Compounds

Patent metadata

Field	Value
Publication number	US-10125141-B2
Application number	US-201515327706-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Jul 22, 2014
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

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 of Formula (I-3) or a pharmaceutically acceptable salt thereof:

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 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
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 N or CR 7 , wherein R 7 is selected from the group consisting of H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, and —S(O) 2 —C 1-3 alkyl, or R 7 is -Q-(CH 2 ) m —W,
wherein
Q is O, N, or CH 2 ,
m is 0 or 1, and
W is selected from the group consisting of C 3-6 cycloalkyl, heterocyclyl, 5 membered heteroaryl and phenyl, wherein said cycloalkyl, heterocyclyl, heteroaryl or phenyl 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;

or when Z or Z′ is CR 6 and V is CR 7 , R 6 and R 7 together may form a 4,7-dioxaspiro[2.6]nonane,
with the proviso that the compound of Formula (I-3) is not
4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,
4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile, or
4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile.

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 5-membered saturated, unsubstituted ring, which ring optionally contains one additional heteroatom ring member selected from N, O and C(O); and
R 3 is H;
R 4 is H;
X is O;
n is 1 or 2; and
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 N or CR 7 , wherein R 7 is selected from the group consisting of H, halo, CN, C 1-3 alkyl, C 1-3 haloalkyl, —S(O) 2 —C 1-3 alkyl, or R 7 is -Q-(CH 2 ) m —W, wherein
Q is O, N, or CH 2 ,
m is 0 or 1, and
W is selected from the group consisting of C 3-6 cycloalkyl, heterocyclyl, 5 membered heteroaryl and phenyl, wherein said cycloalkyl, heterocyclyl, heteroaryl or phenyl 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.

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 5-membered saturated ring, which ring optionally contains one additional heteroatom ring member selected from 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 1 and R 2 together with the nitrogen and carbon to which they are attached form a 5 membered unsubstituted, saturated heterocycle, which contains no additional heteroatom ring member, and R 3 is H.

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

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

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

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 5 membered heteroaryl or phenyl, wherein said heteroaryl or phenyl 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.

9. 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 pyrazolyl or phenyl, wherein said pyrazolyl or phenyl is optionally substituted with one or more substituents independently selected from the group consisting of CF 3 and CH 3 .

10. The compound or pharmaceutically acceptable salts thereof according to claim 1 has the following structure:

wherein
R 1 and R 2 together with the nitrogen and carbon to which they are attached form a 5-membered saturated ring, which ring optionally contains one additional heteroatom ring member selected from the group consisting

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

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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