US2015148343A1PendingUtilityA1
Chromenone analogs as sirtuin modulators
Est. expirySep 29, 2028(~2.2 yrs left)· nominal 20-yr term from priority
A61P 3/06A61P 9/12A61P 9/04A61P 35/00A61P 3/10A61P 9/00A61P 9/10A61P 5/50A61P 43/00A61P 3/00A61P 27/02A61P 3/04A61P 25/28A61P 25/00C07D 417/14C07D 311/30A61P 15/00C07D 405/14A61K 31/4433A61P 19/10A61K 31/353A61K 31/427A61P 1/16C07D 405/12A61K 31/422A61K 31/506A61K 31/4025A61K 31/497A61P 19/06A61P 13/08A61K 31/4155A61P 15/08C07D 417/12A61K 45/06A61P 19/02A61K 31/5377A61P 11/00A61P 1/04A61K 31/4439C07D 311/22A61P 13/12
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
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 R 20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from a carbocycle and a heterocycle, wherein R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), and when R 11 is phenyl, R 11 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 C 1 -C 4 alkyl-substituted O-(saturated heterocycle), wherein
each R 13 is independently selected from hydrogen and —C 1 -C 4 alkyl; or two R 13 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 R 13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 13 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, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a carbocycle and a heterocycle other than optionally substituted tetrazolyl, wherein R 12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and when R 12 is phenyl, R 12 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 R 12 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 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 —NR 15 -†, —NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, —OC(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —NH—CR 15 R 16 -†, —CR 15 R 16 —NH-†, —NH—C(═NR 15 )-†, —C(═NR 15 )—NH-†, —C(═O)—NH—CR 15 R 16 -†, —CR 15 R 16 —NH—C(O)-†, —NH—C(═S)—CR 15 R 16 -†, —CR 15 R 16 —C(═S)—NH-†, —NH—S(O)—CR 15 R 16 -†, —CR 15 R 16 —S(O)—NH-†, —NH—S(O) 2 —CR 15 R 16 -†, —CR 15 R 16 —S(O) 2 —NH-†, —NH—C(═O)—O—CR 15 R 16 -†, —CR 15 R 16 —O—C(═O)—NH-†, —NH—C(═O)—NR 15 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†, wherein:
† represents where X 1 is bound to R 11 ; and
each of R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3 ,
wherein:
when R 14 is H, and X 1 is —NH—CR 15 R 16 -† or —CR 15 R 16 —NH-†, then R 12 is other than optionally substituted pyridin-4-yl, optionally substituted pyridin-3-yl or unsubstituted morpholin-4-yl;
when R 14 is H; R 12 is phenyl; and X 1 is —C(═O)—NH-†, then R 11 is other than 1H-pyrazol-3-yl, or tetrazol-5-yl, or [1,3,4]thiadiazol-2-yl; and
when R 14 is C 1 -C 4 alkyl, R 12 is other than optionally substituted phenyl; or
a pharmaceutically acceptable salt thereof:
2 . The method according to claim 1 , wherein R 12 is bound to the rest of the molecule through a ring carbon atom; and R 11 is other than optionally substituted piperidine or optionally substituted pyrrolidine.
3 . The method according to claim 1 , wherein X 1 is selected from —NH—C(O)-†, and —C(O)—NH-†.
4 . The method according to claim 1 , wherein:
R 11 is selected from:
wherein:
R 11 is optionally substituted with one to two substituents independently selected from halo, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), and —O—R 13 .
5 . The method according to claim 4 , wherein:
R 11 is selected from:
6 . The method according to claim 5 , wherein:
R 11 is selected from
and X 1 is —NH—C(O)-†.
7 . The method according to claim 1 , wherein:
R 12 is selected from:
wherein:
R 12 is optionally substituted with one or more groups independently selected from halo, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —SO 2 —R 13 , —N(R 13 )(R 13 ), and —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ).
8 . The method according to claim 7 , wherein:
R 12 is selected from:
9 . The method according to claim 8 , wherein:
R 12 is selected from
and
X 1 is —NH—C(O)-†.
10 . 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 R 20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from:
wherein:
R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), and when R 11 is phenyl, R 11 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
C 1 -C 4 alkyl-substituted O-(saturated heterocycle);
wherein:
each R 13 is independently selected from hydrogen and —C 1 -C 4 alkyl; or
two R 13 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 R 13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 13 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, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a 5-7 membered aryl or heteroaryl other than optionally substituted tetrazolyl;
wherein:
R 12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and
when R 12 is phenyl, R 12 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 R 12 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 is —NH—C(═O)-†;
wherein:
† represents where X 1 is bound to R 11 ; and
each of R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3
wherein:
when R 14 is C 1 -C 4 alkyl, R 12 is other than optionally substituted phenyl; or
a pharmaceutically acceptable salt thereof.
