Compounds

Patent metadata

Field	Value
Publication number	US-11999746-B2
Application number	US-201916524238-A
Country	US
Kind code	B2
Filing date	Jul 29, 2019
Priority date	Jul 22, 2014
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

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

What is claimed is:

1. A compound or a pharmaceutically acceptable salt thereof having the structure of Formula (I-4)

wherein
R 1 is selected from the group consisting of H, C 1-3 alkyl, and —C(O)—C 1-3 alkyl; and
R 2 and R 3 together with the carbon to which they are attached form a 4-, 5- or 6-membered saturated ring, which ring
optionally contains one heteroatom ring member selected from N or O, and
is optionally substituted with one substituent of -L-K, wherein
L is selected from the group consisting of C(O), CH 2 , and S(O) 2 , and
K is selected from the group consisting of C 1-3 alkyl, phenyl, and C 3-6 cycloalkyl;

or R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 6-membered saturated ring, which ring
optionally contains one or two additional heteroatom ring members 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; and
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 pyridyl, and
wherein said pyridyl 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.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 6-membered saturated, unsubstituted ring, which ring contains one additional heteroatom ring member selected from the group consisting of N, O, and C(O); and
R 3 is H;
each R 4 is H;
X is O;
n is 1 or 2; and
A is

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 6-membered saturated ring, which ring optionally contains one additional heteroatom ring member selected from the group consisting of N, O, and C(O), and R 3 is H.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is H.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein X is O.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 1.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein A is

wherein
R 5 and R 9 are independently H or F, and
R 6 and R 8 are independently selected from the group consisting of H, CN, and F, and
R 7 is —O—W.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein A is

wherein
R 5 and R 9 are independently H or F, and
R 6 and R 8 are independently selected from the group consisting of H, CN, and F, and
R 7 is —O—W, wherein W is pyridyl, and said pyridyl is optionally substituted with one or more substituents independently selected from the group consisting of CF 3 and CH 3 .

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 having the structure of Formula (A-4),

wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 6-membered saturated ring, which ring contains one additional heteroatom ring member selected from the group consisting of N, O, and C(O), and which ring has no further substitution;
R 5 and R 9 are independently H or F;
R 6 and R 8 are independently selected from the group consisting of H or F; and
W 1 is pyridyl, wherein said pyridyl is optionally substituted with one or two substituents independently selected from the group consisting of CF 3 and CH 3 .

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 having the structure of Formula (A-5),

wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 6-membered saturated ring, which ring contains one additional heteroatom ring member O and which ring has no further substitution;
R 5 and R 9 are independently H or F;
R 6 and R 8 are independently selected from the group consisting of H or F; and
W 1 is pyridyl, wherein said pyridyl is optionally substituted with one or two substituents independently selected from the group consisting of CF 3 and CH 3 .

11. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

12. A method for treating neurodegeneration disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1 .

13. The method according to claim 12 , wherein the neurodegeneration disease is Alzheimer's disease.

14. A method for treating atherosclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1 .

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 Ernst
• Patel Vipulkumar Kantibhai

Classifications

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D471/20

  Spiro-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title