Pyrazole derivatives useful as 5-lipoxygenase activating protein (FLAP) inhibitors

Patent metadata

Field	Value
Publication number	US-11001589-B2
Application number	US-201916668743-A
Country	US
Kind code	B2
Filing date	Oct 30, 2019
Priority date	May 4, 2015
Publication date	May 11, 2021
Grant date	May 11, 2021

Abstract

The present application relates to novel compounds of formula (I)

to their utility in treating and/or preventing clinical conditions including cardiovascular diseases (CVD), to methods for their therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.

First claim

The invention claimed is:

1. A method of treating diseases or conditions in which inhibition of FLAP is beneficial, comprising administering to a patient in need thereof an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CH or CCH 3 ;
R 2 is —H or —F;
R 4 is —H or —CH 3 ; and
R 8 is —H or CH 3 .

2. Method of treatment according to claim 1 , wherein the compound of formula (IV) is a compound in which X 1 is CH.

3. Method of treatment according to claim 1 , wherein the compound of formula (IV) is a compound in which R 2 is H.

4. Method of treatment according to claim 1 , wherein the compound of formula (IV) is a compound in which R 4 is —CH 3 .

5. Method of treatment according to claim 1 , wherein the compound of formula (IV) is a compound in which R 8 is H.

6. Method of treatment according to claim 1 , wherein the compound of formula (IV) is selected from:
(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;
(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-(5-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-(4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide; and
(1R,2R)—N-(2-Methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide.

7. Method of treatment according to claim 1 , wherein the compound of formula (IV) is (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.

8. Method of treatment according to claim 1 , wherein the compound of formula (IV) is (1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide.

9. A method of treating diseases or conditions in which inhibition of FLAP is beneficial, comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

10. Method of treatment according to claim 1 , wherein the disease or condition in which inhibition of FLAP is beneficial is cardiovascular disease (CVD).

11. Method of treatment according to claim 10 , wherein the disease or condition in which inhibition of FLAP is beneficial is atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, restenosis following revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD), stroke, transient ischemic attack (TIA), reversible ischemic neurologic disease (RIND), multi-infarct dementia, and renal arterial disease.

Assignees

• Astrazeneca Ab

Inventors

• Broddefalk Johan Olof
• Emtenâs Hans Fredrik
• Granberg Kenneth Lars
• Lemurell Malin Anita
• Pettersen Daniel Tor
• Plowright Alleyn Thomas
• Ulander Lars Johan Andreas

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D231/40 Primary

  Acylated on said nitrogen atom · CPC title