11 . 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 pharmaceutical composition comprising a compound of Formula (II) to the subject in need thereof:
wherein:
each R 20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from a carbocycle and a heterocycle, wherein R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), and when R 11 is phenyl, R 11 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
C 1 -C 4 alkyl-substituted O-(saturated heterocycle), wherein
each R 13 is independently selected from hydrogen and —C 1 -C 4 alkyl; or two R 13 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 R 13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 13 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, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a carbocycle and a heterocycle other than optionally substituted tetrazolyl, wherein R 12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and when R 12 is phenyl, R 12 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 R 12 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 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 —NR 15 -†, —NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, —OC(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —NH—CR 15 R 16 -†, —CR 15 R 16 —NH-†, —NH—C(═NR 15 )-†, —C(═NR 15 )—NH-†, —C(═O)—NH—CR 15 R 16 -†, —CR 15 R 16 —NH—C(O)-†, —NH—C(═S)—CR 15 R 16 -†, —CR 15 R 16 —C(═S)—NH-†, —NH—S(O)—CR 15 R 16 -1, —CR 15 R 16 —S(O)—NH-†, —NH—S(O) 2 —CR 15 R 16 -†, —CR 15 R 16 —S(O) 2 —NH-†, —NH—C(═O)—O—CR 15 R 16 -†, —CR 15 R 16 —O—C(═O)—NH-†, —NH—C(═O)—NR 15 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†;
wherein:
† represents where X 1 is bound to R 11 ; and
each of R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3 ,
wherein:
when R 14 is H, and X 1 is —NH—CR 15 R 16 -† or —CR 15 R 16 —NH-†, then R 12 is other than optionally substituted pyridin-4-yl, optionally substituted pyridin-3-yl or unsubstituted morpholin-4-yl;
when R 14 is H; R 12 is phenyl; and X 1 is —C(═O)—NH-†, then R 11 is other than 1H-pyrazol-3-yl, or tetrazol-5-yl, or [1,3,4]thiadiazol-2-yl; and
when R 14 is C 1 -C 4 alkyl, R 12 is other than optionally substituted phenyl; or
a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable carrier or diluents.
12 . 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 pharmaceutical composition comprising a compound of Formula (II) to the subject in need thereof:
wherein:
each R 20 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from:
wherein:
R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), and when R 11 is phenyl, R 11 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 C 1 -C 4 alkyl-substituted O-(saturated heterocycle);
wherein:
each R 13 is independently selected from hydrogen and —C 1 -C 4 alkyl; or
two R 13 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 R 13 is alkyl, the alkyl is optionally substituted with one or more substituents selected from —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), and —N(CH 2 CH 2 OCH 3 ) 2 and
when two R 13 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, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a 5-7 membered aryl or heteroaryl other than optionally substituted tetrazolyl;
wherein:
R 12 is optionally substituted with one or more substitutents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and
when R 12 is phenyl, R 12 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 R 12 is optionally substituted with halo, —C≡N, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 is —NH—C(═O)-†;
wherein:
† represents where X 1 is bound to R 11 ; and
each of R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3
wherein:
when R 14 is C 1 -C 4 alkyl, R 12 is other than optionally substituted phenyl; or
a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable carrier or diluents.
13 . The method according to claim 1 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 (I) which is selected from:
Compd No
[M + H]+
Structure
227
417
231
428
234
428
250
414
251
411
252
412
253
412
256
414
257
414
261
412
268
415
273
358
280
378
281
383
282
394
283
399
286
386
296
396
307
418
315
510
316
497
318
501
319
463
320
494
322
496
323
480
324
462
325
446
327
460
329
445
331
476
334
467
335
378
337
380
338
483
339
492
or
a pharmaceutically acceptable salt thereof.
14 . A method according to claim 12 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 pharmaceutical composition comprising a compound if Formula (I) which is selected from:
Compd No
[M + H]+
Structure
227
417
231
428
234
428
250
414
251
411
252
412
253
412
256
414
257
414
261
412
268
415
273
358
280
378
281
383
282
394
283
399
286
386
296
396
307
418
315
510
316
497
318
501
319
463
320
494
322
496
323
480
324
462
325
446
327
460
329
445
331
476
334
467
335
378
337
380
338
483
339
492
or
a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable carrier or diluents.Join the waitlist — get patent alerts
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