Compounds

Patent metadata

Field	Value
Publication number	US-2024300965-A1
Application number	US-202418646178-A
Country	US
Kind code	A1
Filing date	Apr 25, 2024
Priority date	Jul 22, 2014
Publication date	Sep 12, 2024
Grant date	—

Abstract

The present invention relates to novel compounds that inhibit Lp-PLA 2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA 2 , for example Alzheimer's disease.

First claim

1 - 28 . (canceled)

29 . A compound of Formula (II-3) or a pharmaceutically acceptable salt thereof:

wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 5-membered saturated heterocyclic ring, which ring
optionally contains one or two additional heteroatom ring member independently selected from the group consisting of N, O, C(O), S, S(O), and S(O) 2 , and
is optionally substituted with one or more substituents independently selected from the group consisting of OH, halo, NR 1a R 1b , COOH, and —Y—R c , wherein
Y is absent or is selected from the group consisting of C(O), S(O) 2 , —C(O)—C(O)—, and CH 2 , and
R c is selected from the group consisting of
C 1-5 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 2a R 2b , C 3-6 cycloalkyl, and —COOH,
C 1-3 haloalkyl,
C 1-3 alkoxyl,
NR 3a R 3b ,
—(CH 2 ) p —C(O)—O—C 1-3 alkyl, wherein p is 1, 2, or 3 and the —(CH 2 ) p — is optionally substituted by one or more methyl,
—(CH 2 ) q —C 3-6 cycloalkyl wherein q is 1, 2, or 3, the cycloalkyl is optionally substituted with NR 4a R 4b , and the —(CH 2 ) q — is optionally substituted by one or more methyl, and
heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halo and NR 5a R 5b ,

wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are independently H or C 1-3 alkyl; and

R 3 is H;
each occurrence of R 4 is independently H or D;
X is absent or is selected from the group consisting of
—O—,
—NH—, and
—N(C 1-3 alkyl)-,

n is 1 or 2; or
X is —O—CH 2 -bicyclo[1.1.1]pentanyl-CH 2 —O— and n is 0;
A is unsubstituted thiophenyl, or
A is

 wherein
R 5 and R 9 are independently H or halo,
Z′ is N or CR 6 ,
Z is N or CR 8 ,
wherein R 6 and R 8 are independently selected from the group consisting of H, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, —S(O) 2 —C 1-3 alkyl and —S(O)—C 1-3 alkyl, and

V is CR 7 , wherein R 7 is -Q-(CH 2 ) m —W, wherein
Q is O, N, or CH 2 ,
m is 0 or 1, and
W is 6 membered heteroaryl, wherein the 6 membered heteroaryl is pyridinyl, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1-3 haloalkyl, CN, halo and C 1-5 alkyl.

30 . The compound or a pharmaceutically acceptable salt thereof according to claim 29 , wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 5-membered saturated heterocyclic ring, which ring is optionally substituted with one or more substituents independently selected from the group consisting of OH, halo, NR 1a R 1b , and COOH, and wherein R 1a and R 1b are independently H or C 1-3 alkyl; and R 3 is H; each occurrence of R 4 is H; X is absent or is selected from the group consisting of
—O—,
—NH—, and
—N(C 1-3 alkyl)-,
n is 1 or 2; or X is —O—CH 2 -bicyclo[1.1.1]pentanyl-CH 2 —O— and n is 0; A is

wherein
R 5 and R 9 are independently H or halo,
Z′ is N or CR 6 ,
Z is N or CR 8 ,
wherein R 6 and R 8 are independently selected from the group consisting of H, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, —S(O) 2 —C 1-3 alkyl and —S(O)—C 1-3 alkyl, and

V is CR 7 , wherein R 7 is -Q-(CH 2 ) m —W, wherein
Q is O, N, or CH 2 ,
m is 0 or 1, and
W is 6 membered heteroaryl, wherein the 6 membered heteroaryl is pyridinyl, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1-3 haloalkyl, CN, halo and C 1-5 alkyl.

31 . The compound or a pharmaceutically acceptable salt thereof according to claim 30 , wherein R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 5-membered saturated heterocyclic ring, which ring is optionally substituted with one or more OH groups.

32 . The compound or a pharmaceutically acceptable salt thereof according to claim 31 , wherein X is —O— and n is 1.

33 . The compound or a pharmaceutically acceptable salt thereof according to claim 32 , wherein A is

wherein
R 5 and R 9 are each H,
Z′ is N or CR 6 ,
Z is N or CR 8 ,
wherein R 6 and R 8 are each halo, and
V is CR 7 , wherein R 7 is -Q-(CH 2 ) m —W, wherein
Q is O, N, or CH 2 ,
m is 0 or 1, and
W is 6 membered heteroaryl, wherein the 6 membered heteroaryl is pyridinyl, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1-3 haloalkyl, CN, halo and C 1-5 alkyl.

34 . The compound or a pharmaceutically acceptable salt thereof according to claim 33 , wherein R 6 and R 8 are each F, and
V is CR 7 , wherein R 7 is -Q-(CH 2 ) m —W, wherein
Q is O,
m is 0, and
W is pyridinyl, wherein said pyridinyl is optionally substituted with C 1-3 haloalkyl.

35 . The compound or a pharmaceutically acceptable salt thereof according to claim 29 , wherein the compound has the following structure:

wherein
L1, L2, and L3 are each independently H or OH;
R 3 is H;
R 5 , R 6 , R 8 , and Rº are each independently H or F; and
W 1 is 6 membered heteroaryl, wherein the 6 membered heteroaryl is pyridinyl, and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1-3 haloalkyl, CN, halo and C 1-5 alkyl.

36 . The compound or a pharmaceutically acceptable salt thereof according to claim 29 , wherein the compound is

37 . The compound or a pharmaceutically acceptable salt thereof according to claim 29 , wherein the compound is

38 . The compound or a pharmaceutically acceptable salt thereof according to claim 29 , wherein the compound is

39 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 29 , and a pharmaceutically acceptable excipient.

40 . A method for treating neurodegeneration disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 29 .

41 . The method according to claim 40 , wherein the neurodegeneration disease is Alzheimer's disease.

42 . The method according to claim 40 , wherein the subject is a human.

43 . A method for treating atherosclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 29 .

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Wan Zehong
• Zhang Xiaomin
• Wang Jian
• Sender Matthew Robert
• Manas Eric Steven
• Rivero Raphael Anthony
• Pero Joseph E
• Neipp Christopher Emst
• Patel Vipulkumar Kantibhai

Classifications

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/20

  Spiro-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title