US 2023/0219967 A1Published application

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

AssigneeAstraZeneca AB

InventorsJohan Olof BRODDEFALK, Hans Fredrik EMTENÂS, Kenneth Lars GRANBERG, Malin Anita LEMURELL, Daniel Tor PETTERSEN, Alleyn Thomas PLOWRIGHT, Lars Johan Andreas ULANDER

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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.

Claims21

Dependent claims

A compound according to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, C1-C3 alkyl, halo, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy;
each of R2 and R3 is independently H, C1-C3 alkyl, C1-C3 alkoxy, —CN or halo;
R4 is H, —CH3, —CH2F, —CHF2, —CF3 or halo;
Ring A contains 2 double bonds;
each X1, X2, X3 and X4 of Ring A is independently CR5, CH, O, S, NR6 or N;
wherein at least one of X1, X2, X3 and X4 in Ring A is NR6;
each R5 is optionally and independently C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, —S(O)pR7, —CN, —CONR′R″, or C3-C6 cycloalkyl;
each p is independently 0, 1 or 2;
R6 is H, —CH3 or —CH2CH3;
or wherein when X4 is CR5 and X3 is NR6, then the R5 and R6 may be taken together to form a 5 to 6-membered heterocyclyl ring fused to Ring A, which heterocyclyl may optionally contain an additional heteroatom selected from N, O and S;
said fused heterocyclyl may additionally contain a carbonyl or a —S(O)2 directly adjacent to a heteroatom therein;
and may be further substituted with one or two substituents selected from the group consisting of —CH3 and halo;
R7 is —CH3 or —NR′R″;
and
each R′ and R″ is independently —H or —CH3;
provided that the total number of substituents on Ring A is 0, 1 or 2;
and further provided that when R5 and R6 are not combined to form a heterocyclyl ring fused to Ring A, that the total number of R5 and R6 substituents which is alkyl and/or haloalkyl is 0 or 1.

15 more elements

A compound selected from the group consisting of:

Trans(+) or Trans(−) 1-Methyl-4-[({(1R,2R or 1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;
1-Methyl-4-[({(1R,2R)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;
1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;
1-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;
Trans(−) (1S,2S or 1R,2R)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(+) (1R,2R or 1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1H-pyrazol-4-yl)cyclohexanecarboxamide;
(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-[1-Methyl-5-(methylsulfonyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-[3-(Difluoromethoxy)-1-methyl-1H-pyrazol-4-yl]-2-(4-(1H-pyrazol-5-yl)benzoyl)-cyclohexanecarboxamide;
(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-3-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;
(1R,2R)—N-(2,3-Dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(−) (1R,2R or 1S,2S)—N-(3-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1-methyl-5-sulfamoyl-1H-pyrazol-4-yl)cyclohexanecarboxamide;
Trans (+/−) (1R,2R and 1S,2S)—N-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-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-(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;
Trans(−) (1R,2R or 1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
Trans(+) (1S,2S or 1R,2R)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
1-Ethyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;
Trans(±)-N,1-Dimethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;
N,1-Dimethyl-4-[({(1R,2R)-2-[4-(5-methyl-1H-pyrazol-3-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;
5-Methyl-4-[({(1R,2R)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxamide;
4-[({(1R,2R)-2-[4-(1H-Pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-5-carboxamide;
(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-[1-Methyl-5-(methylsulfamoyl)-1H-pyrazol-4-yl]-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-(1-Methyl-3-sulfamoyl-1H-pyrazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
(1R,2R)—N-[5-(Dimethylsulfamoyl)-1-methyl-1H-pyrazol-4-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;
(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;
and
(1R,2R)—N-[5-(Difluoromethyl)-1H-pyrazol-4-yl]-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexanecarboxamide;
Trans(±)-4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
Trans(±)-4-[({(1R,2R and 1S,2S)-2-[2-Chloro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(5-Cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-cyclohexyl}carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1-methyl-1H-pyrazole-5-carboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-5-carboxamide;
(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]-N-(4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide;
4-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1,2,5-oxadiazole-3-carboxamide;
3-[({(1R,2R or 1S,2S)-2-[2-Fluoro-4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}carbonyl)-amino]-5-methyl-1,2-oxazole-4-carboxamide;
Trans(±)-1-Ethyl-4-[({(1R,2R and 1S,2S)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexyl}-carbonyl)amino]-1H-pyrazole-3-carboxamide;
(1R,2R)-2-[4-(3-Methyl-1H-pyrazol-5-yl)benzoyl]-N-(1,3,4-oxadiazol-2-yl)cyclohexanecarboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(3-Methyl-1,2-oxazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(4-Methyl-1,3-oxazol-2-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(5-Cyano-1-methyl-1H-pyrazol-4-yl)-2-[4-(3-methyl-1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(3-Cyclopropyl-1,2,4-thiadiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
Trans(±)-(1R,2R and 1S,2S)—N-(3-Methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
and
Trans(±)-(1R,2R and 1S,1S)—N-(4-Cyano-3-methyl-1,2-thiazol-5-yl)-2-[4-(1H-pyrazol-5-yl)benzoyl]cyclohexanecarboxamide;
or a pharmaceutically acceptable salt thereof.

51 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/174,832Filed 27 Feb 2023
Priority: 4 May 2015
Published: 13 Jul 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/4985
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrazines or piperazines…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application62/156,424Us provisional application · filed 4 May 2015
Application15/571,291Continuation · filed 2 Nov 2017
Application16/196,217Continuation · filed 20 Nov 2018
Application16/668,743Continuation · filed 30 Oct 2019
Application17/237,656Continuation · filed 22 Apr 2021
Application18/174,832Continuation
US 10,183,947 B2Related patent
US 10,508,119 B2Related patent
US 11,001,589 B2Related patent
US 11,691,978 B2Related patent
US 12,024,523 B2Related patent
US 2018/0237439 A1Published application
US 2019/0084991 A1Published application
US 2020/0157113 A1Published application
US 2021/0355127 A1Published application
US 2023/0219967 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

18/174,832Filed 27 Feb 2023

Priority

4 May 2015

Published

13 Jul 2023

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/4155
1,2-Diazoles: non condensed and containing further heterocyclic rings
A61K 31/4985
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrazines or piperazines…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application62/156,424Us provisional application · filed 4 May 2015

Application15/571,291Continuation · filed 2 Nov 2017

Application16/196,217Continuation · filed 20 Nov 2018

Application16/668,743Continuation · filed 30 Oct 2019

Application17/237,656Continuation · filed 22 Apr 2021

Application18/174,832Continuation

US 10,183,947 B2Related patent

US 10,508,119 B2Related patent

US 11,001,589 B2Related patent

US 11,691,978 B2Related patent

US 12,024,523 B2Related patent

US 2018/0237439 A1Published application

US 2019/0084991 A1Published application

US 2020/0157113 A1Published application

US 2021/0355127 A1Published application

US 2023/0219967 A1This patent

From the US filing history. Foreign family members aren’t listed.