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

Patent metadata

Field	Value
Publication number	US-10787422-B2
Application number	US-201916299636-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Dec 26, 2014
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

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

What is claimed is:

1. A method of treating and/or alleviating diabetes and diabetic complications in a subject, comprising administering to the subject an effective amount of 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 an phenyl ring 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, and halo-C 1 -C 6 alkyl;
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 method 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; and
(4) X is O.

3. The method 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 method 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 method according to claim 1 , wherein said compound of general formula I is:

6. The method according to claim 1 , wherein the said diabetic complication is diabetic eye disease.

7. The method according to claim 1 , wherein the said diabetic complication is diabetic kidney disease.

8. The method according to claim 1 , wherein the said diabetic eye disease is diabetic macular edema.

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

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

Classifications

• C07D239/56

  One oxygen atom and one sulfur atom · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D239/54 Primary

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

• A61P9/12

  Antihypertensives · CPC title