CHROMENONE ANALOGS AS SIRTUIN MODULATORS

摘要

The present invention relates to novel sirtuin-modulating compounds, corresponding pharmaceutical compositions comprising a sirtuin-modulating compound, alone and/or in combination with another therapeutic agent, and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity.

主权项

1. A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering a compound of Formula (II) to a subject in need thereof:wherein:
each R20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C1-C2 alkyl, —O—(C1-C2) fluoro-substituted alkyl, —S—(C1-C2) fluoro-substituted alkyl, C1-C4 alkyl, —S—(C1-C4) alkyl, C3-C7 cycloalkyl, —(C1-C2) alkyl-N(R13)(R13), —O—CH2CH(OH)CH2OH, —O—(C1-C3) alkyl-N(R13)(R13), and —N(R13)(R13); R11 is selected from a carbocycle and a heterocycle, wherein R11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C1-C4 alkyl, ═O, C3-C7 cycloalkyl, fluoro-substituted C1-C4 alkyl, —O—R13, —S—R13, —(C1-C4 alkyl)-N(R13)(R13), —N(R13)(R13), —O—(C1-C4 alkyl)-N(R13)(R13), —(C1-C4 alkyl)-O—(C1-C4 alkyl)-N(R13)(R13), —C(O)—N(R13)(R13), and —(C1-C4 alkyl)-C(O)—N(R13)(R13), and when R11 is phenyl, R11 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, O-(saturated heterocycle), fluoro-substituted —O-(saturated heterocycle), or C1-C4 alkyl-substituted O-(saturated heterocycle), wherein each R13 is independently selected from hydrogen and —C1-C4 alkyl; or two R13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatomic unit selected from NH, S, S(═O), S(═O)2, and O, wherein
when R13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(CH2CH2OCH3), and —N(CH2CH2OCH3)2 andwhen two R13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at any carbon atom with —OH, —C1-C4 alkyl, fluoro, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(CH2CH2OCH3), or —N(CH2CH2OCH3)2, and optionally substituted at any substitutable nitrogen atom with —C1-C4 alkyl, fluoro-substituted C1-C4 alkyl, or —(CH2)2—O—CH3; R12 is selected from a carbocycle and a heterocycle other than optionally substituted tetrazolyl, wherein R12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C2 fluoro-substituted alkyl, —O—R13, —S—R13, —S(O)—R13, —S(O)2—R13, —(C1-C4 alkyl)-N(R13)(R13), —N(R13)(R13), —O—(C1-C4 alkyl)-N(R13)(R13), —(C1-C4 alkyl)-O—(C1-C4 alkyl)-N(R13)(R13), —C(O)—N(R13)(R13), —(C1-C4 alkyl)-C(O)—N(R13)(R13), —O-phenyl, phenyl, and a second heterocycle, and when R12 is phenyl, R12 may also be optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle), wherein any phenyl, second heterocycle or saturated heterocycle portion of a substituent of R12 is optionally substituted with halo, —C≡N, C1-C4 alkyl, fluoro-substituted C1-C2 alkyl, —O—(C1-C2) fluoro-substituted alkyl, —O—(C1-C4) alkyl, —S—(C1-C4) alkyl, —S—(C1-C2) fluoro-substituted alkyl, —NH—(C1-C4) alkyl and —N—(C1-C4)2 alkyl; R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluoro-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)—N(R13)(R13), C1-C4 alkyl-O—R13, and C1-C4 alkyl-NR13—C(O)R13; X1 is selected from —NH—C(═O)-†, —C(═O)—NH-†, —NH—C(═S)-†, —C(═S)—NH-†, —NH—S(═O)-†, —S(═O)—NH-†, —S(═O)2—NH-†, —NH—S(═O)2-†, —NH—S(O)2—NR15-†, —NR15—S(O)2—NH-†, —NH—C(═O)O-†, —OC(═O)NH-†, —NH—C(═O)NR15-†, —NR15—C(═O)NH-†, —NH—NR15-†, —NR15—NH-†, —O—NH-†, —NH—O-†, —NH—CR15R16-†, —CR15R16—NH-†, —NH—C(═NR15)-†, —C(═NR15)—NH-†, —C(═O)—NH—CR15R16-†, —CR15R16—NH—C(O)-†, —NH—C(═S)—CR15R16-†, —CR15R16—C(═S)—NH-†, —NH—S(O)—CR15R16-†, —CR15R16—S(O)—NH-†, —NH—S(O)2—CR15R16-†, —CR15R16—S(O)2—NH-†, —NH—C(═O)—O—CR15R16-†, —CR15R16—O—C(═O)—NH-†, —NH—C(═O)—NR15—CR15R16-†, —NH—C(═O)—CR15R16-†, and —CR15R16—NH—C(═O)—O-†, wherein:
† represents where X1 is bound to R11; andeach of R15 and R16 is independently selected from hydrogen, C1-C4 alkyl, —CF3 and (C1-C3 alkyl)-CF3,wherein:
when R14 is H, and X1 is —NH—CR15R16-† or —CR15R16—NH-†, then R12 is other than optionally substituted pyridin-4-yl, optionally substituted pyridin-3-yl or unsubstituted morpholin-4-yl; when R14 is H; R12 is phenyl; and X1 is —C(═O)—NH-†, then R11 is other than 1H-pyrazol-3-yl, or tetrazol-5-yl, or [1,3,4]thiadiazol-2-yl; and when R14 is C1-C4 alkyl, R12 is other than optionally substituted phenyl; ora pharmaceutically acceptable salt thereof: