Pyrimidone compounds used as Lp-PLA2 inhibitors and pharmaceutical compositions thereof

Patent metadata

Field	Value
Publication number	US-10280146-B2
Application number	US-201515540025-A
Country	US
Kind code	B2
Filing date	Dec 28, 2015
Priority date	Dec 26, 2014
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The present invention relates to pyrimidone compounds used as Lp-PLA 2 inhibitors and pharmaceutical compositions thereof. The structure of the pyrimidone compounds is represented by general formula (I), wherein R 1 , R 2 , R 3 , X, Ar, Y and n are defined as in the specification and claims. The compounds of general formula (I) in the present invention, stereoisomers and pharmaceutically acceptable salts thereof can be used as Lp-PLA 2 inhibitors for preventing, treating and/or ameliorating diseases associated with the activity of Lp-PLA 2 enzyme.

First claim

The invention claimed is:

1. A compound of general formula I, a deuterated form, a stereoisomer or pharmaceutically acceptable salt thereof:

wherein, R 1 is selected from the group consisting of C 1 -C 6 alkyl, —(CH 2 ) q -(3-8 membered heteroaryl);
R 2 is C 1 -C 6 alkyl, 3-8 membered heterocyclic radical, C 1 -C 6 alkoxy, C 6 -C 10 aryl, —(CH 2 ) m -(3-8 membered heteroaryl) or —NR 4 R 5 ;
R 3 is H;
X is O, S, or —N(R 4 )—;
n is 1, 2, 3 or 4;
Ar is C 6 -C 10 aryl or 3-8 membered heteroaryl;
Y is absent, -A-(C 6 -C 10 aryl) or -A-(3-8 membered heteroaryl), wherein, A is O or S,
wherein,
said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-8 membered heteroaryl, 3-8 membered heterocyclic radical, C 6 -C 10 aryl are optionally substituted with a group selected from the group consisting of: —CN, ═O, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, halogen, halo-C 1 -C 6 alkyl;
each R 4 and each R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) m1 —(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl;
m is 0, 1, 2, 3 or 4; and
m1 is independently 1, 2, 3 or 4.

2. The compound of general formula I, a stereoisomer, deuterated form or pharmaceutically acceptable salt thereof according to claim 1 , wherein said compound of general formula I has one or more of the following features:
(1) R 1 is C 1 -C 3 alkyl;
(2) R 3 is H;
(3) n is 1 or 2;
(4) X is O.

3. The compound of general formula I, a stereoisomer, deuterated form or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is C 1 -C 6 alkyl, 3-8 membered heterocyclic radical, C 1 -C 6 alkoxy, C 6 -C 10 aryl, —(CH 2 ) m -(3-8 membered heteroaryl) or —NR 4 R 5 , wherein,
said 3-8 membered heterocyclic radical, C 1 -C 6 alkoxy, C 6 -C 10 aryl, —(CH 2 ) m -(3-8 membered heteroaryl) are optionally substituted with a group selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, halogen;

said m is O;
R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) m1 —(C 1 -C 6 alkoxy), C 3 -C 8 cycloalkyl; wherein
m1 is 2 or 3.

4. The compound of general formula I, a stereoisomer, deuterated form or pharmaceutically acceptable salt thereof according to claim 1 , wherein said compound of general formula I has one or two of the following features:
(1) Ar is substituted or unsubstituted phenyl, wherein said substitution means that the phenyl has 1-4 substituents selected from the group consisting of: —CN, C 1 -C 6 alkyl, halogen, hydroxyl, halo-C 1 -C 6 alkyl, and halo-C 1 -C 6 alkoxy;
(2) Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein, A is O or S; said C 6 -C 10 aryl or 5-6 membered heteroaryl optionally has 1-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, —CN, halogen, halo-C 1 -C 6 alkyl.

5. The compound of general formula I, a stereoisomer, deuterated form or pharmaceutically acceptable salt thereof according to claim 1 , wherein said compound of general formula I is:

6. A pharmaceutical composition, which comprises the compound of general formula I, a stereoisomer, deuterated form or pharmaceutically acceptable salt thereof according to claim 1 ; and a pharmaceutically acceptable carrier.

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Shen Jianhua
• Wang Yiping
• Chen Xinde
• Xu Wenwei
• Wang Kai

Classifications

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title