Methods of treating pulmonary hypertension

Patent metadata

Field	Value
Publication number	US-2016166556-A1
Application number	US-201514823457-A
Country	US
Kind code	A1
Filing date	Aug 11, 2015
Priority date	Aug 13, 2014
Publication date	Jun 16, 2016
Grant date	—

Abstract

The present disclosure relates to a method of preventing and/or treating pulmonary vascular disease and/or right ventricular dysfunction, including but not limited to pulmonary hypertension or pulmonary arterial hypertension, comprising administering a therapeutically effective amount of an ASK1 inhibitor.

First claim

What is claimed is:

1 . A method of treating and/or preventing pulmonary vascular disease and/or right ventricle dysfunction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor.

2 . The method of claim 1 , wherein the ASK1 inhibitor is a compound of formula (I):

wherein:
R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to three substituents selected from halo, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, —NO 2 , R 6 , —C(O)—R 6 , —OC(O)—R 6 —C(O)—O—R 6 , C(O)—N(R 6 )(R 7 ), —OC(O)—N(R 6 )(R 7 ), —S—R 6 , —S(═O)—R 6 , —S(═O) 2 R 6 , —S(═O) 2 —N(R 6 )(R 7 ), —S(═O) 2 —O—R 6 , —N(R 6 )(R 7 ), —N(R 6 )—C(O)—R 7 , —N(R 6 )—C(O)—O—R 7 , —N(R 6 )—C(O)—N(R 6 )(R 7 ), —N(R 6 )—S(═O) 2 —R 6 , —CN, and —O—R 6 , and wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, and phenoxy are optionally substituted by from one to three substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo; wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1 -C 15 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, all of which are optionally substituted with from one to three substituents selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —CN, lower alkoxy, —CF 3 , aryl, and heteroaryl; or
R 6 and R 7 when taken together with the nitrogen to which they are attached form a heterocycle;
R 2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;
R 3 is aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to five substituents selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo, —NO 2 , haloalkyl, haloalkoxy, —CN, —O—R 6 , —O—C(O)—R 6 , —O—C(O)—N(R 6 )(R 7 ), —S—R 6 , —N(R 6 )(R 7 ), —S(═O)—R 6 , —S(═O) 2 R 6 , —S(═O) 2 —N(R 6 )(R 7 ), —S(═O) 2 —O—R 6 , —N(R 6 )—C(O)—R 7 , —N(R 6 )—C(O)—O—R 7 , —N(R 6 )—C(O)—N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—R 6 , —C(O)—N(R 6 )(R 7 ), and —N(R 6 )—S(═O) 2 —R 7 , wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with from one to five substituents selected from halo, oxo, —NO 2 , alkyl, haloalkyl, haloalkoxy, —N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—O—R 6 , —C(O)—N(R 6 )(R 7 ), —CN, —O—R 6 , cycloalkyl, aryl, heteroaryl and heterocyclyl; with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom;
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are independently C(R 4 ) or N, in which each R 4 is independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NO 2 , haloalkyl, haloalkoxy, —CN, —O—R 6 , —S—R 6 , —N(R 6 )(R 7 ), —S(═O)—R 6 , —S(═O) 2 R 6 , —S(═O) 2 —N(R 6 )(R 7 ), —S(═O) 2 —O—R 6 , —N(R 6 )—C(O)—R 7 , —N(R 6 )—C(O)—O—R 7 , —N(R 6 )—C(O)—N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—O—R 6 , —C(O)—N(R 6 )(R 7 ), or —N(R 6 )—S(═O) 2 —R 7 , wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with from one to five substituents selected from halo, oxo, —NO 2 , —CF 3 , —O—CF 3 , —N(R 6 )(R 7 ), —C(O)—R 6 , —C(O)—O—R 7 , —C(O)—N(R 6 )(R 7 ), —CN, —O—R 6 ; or
X 5 and X 6 or X 6 and X 7 are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryl; and
with the proviso that at least one of X 2 , X 3 , and X 4 is C(R 4 ); at least two of X 5 , X 6 , X 7 , and X 8 are C(R 4 ); and at least one of X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 is N;
or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

3 . The method of any of claim 1 , wherein the ASK1 inhibitor is a compound selected from the group consisting of 3-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzamide, 3-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide, 5-(4-cyclopropyl-1 H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide, 4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)picolinamide, and (S)-5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-(6-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzamide, or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein the ASK1 inhibitor is a compound of formula (II):

wherein:
R 21 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to four substituents selected from the group consisting of halo, hydroxyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, NO 2 , R 26 , C(O)R 26 , OC(O)R 26 C(O)OR 26 , C(O)N(R 26 )(R 27 ), OC(O)N(R 26 )(R 27 ), SR 26 , S(═O)R 26 , S(═O) 2 R 26 , S(═O) 2 N(R 26 )(R 27 ), S(═O) 2 OR 26 , N(R 26 )(R 27 ), N(R 26 )C(O)R 27 , N(R 26 )C(O)OR 27 , N(R 26 )C(O)N(R 26 )(R 27 ), N(R 26 )S(═O) 2 R 26 , CN, and OR 26 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and aryloxy are optionally substituted with from one to three substituents selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo;
R 26 and R 27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with from one to three substituents selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, lower alkoxy, CF 3 , aryl, and heteroaryl; or
R 26 and R 27 when taken together with the nitrogen to which they are attached form a heterocycle;
R 22 is aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to five substituents selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo, NO 2 , haloalkyl, haloalkoxy, CN, OR 26 , OC(O)R 26 , OC(O)N(R 26 )(R 27 ), SR 26 , N(R 26 )(R 27 ), S(═O)R 26 , S(═O) 2 R 26 , S(═O) 2 N(R 26 )(R 27 ), S(═O) 2 OR 26 , N(R 26 )C(O)R 27 , N(R 26 )C(O)OR 27 , N(R 26 )C(O)N(R 26 )(R 27 ), C(O)R 26 , C(O)OR 26 , C(O)N(R 26 )(R 27 ), and N(R 26 )S(═O) 2 R 27 and wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from halo, oxo, NO 2 , alkyl, haloalkyl, haloalkoxy, N(R 26 )(R 27 ), C(O)R 26 , C(O)OR 26 , C(O)N(R 26 )(R 27 ), CN, OR 26 , cycloalkyl, aryl, heteroaryl and heterocyclyl; with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom;
R 24 and R 25 are independently hydrogen, halo, cyano, alkyl, alkoxy, or cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally substituted by halo or cycloalkyl;
X 21 and X 25 are independently C(R 23 ) or N, wherein each R 23 is independently hydrogen, halo, alkyl, alkoxy or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with from one to five substituents selected from halo, oxo, CF 3 , OCF 3 , N(R 26 )(R 27 ), C(O)R 26 , C(O)OR 27 , C(

Assignees

• Gilead Sciences Inc

Inventors

• Budas Grant Raymond
• Liles John T
• Phan Dillon Thanh

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title