Pyrimidinone compounds and their use

Patent metadata

Field	Value
Publication number	US-10085986-B2
Application number	US-201214131337-A
Country	US
Kind code	B2
Filing date	Jul 5, 2012
Priority date	Jul 7, 2011
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

The present invention provides compounds of formula (1) and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , Y and Z are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

First claim

The invention claimed is:

1. A compound of formula (1):

wherein:
R 1 is chosen from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, and C 1-6 alkoxy;
R 2 is chosen from H and C 1-6 alkyl;
Y is chosen from a -A 1 -S(O) p -A 2 -, a -A 1 -C(O)-A 2 -, and a -A 5 -O-A 6 -, wherein a indicates the point of attachment to the pyrimidinyl ring;
p is chosen from 0, 1, and 2;
A 1 is a covalent bond and A 2 is C 1-3 alkylene unsubstituted or substituted with at least one R 8 , wherein each R 8 may be the same or different;
A 5 is a covalent bond; A 6 is C 1-3 alkylene unsubstituted or substituted with at least one R 8 , wherein each R 8 may be the same or different;
R 8 represents C 1-6 alkyl;
Z is chosen from aryl, heteroaryl, C 3-8 cycloalkyl, and heterocyclyl; wherein the aryl, heteroaryl, C 3-8 cycloalkyl and heterocyclyl groups are unsubstituted or substituted by at least one R 10 ; wherein each R 10 may be the same or different;
R 10 is chosen from -halogen, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 0-6 alkylCN, —NO 2 , —C 0-6 alkyl-CO 2 R 11 , —C 0-6 alkyl-COR 11 , —C 0-6 alkyl-NR 11 R 14 , —C 0-6 alkyl-CONR 11 R 12 , —C 0-6 alkyl-NR 11 COR 12 , —C 0-6 alkyl-NR 11 SO 2 R 12 , —C 0-6 alkyl-SO 2 NR 11 R 12 , —C 0-6 alkyl-OCONR 11 R 12 , —C 0-6 alkyl-NR 11 CO 2 R 12 , —C 0-6 alkyl-NR 11 CONR 11 R 12 , —C 0-6 alkyl-OR 13 , —C 0-6 alkyl-SR 14 , —C 0-6 alkyl-SOR 14 , —C 0-6 alkyl-SO 2 R 14 , —C 0-6 alkyl-OSO 2 R 14 , —C 0-6 alkyl-C 3-6 cycloalkyl, —C 0-6 alkyl-aryl, —C 0-6 alkyl-heteroaryl, and —C 0-6 alkyl-heterocyclyl,
wherein the C 1-6 alkyl, —C 0-6 alkyl-C 3-6 cycloalkyl, —C 0-6 alkyl-aryl, —C 0-6 alkyl-heteroaryl, and —C 0-6 alkyl-heterocyclyl groups are unsubstituted or substituted with at least one R 15 , wherein each R 15 may be the same or different;

R 11 and R 12 independently are chosen from H and C 1-6 alkyl;
R 13 is chosen from H, C 1-6 alkyl, C 3-6 cycloalkyl, —C 1-6 alkyl-OR 18 , and haloC 1-6 alkyl;
R 14 represents C 1-6 alkyl;
R 15 is chosen from halogen, C 1-6 alkyl, haloC 1-6 alkyl, —C 0-6 alkylCN, —NO 2 , ═O, —C 0-6 alkyl-C 02 R 16 , —C 0-6 alkyl-COR 16 , —C 0-6 alkyl-NR 16 R 17 , —C 0-6 alkyl-CONR 16 R 17 , —C 0-6 alkyl-NR 16 COR 17 , —C 0-6 alkyl-NR 16 SO 2 R 17 , —C 0-6 alkyl-SO 2 NR 16 R 17 , —C 0-6 alkyl-OCONR 16 R 17 , —C 0-6 alkyl-NR 16 CO 2 R 17 , —C 0-6 alkyl-NR 16 CONR 16 R 17 , —C 0-6 alkyl-OR 18 , —C 0-6 alkyl-SR 19 , —C 0-6 alkyl-SOR 19 , —C 0-6 alkyl-SO 2 R 19 , and —C 0-6 alkyl-OSO 2 R 19 ;
R 16 and R 17 independently are chosen from H and C 1-6 alkyl;
R 18 is chosen from H, C 1-6 alkyl, and -haloC 1-6 alkyl; and
R 19 represents C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 represents a hydrogen atom.

