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US 10,238,636 B2Granted
Methods of treating liver disease
AssigneeGilead Sciences, Inc.
InventorsJamie Geier Bates, David Gordon Clarkson Breckenridge, John T. Liles, William J. Watkins
Life of this patent
Estimating the term…
Abstract
The present disclosure relates to a method of preventing and/or treating liver disease comprising administering an ASK1 inhibitor in combination with a FXR agonist, to a patient in need thereof.
Claims18
A method of treating or preventing nonalcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor in combination with a therapeutically effective amount of a FXR agonist, wherein the ASK1 inhibitor is a compound of formula (I):
- wherein:
- R1 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 independently selected from halo, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, —NO2, R6, —C(O)—R6, —OC(O)—R6—C(O)—O—R6, C(O)—N(R6)(R7), —OC(O)—N(R6)(R7), —S—R6, —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)(R7), —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —N(R6)—S(═O)2—R6, —CN, and —O—R6, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and aryloxy are optionally substituted by from one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo;
- wherein R6 and R7 are independently selected from the group consisting of hydrogen, C1-C15 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, all of which are optionally substituted with from one to three substituents independently selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —CN, lower alkoxy, —CF3, aryl, and heteroaryl;
- or
- R6 and R7 when taken together with the nitrogen to which they are attached form a heterocycle;
- R2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;
- R3 is aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to five substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo, —NO2, haloalkyl, haloalkoxy, —CN, —O—R6, —O—C(O)—R6, —O—C(O)—N(R6)(R7), —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—R6, —C(O)—N(R6)(R7), and —N(R6)—S(═O)2—R7, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with from one to five substituents independently selected from halo, oxo, —NO2, alkyl, haloalkyl, haloalkoxy, —N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), —CN, —O—R6, cycloalkyl, aryl, heteroaryl and heterocyclyl;
- with the proviso that the heteroaryl or heterocyclyl moiety of R3 includes at least one ring nitrogen atom;
- X1, X2, X3, X4, X5, X6, X7 and X8 are independently C(R4) or N, in which each R4 is independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NO2, haloalkyl, haloalkoxy, —CN, —O—R6, —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), or —N(R6)—S(═O)2—R7, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with from one to five substituents independently selected from halo, oxo, —NO2, —CF3, —O—CF3, —N(R6)(R7), —C(O)—R6, —C(O)—O—R7, —C(O)—N(R6)(R7), —CN, —O—R6;
- or
- X5 and X6 or X6 and X7 are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryl;
- and
- with the proviso that at least one of X2, X3, and X4 is C(R4);
- at least two of X5, X6, X7, and X8 are C(R4);
- and at least one of X2, X3, X4, X5, X6, X7 and X8 is N;
- or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.
13 more elements
A method of treating or preventing nonalcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor in combination with a therapeutically effective amount of a FXR agonist, wherein the ASK1 inhibitor is a compound of formula (II):
- wherein:
- R21 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 independently selected from the group consisting of halo, hydroxyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, NO2, R26, C(O)R26, OC(O)R26C(O)OR26, C(O)N(R26)(R27), OC(O)N(R26)(R27), SR26, S(═O)R26, S(═O)2R26, S(═O)2N(R26)(R27), S(═O)2OR26, N(R26)(R27), N(R26)C(O)R27, N(R26)C(O)OR27, N(R26)C(O)N(R26)(R27), N(R26)S(═O)2R26, CN, and OR26, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and aryloxy are optionally substituted with from one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo;
- R26 and R27 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 independently selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, lower alkoxy, CF3, aryl, and heteroaryl;
- or
- R26 and R27 when taken together with the nitrogen to which they are attached form a heterocycle;
- R22 is aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to five substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo, NO2, haloalkyl, haloalkoxy, CN, OR26, OC(O)R26, OC(O)N(R26)(R27), SR26, N(R26)(R27), S(═O)R26, S(═O)2R26, S(═O)2N(R26)(R27), S(═O)2OR26, N(R26)C(O)R27, N(R26)C(O)OR27, N(R26)C(O)N(R26)(R27), C(O)R26, C(O)OR26, C(O)N(R26)(R27), and N(R26)S(═O)2R27, and wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more substituents selected from halo, oxo, NO2, alkyl, haloalkyl, haloalkoxy, N(R26)(R27), C(O)R26, C(O)OR26, C(O)N(R26)(R27), CN, OR26, cycloalkyl, aryl, heteroaryl and heterocyclyl;
- with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom;
- R24 and R25 are independently hydrogen, halo, cyano, alkyl, alkoxy, or cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally substituted by halo or cycloalkyl;
- X21 and X25 are independently C(R23) or N, wherein each R23 is independently hydrogen, halo, alkyl, alkoxy or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with from one to five substituents independently selected from halo, oxo, CF3, OCF3, N(R26)(R27), C(O)R26, C(O)OR27, C(O)N(R26)(R27), CN, and OR26;
- and
- X22, X23 and X24 are independently C(R23), N, O, or S;
- with the proviso that at least one of X22, X23, and X24 is C(R23);
- and only one of X22, X23, and X24 is O or S;
- or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.
