US 12,655,156 B2 · Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

Abstract

The disclosure provide compounds of Formula I and the pharmaceutically acceptable salts thereof. The variables, R1, R2, R3, X1, X2, and Z are defined herein. Certain compounds of Formula I act as selective mitochondrial protonophore uncouplers that do not affect the plasma membrane potential. Compounds and salts of Formula I are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as cancer, obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Because mitochondrial uncouplers decrease the production of reactive oxygen species (ROS), which are known to contribute to age-related cell damage, compounds of Formula I are useful for increasing lifespan. Compounds and salts of Formula I are also useful for regulating glucose homeostasis or insulin action in a patient.

A pharmaceutical composition comprising a compound of Formula I

or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, wherein:
X1 and X2 are C or N, with at least one of X1 and X2 being N;
Z is O;
R1 is hydrogen or C1-C8alkyl;
R2 is C2-C8alkenyl or C2-C8alkynyl;
or
R2 is -C0-C4alkyl-Q where Q is phenyl, naphthyl, pyridyl, quinolinyl, adamantan-1-yl, benzo[d]dioxolyl, fluorenyl, cyclohexyl, thiazolyl, or benzo[d]thiazolyl, wherein said C0-C4alkyl is optionally substituted with one or more substituents R13, and wherein each of said phenyl, naphthyl, pyridyl, quinolinyl, adamantan-1-yl, benzo[d]dioxolyl, fluorenyl, cyclohexyl, thiazolyl, and benzo[d]thiazolyl is optionally substituted with one or more substituents independently chosen from R11 and 0 or 1 substituent R12;
or
R2 is —C(O)-phenyl or —C(O)-adamantan-1-yl, wherein each of said phenyl and adamantan-1-yl is optionally substituted with one or more substituents independently chosen from R11 and 0 or 1 substituent R12;
or
R2 is —S(O)2-phenyl, wherein said phenyl is optionally substituted with one or more substituents independently chosen from R11 and 0 or 1 substituent R12;
or
R1 and R2 are joined to form a 4-6 membered heterocyclic ring comprising one or more heteroatoms selected from the group consisting of N and O, wherein said heterocyclic ring is optionally substituted with one or more substituents independently chosen from halogen, C1-C8alkyl, and C1-C8haloalkyl;
R3 is H or C1-C8alkyl, which C1-C8alkyl is optionally substituted by one or more substituents chosen from halogen and hydroxyl;
R10 is independently chosen at each occurrence from hydrogen, C1-C6alkyl, and -C0-C2alkyl (C3-C7cycloalkyl);
R11 is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, halosulfanyl, C1-C8alkyl, C2-C8alkenyl, and C2-C8alkynyl, wherein in each C1-C8alkyl, C2-C8alkenyl, and C2-C8alkynyl in the definition of R11 one or more carbon atoms is optionally replaced by O, NR10, —C(O)—, —C(O)O—, —OC(O), —S(O)n—, —S(O)nNR10, —NR10S(O)n—, —NR10C(O)NR10, —C(O)NR10—, or —NR10C(O)— where n is 0, 1, or 2, and in which the C1-C8alkyl, C2-C8alkenyl, or C2-C8alkynyl is optionally substituted with one or more substituents R13;
R12 is selected from -C0-C4alkyl(C3-C7cycloalkyl), —O-C0-C4alkyl(C3-C7cycloalkyl), -C0-C4alkyl(aryl), —O-C0-C4alkyl(aryl), -C0-C4alkyl(5- to 6-membered heteroaryl), —O-C0-C4alkyl(5- to 6-membered heteroaryl), -C0-C4alkyl(3- to 6-membered heterocycloalkyl), and —O-C0-C4alkyl(3- to 6-membered heterocycloalkyl), each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C1-C2 haloalkyl, C1-C2 haloalkoxy, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylester, -C0-C4alkyl(mono- or di-C1-C6alkylamino), C2-C6alkanoyl, C2-C6alkenyl, and C2-C6alkynyl;
and
R13 is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C3-C7cycloalkyl, and phenyl;
with the proviso that:
(1) when X1 and X2 are both N, Z is O, R1 is methyl, and R3 is hydrogen, R2 is not unsubstituted phenyl;
and
(2) when X1 and X2 are both N, Z is O, and R1 is hydrogen:
(i) R2 is not naphthyl, 3,4-di-chloro-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, or 3-Cl-4-methyl-phenyl when R3 is hydrogen;
and
(ii) R2 is not 4-nitro-phenyl when R3 is methyl.

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Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

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Oxadiazolopyrazines and oxadiazolopyridines useful as mitochondrial uncouplers

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Abstract

Claims13