3. The compound according to claim 1 , wherein R 2 represents a hydrogen atom.

4. The compound according to claim 1 , wherein Y is chosen from a -A 1 -S(O) p -A 2 - and a -A 5 -O-A 6 -.

5. The compound according to claim 1 , wherein Y is chosen from a —S—CH 2 — and a —S—CH(CH 3 )—.

6. The compound according to claim 1 , wherein Z is chosen from aryl, heteroaryl, and C 3-8 cycloalkyl, wherein the aryl, heteroaryl and C 3-8 cycloalkyl groups are unsubstituted or substituted with at least one R 10 .

7. The compound according to claim 1 , wherein Z is chosen from phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1-benzofuran-5-yl, pyrazolyl, pyridinyl, isoquinolinyl, imidazopyridinyl and cyclopropyl, each of which may be unsubstituted or substituted with at least one R 10 .

8. The compound according to claim 1 , wherein R 10 is chosen from -halogen, —C 1-6 alkyl, -haloC 1-6 alkyl, —C 0-6 alkyl-OR 13 , and —C 0-6 alkyl-heteroaryl, and wherein the —C 1-6 alkyl and —C 0-6 alkyl-heteroaryl groups are unsubstituted or substituted with at least one R 15 .

9. The compound according to claim 1 , chosen from:
2-(3-chlorobenzylthio)-5-hydroxypyrimidin-4(3H)-one;
2-(benzylsulfanyl)-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(3-methylbenzyl)sulfanyl]pyrimidin-4(3H)-one;
2-[(4-chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(naphthalen-2-ylmethyl)sulfanyl]pyrimidin-4(3H)-one;
2-[(3-fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(4-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one;
2-[(3,4-difluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(3-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one;
5-hydroxy-2-{[3-(trifluoromethyl)benzyl]sulfanyl}pyrimidin-4(3H)-one;
2-[(3-chloro-5-fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-sulfanyl}-pyrimidin-4(3H)-one;
2-[(2-chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(1-phenylethyl)sulfanyl]pyrimidin-4(3H)-one;
2-(cyclopropylmethylthio)-5-hydroxypyrimidin-4(3H)-one;
2-[(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-(pyridin-2-ylmethylthio)pyrimidin-4(3H)-one;
2-(3-(difluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-((4-methylpyridin-2-yl)methylthio)pyrimidin-4(3H)-one;
5-hydroxy-2-(pyridin-3-ylmethylthio)pyrimidin-4(3H)-one;
2-((1,3-dimethyl-1H-pyrazol-5-yl)methylthio)-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-(pyridin-4-ylmethylthio)pyrimidin-4(3H)-one;
2-(4-fluoro-3-(trifluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(isoquinolin-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one;
5-hydroxy-2-{[2-(2,2,2-trifluoroethoxy)benzyl]sulfanyl}-pyrimidin-4(3H)-one;
5-hydroxy-2-[(imidazo[1,2-a]pyridin-6-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one;
2-[(2,3-dihydro-1-benzofuran-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one;
5-hydroxy-2-[(naphthalen-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one;
5-hydroxy-2-[(imidazo[1,2-a]pyridin-2-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one;
2-(benzylsulfanyl)-5-hydroxy-6-(trifluoromethyl)pyrimidin-4(3H)-one;
5-methoxy-2-(4-methoxybenzylthio)pyrimidin-4(3H)-one;
and a pharmaceutically acceptable salt thereof.

10. The compound according to claim 2 , wherein R 2 represents a hydrogen atom.

11. The compound according to claim 2 , wherein Y is chosen from a -A 1 -S(O) p -A 2 - and a -A 5 -O-A 6 -.

12. The compound according to claim 3 , wherein Y is chosen from a -A 1 -S(O) p -A 2 - and a -A 5 -O-A 6 -.

Assignees

• Cockcroft Xiao Ling Fan
• Farnaby William
• Kinsella Natasha
• Merchant Kevin
• Miller David
• Takeda Pharmaceuticals Co

Inventors

• Cockcroft Xiao-Ling Fan
• Farnaby William
• Kinsella Natasha
• Merchant Kevin
• Miller David

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D239/22

  with hetero atoms directly attached to ring carbon atoms · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title