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US 2011/0257174 A1Published application
Chromenone analogs as sirtuin modulators
AssigneeSirtris Pharmaceuticals, Inc.
InventorsChristopher Oalmann, Robert B. Perni, Chi B. Vu
Life of this patent
Estimating the term…
Abstract
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.
Claims15
A compound of the formula (II):
- or a salt 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-C4alkyl)-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 and
- when 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;
- and
- each 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 RH is other than 1H-pyrazol-3-yl or tetrazol-5-yl;
- and
- when R14 is C1-C4 alkyl, R12 is other than optionally substituted phenyl.
17 more elements
A compound of the formula (III):
- or a salt 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);
- R21 is selected from a carbocycle and a heterocycle other than 1H-pyrazol-3-yl or tetrazol-5-yl, wherein R21 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, 0-(saturated heterocycle), fluoro-substituted —O-(saturated heterocycle), or
- C1-C4 alkyl-substituted O-(saturated heterocycle);
- 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 and
- when 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;
- R24 is selected from hydrogen, 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;
- and
- X2 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—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;
- and
- each of R15 and R16 is independently selected from hydrogen, C1-C4 alkyl, —CF3 and (C1-C3 alkyl)-CF3.
14 more elements
A compound of the formula (IV):
- or a salt 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);
- R21 is selected from a carbocycle and a heterocycle, wherein R21 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-C4alkyl)-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, 0-(saturated heterocycle), fluoro-substituted —O-(saturated heterocycle), or C1-C4 alkyl-substituted O-(saturated heterocycle);
- 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 and
- when 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 having from 1 to 3 heteroatoms, 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 is substituted with at least one substituent which may further be selected from 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, —CN, 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;
- R24 is selected from hydrogen, 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;
- and
- X2 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—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;
- and
- each of R15 and R16 is independently selected from hydrogen, C1-C4 alkyl, —CF3 and (C1-C3 alkyl)-CF3.
13 more elements
Dependencies are inferred from the claim text.