Benzimidazoles and related analogs as sirtuin modulators

1. A compound of the formula (IIc):

or a salt thereof wherein:

R 13 is selected from hydrogen, halo, —OH, —CN, 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;

R is selected from hydrogen, —(C 2 -C 4 ) alkyl, —(C 1 -C 4 ) fluoro-substituted alkyl, —(C 1 -C 4 ) alkyl-N(R 7 )(R 7 ), —(C 1 -C 4 ) alkyl-C(O)—N(R 7 )(R 7 ), —(C 2 -C 4 ) alkyl-O—R 7 , and —(C 2 -C 4 ) alkyl-N(R 7 )—C(O)—R 7 , wherein:

each R 7 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or

two R 7 bound to the same nitrogen atom are taken together with the nitrogen atom to form a 4- to 7-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O, wherein the saturated heterocycle is optionally substituted at a single 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 ;

R 4 is selected from hydrogen, halo, —CN, fluoro-substituted C 1 -C 2 alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl and C 3 -C 7 cycloalkyl;

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 -†, —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—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 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 a heterocycle, wherein R 11 is optionally substituted with one to two substitutents independently selected from halo, —C≡N, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 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 ), 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 a carbocycle having at least five ring atoms, wherein R 12 is optionally substituted with one to two 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—C 1 -C 4 alkyl, wherein 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 , —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 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 or 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 .

2. A compound of the formula (I):

or a salt thereof wherein:

Z 1 and Z 2 are CR 3 , wherein

R 3 is selected at each occurrence from hydrogen, hydroxy, 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, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, and C 3 -C 7 cycloalkyl;

R is selected from hydrogen, —(C 2 -C 4 ) alkyl, —(C 1 -C 4 ) fluoro-substituted alkyl, —(C 1 -C 4 ) alkyl-N(R 7 )(R 7 ), —(C 1 -C 4 ) alkyl-C(O)—N(R 7 )(R 7 ), —(C 2 -C 4 ) alkyl-O—R 7 , and —(C 2 -C 4 ) alkyl-N(R 7 )—C(O)—R 7 , wherein:

each R 7 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or

two R 7 bound to the same nitrogen atom are taken together with the nitrogen atom to form a 4- to 7-membered saturated heterocycle optionally comprising one additional heteroatom selected from N, S, S(═O), S(═O) 2 , and O, wherein the saturated heterocycle is optionally substituted at a single 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 ;

R 1 is selected from a carbocycle and a heterocycle, wherein R 1 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 3 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 2 alkyl, —O—R 8 , —S—R 8 , —(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —N(R 8 )(R 8 ), —O—(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —(C 1 -C 2 alkyl)-O—(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —C(O)—N(R 8 )(R 8 ), and —(C 1 -C 2 alkyl)-C(O)—N(R 8 )(R 8 ), and when R 1 is phenyl, R 1 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, and fluoro-substituted 3,4-ethylenedioxy;

each R 8 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or

two R 8 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 the alkyl is optionally substituted with one or more —OH, 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 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 ;

R 2 is a carbocycle having at least five ring atoms, wherein R 2 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, O—C 1 -C 4 alkyl, wherein the alkyl is optionally substituted with one or more —OH, 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 , —S—R 8 , —(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —N(R 8 )(R 8 ), —O—(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —(C 1 -C 2 alkyl)-O—(C 1 -C 2 alkyl)-N(R 8 )(R 8 ), —C(O)—N(R 8 )(R 8 ), —(C 1 -C 2 alkyl)-C(O)—N(R 8 )(R 8 ), —O-phenyl, phenyl, and a saturated heterocycle, and when R 2 is phenyl, R 2 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, wherein any phenyl or saturated heterocycle substituent of R 2 is optionally substituted with halo; —C≡N; C 1 -C 3 alkyl, C 1 -C 2 fluoro-substituted alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 3 ) alkyl, —S—(C 1 -C 3 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 3 ) alkyl and —N—(C 1 -C 3 ) 2 alkyl; and

R 4 is selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl and C 3 -C 7 cycloalkyl;

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—C(═O)O-†, —OC(═O)NH-†, —NH—C(═O)NR 5 -†, —NR 5 —C(═O)NH-†, —NH—NR 5 -†, —NR 5 —NH-†, —NH—CR 5 R 6 -†, —CR 5 R 6 —NH-†, —NH—C(═NR 5 )-†, —C(═NR 5 )—NH-†, —C(═O)—NH—CR 5 R 6 -†, —CR 5 R 6 —NH—C(O)-†, —NH—C(═S)—CR 5 R 6 -†, —CR 5 R 6 —C(═S)—NH-†, —NH—S(O)—CR 5 R 6 -†, —CR 5 R 6 —S(O)—NH-†, —NH—S(O) 2 —CR 5 R 6 -†, —CR 5 R 6 —S(O) 2 —NH-†, —NH—C(═O)—O—CR 5 R 6 -†, —CR 5 R 6 —O—C(═O)—NH-†, —NH—C(═O)—NR 5 —CR 5 R 6 -†, —CR 5 R 6 —O—C(═O)—NH-†, —NH—S(O) 2 —NR 5 -† and —NR 5 —S(O) 2 —NH-†, wherein:

t represents where X is bound to R 1 ; and

each R 5 and R 6 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 , and (C 1 -C 2 alkyl)-CF 3 .

3. The compound of claim 1 , wherein R is hydrogen.

4. The compound of claim 2 , wherein R is hydrogen.

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

6. The compound of claim 2 , wherein X is —C(O)—NH-†.

7. The compound or salt of claim 1 , wherein R 11 is selected from:

wherein R 11 is optionally further substituted.

8. The compound or salt of claim 1 , wherein R 12 is selected from:

wherein R 12 is optionally further substituted.

9. The compound of claim 2 , wherein R 1 is selected from:

10. The compound of claim 2 , wherein R 2 is selected from:

11. The compound of claim 1 selected from:

or a salt thereof.

12. The compound of claim 2 selected from:

or a salt thereof.

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

14. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 13 , further comprising an additional active agent.

16. The pharmaceutical composition of claim 14 , further comprising an additional active agent.

17. A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, or diabetes, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier wherein treating does not embrace curing.

18. A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, or diabetes, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a pharmaceutical composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier wherein treating does not embrace curing.