# US 11,999,746 B2 · Compounds

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- Number: US 11,999,746 B2
- Document ID: US11999746B2
- Status: Granted
- Kind: B2
- Application number: 16/524,238
- Filed: 2019-07-29
- Published: 2020-02-20
- Granted: 2024-06-04
- Earliest claimed: 2014-07-22
- Assignees: GlaxoSmithKline Intellectual Property Development Limited
- Applicants: GlaxoSmithKline Intellectual Property Development Limited
- Inventors: Zehong Wan; Xiaomin Zhang; Jian Wang; Matthew Robert Sender; Eric Steven Manas; Raphael Anthony Rivero; Joseph E Pero; Christopher Ernst Neipp; Vipulkumar Kantibhai Patel
- Web page: https://patentgrep.com/patent/US11999746B2

## CPC

- C07D 487/14: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/18: of the parathyroid hormones
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: 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
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/14: Ortho-condensed systems
- C07D 471/20: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/20: Spiro-condensed systems
- C07D 498/14: Ortho-condensed systems
- C07D 513/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel compounds that inhibit Lp-PLA2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA2, for example Alzheimer's disease.

## Claims

### Claim 1

A compound or a pharmaceutically acceptable salt thereof having the structure of Formula (I-4)
wherein
R1 is selected from the group consisting of H, C1-3alkyl, and —C(O)—C1-3alkyl; and
R2 and R3 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), CH2, and S(O)2, and
K is selected from the group consisting of C1-3alkyl, phenyl, and C3-6cycloalkyl;
or R1 and R2 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, NR1aR1b, COOH, and —Y—Rc, wherein
Y is absent or is selected from the group consisting of C(O), S(O)2, —C(O)—C(O)—, and CH2, and
Rc is selected from the group consisting of
C1-5alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR2aR2b, C3-6 cycloalkyl, and —COOH,
C1-3haloalkyl,
C1-3alkoxyl,
NR3aR3b,
—(CH2)p—C(O)—O—C1-3alkyl, wherein p is 1, 2, or 3 and the —(CH2)p— is optionally substituted by one or more methyl,
—(CH2)q—C3-6 cycloalkyl, wherein q is 1, 2, or 3, the cycloalkyl is optionally substituted with NR4aR4b, and the —(CH2)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 NR5aR5b,
wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b are independently H or C1-3alkyl; and
R3 is H;
each occurrence of R4 is independently H or D;
X is absent or is selected from the group consisting of
—O—,
—NH—, and
—N(C1-3 alkyl)-,
n is 1 or 2; or
X is —O—CH2-bicyclo[1.1.1]pentanyl-CH2—O— and n is 0; and
A is unsubstituted thiophenyl, or
A is
wherein
R5 and R9 are independently H or halo,
Z′ is N or CR6,
Z is N or CR8,
wherein R6 and R8 are independently selected from the group consisting of H, CN, halo, C1-3alkyl, C1-3haloalkyl, —S(O)2—C1-3alkyl and —S(O)—C1-3alkyl, and
V is CR7, wherein R7 is -Q-(CH2)m—W, wherein
Q is O, N, or CH2,
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 C1-3haloalkyl, CN, halo, and C1-5 alkyl.

### Claim 2 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
R1 and R2 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
R3 is H;
each R4 is H;
X is O;
n is 1 or 2; and
A is

### Claim 3 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R2 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 R3 is H.

### Claim 4 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is H.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is
wherein
R5 and R9 are independently H or F, and
R6 and R8 are independently selected from the group consisting of H, CN, and F, and
R7 is —O—W.

### Claim 8 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is
wherein
R5 and R9 are independently H or F, and
R6 and R8 are independently selected from the group consisting of H, CN, and F, and
R7 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 CF3 and CH3.

### Claim 9 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1 having the structure of Formula (A-4),
wherein
R1 and R2 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;
R5 and R9 are independently H or F;
R6 and R8 are independently selected from the group consisting of H or F; and
W1 is pyridyl, wherein said pyridyl is optionally substituted with one or two substituents independently selected from the group consisting of CF3 and CH3.

### Claim 10 (depends on 1)

The compound or a pharmaceutically acceptable salt thereof according to claim 1 having the structure of Formula (A-5),
wherein
R1 and R2 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;
R5 and R9 are independently H or F;
R6 and R8 are independently selected from the group consisting of H or F; and
W1 is pyridyl, wherein said pyridyl is optionally substituted with one or two substituents independently selected from the group consisting of CF3 and CH3.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 12)

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

### Claim 14 (depends on 1)

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.