Quinazolinone, quinolone and related analogs as sirtuin modulators

摘要

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds 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. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

主权项

1. A compound of Formula (IIA) or Formula (IIB):wherein:
each R9 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 substituents 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; ortwo 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 heteroatom selected from N(R13), S, S(═O), S(═O)2, and O, whereinwhen R13 is alkyl, the alkyl is optionally substituted with one or more —OH, fluoro, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —NH(CH2CH2OCH3), or —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 a 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 tetrazolyl;
wherein:
R12 is optionally substituted with one to two substituents 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, andwhen R12 is phenyl, R12 is also 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-†, or —NH—S(═O)2-†; wherein:
† represents where X1 is bound to R11; andeach R15 and R16 is independently selected from hydrogen, C1-C4 alkyl, —CF3 and (C1-C3 alkyl)-CF3; ora pharmaceutically acceptable salt thereof.