Quinolines and related analogs as sirtuin modulators

1. A compound represented by the formula:

(III), or a salt thereof, wherein:

each of Z 11 , Z 12 , Z 13 , and Z 14 is independently selected from N and CR, wherein R is selected from hydrogen, halo, —OH, —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, —(C 1 -C 2 alkyl)-N(R 14 )(R 14 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 4 ) alkyl, —O—(C 1 -C 3 ) alkyl-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —S—(C 1 -C 4 ) alkyl and C 3 -C 7 cycloalkyl;

Y is selected from N and CR 13 , wherein R 13 is selected from hydrogen, halo, —C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), and —O—(C 1 -C 2 fluoro-substituted alkyl);

no more than two of Z 11 , Z 12 , Z 13 , Z 14 , and Y are N;

X 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 —NR 15 -†, —NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, O—C(═O)—NH-†, —NH—C(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —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 14 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†, wherein

† represents where X is bound to R 11 , and:

R 15 and R 16 are independently selected from hydrogen, C 1 -C 4 alkyl, CF 3 , and —(C 1 -C 4 alkyl)-CF 3 ;

R 11 is selected from a carbocycle and a heterocycle, wherein R 11 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 fluoro-substituted alkyl, ═O, —O—R 14 , —S—R 14 , —(C 1 -C 4 alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4 alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —C(O)—O—R 14 , and —(C 1 -C 4 alkyl)-C(O)—N(R 14 )(R 14 ), 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), and

C 1 -C 4 alkyl-substituted O-(saturated heterocycle), wherein

each R 14 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or

two R 14 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, S, S(═O), S(═O) 2 , and O, wherein:

when R 14 is alkyl, the alkyl is optionally substituted with one or more —OH, —O—(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

when two R 14 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, —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 ; and

R 12 is selected from a carbocycle and a monocylic heterocycle bound to the rest of the compound through a carbon ring atom, wherein R 12 is optionally substituted with one to two substituents 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 14 , —S—R 14 , —S(O)—R 14 , —S(O) 2 —R 14 , —(C 1 -C 4 alkyl)-N(R 14 )(R 14 ), —N(R 14 )(R 14 ), —O—(C 2 -C 4 alkyl)-N(R 14 )(R 14 ), —C(O)—N(R 14 )(R 14 ), —(C 1 -C 4 alkyl)-C(O)—N(R 14 )(R 14 ), —O-phenyl, phenyl, and a second heterocycle, and when R 12 is phenyl, R 12 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle) wherein any phenyl, saturated heterocycle or second heterocycle substituent of R 12 is optionally substituted with halo; —C≡N; C 1 -C 4 alkyl, C 1 -C 2 fluoro-substituted 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 alkyl) 2 ;

wherein the compound is not:

2. The compound of claim 1 , wherein:

X 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 —NR 15 -†, —NR 15 —S(O) 2 —NH-†, —NH—C(═O)O-†, O—C(═O)—NH-†, —NH—C(═O)NH-†, —NH—C(═O)NR 15 -†, —NR 15 —C(═O)NH-†, —NH—NR 15 -†, —NR 15 —NH-†, —O—NH-†, —NH—O-†, —NH—C(═NR 15 )-†, —C(═NR 15 )—NH-†, —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 14 —CR 15 R 16 -†, —NH—C(═O)—CR 15 R 16 -†, and —CR 15 R 16 —NH—C(═O)—O-†.

3. The compound of claim 1 , wherein R 12 is selected from aryl and heteroaryl.

4. The compound of claim 3 , wherein R 12 is selected from:

wherein R 12 is optionally further substituted.

5. The compound of claim 1 , selected from any one of:

6. The compound of claim 5 , wherein the compound is represented by a Structural Formula selected from IIIa, IIIi, IIIj, IIIk, or IIIl.

7. The compound of claim 6 , wherein the compound is represented by Structural Formula IIIa.

8. The compound of claim 1 , wherein X is —NH—C(═O)-† or —C(═O)—NH-†.

9. The compound of claim 1 , wherein R 11 is selected from:

wherein R 11 is optionally further substituted.

10. The compound of claim 9 , represented by the formula:

wherein:

X is selected from —NH—C(═O)-† or —C(═O)—NH-†; and

R 12 is selected from phenyl and pyridyl, wherein R 12 is optionally substituted with one to two substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 14 , —S(O) 2 —R 14 , —(C 1 -C 4 alkyl)-N(R 14 )(R 14 ) and —N(R 14 )(R 14 ), and when R 12 is phenyl, R 12 is also optionally substituted with 3,4-methylenedioxy, or O-(saturated heterocycle).

11. The compound of claim 1 , wherein the compound is selected from any one of:

12. The compound of claim 1 , wherein the salt is a pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , comprising a first active agent comprising a compound of claim 1 and further comprising an additional active agent.

15. A method for treating a subject suffering from insulin resistance, metabolic syndrome, or diabetes, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a composition of claim 13 .