; G3 is 5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl; R1, R2, R3 and A are defined as in any one of claims 1 to 11.

14. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 12 for use as therapeutically active substance.

15. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 12 and a therapeutically inert carrier.

16. The use of a compound according to any one of claims 1 to 12 for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis.

17. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis.

18. The use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for TLR7 and TLR8 and TLR9 antagonist.

19. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 12 for the treatment or prophylaxis of systemic lupus erythematosus or lupus nephritis.

20. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 12, when manufactured according to a process of claim 13.

21. 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 any one of claims 1 to 17.

22. The invention as hereinbefore described.