11 more elements
A method of treating or preventing nonalcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an ASK1 inhibitor in combination with a therapeutically effective amount of a FXR agonist, wherein the ASK1 inhibitor is a compound of formula (III):
- wherein:
- R31 is C1-C3 alkyl or C3-C6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one to three halogen atoms;
- R32 is hydrogen or C1-C6 alkyl wherein the alkyl is optionally substituted with halo;
- R33 is hydrogen or C1-C3 alkyl;
- R34 is hydrogen or C1-C3 alkyl;
- R35 is hydrogen, C1-C3 alkyl, OR3a or —NHR3a;
- R36 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl wherein the cycloalkyl is optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, or 1 or 2 halogen atoms;
- R3a and R3b are independently hydrogen, C1-C3 alkyl or R3a and R3b combine with the nitrogen atom to which they are attached to form a four to six member heterocyclic ring optionally containing an oxygen or a nitrogen atom in the ring;
- or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof.
6 more elements
A pharmaceutical composition comprising a therapeutically effective amount of an ASK1 inhibitor and a therapeutically effective amount of a FXR agonist, wherein the ASK1 inhibitor is a compound of formula (I):
- wherein:
- R1 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 independently selected from halo, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, —NO2, R6, —C(O)—R6, —OC(O)—R6—C(O)—O—R6, C(O)—N(R6)(R7), —OC(O)—N(R6)(R7), —S—R6, —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)(R7), —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —N(R6)—S(═O)2—R6, —CN, and —O—R6, and wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and aryloxy are optionally substituted by from one to three substituents independently selected from alkyl, cycloalkyl, alkoxy, hydroxyl, and halo;
- wherein R6 and R7 are independently selected from the group consisting of hydrogen, C1-C15 alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, all of which are optionally substituted with from one to three substituents independently selected from halo, alkyl, monoalkylamino, dialkylamino, alkyl amide, aryl amide, heteroaryl amide, —CN, lower alkoxy, —CF3, aryl, and heteroaryl;
- or
- R6 and R7 when taken together with the nitrogen to which they are attached form a heterocycle;
- R2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;
- R3 is aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted with from one to five substituents independently selected from alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, oxo —NO2, haloalkyl, haloalkoxy, —CN, —O—R6, —O—C(O)—R6, —O—C(O)—N(R6)(R7), —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—R6, —C(O)—N(R6)(R7), and —N(R6)—S(═O)2—R7, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with from one to five substituents independently selected from halo, oxo, —NO2, alkyl, haloalkyl, haloalkoxy, —N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), —CN, —O—R6, cycloalkyl, aryl, heteroaryl and heterocyclyl;
- with the proviso that the heteroaryl or heterocyclyl moiety of R3 includes at least one ring nitrogen atom;
- X1, X2, X3, X4, X5, X6, X7 and X8 are independently C(R4) or N, in which each R4 is independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NO2 haloalkyl, haloalkoxy, —CN, —O—R6, —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), or —N(R6)—S(═O)2—R7, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally substituted with from one to five substituents independently selected from halo, oxo, —NO2—CF3—O—CF3, —N(R6)(R7), —C(O)—R6, —C(O)—O—R7, —C(O)—N(R6)(R7), —CN, —O—R6;
- or
- X5 and X6 or X6 and X7 are joined to provide optionally substituted fused aryl or optionally substituted fused heteroaryl;
- and
- with the proviso that at least one of X2, X3, and X4 is C(R4);
- at least two of X5, X6, X7, and X8 are C(R4);
- and at least one of X2, X3, X4, X5, X6, X7 and X8 is N;
- or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.
13 more elements
Dependencies are inferred from the claim text.