Bicyclic pyridines and analogs as sirtuin modulators

1. A compound of Formula (I):

wherein:

each Z 1 and Z 2 independently is selected from N and CR;

wherein:

at least one of Z 1 and Z 2 is CR; and

each R independently 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, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl; C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 3 )(R 3 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 3 )(R 3 ), and —N(R 3 )(R 3 );

W is —N(C 1 -C 4 alkyl)-;

each R 6 is independently selected from hydrogen, C 1 -C 4 alkyl and fluoro-substituted C 1 -C 4 alkyl; or

two R 6 bound to the same carbon atom are taken together to form ═O;

R 1 is selected from an aliphatic carbocycle and a heterocycle;

wherein:

R 1 is optionally substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 2 alkyl, —O—R 3 , —S—R 3 , —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 );

R 2 is selected from a carbocycle and a heterocycle;

wherein:

R 2 is optionally substituted with one or more 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 3 , —S—R 3 , —SO 2 —R 3 , ═O, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ), —O-phenyl, phenyl, and a second heterocycle, and when R 2 is phenyl;

R 2 is also optionally substituted with —O-(saturated heterocycle), 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, wherein any phenyl, saturated heterocycle, or second heterocycle substituent of R 2 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;

each R 3 is independently selected from hydrogen and —C 1 -C 4 alkyl; or

two R 3 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 3 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 3 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 hydrogen, —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;

p is 2; and

X 2 is selected from —C(═O)-†, —C(═O)—O†, —S(═O) 2 -†, and —C(═O)—NH-†,

wherein:

† represents where X 2 is bound to R 1 ; and

a corresponding tautomer or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (VI):

wherein:

each of Z 1 and Z 2 is independently selected from N and CR;

wherein:

at least one of Z 1 and Z 2 is CR; and

each R is independently 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, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl; C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 3 )(R 3 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 3 )(R 3 ), and —N(R 3 )(R 3 );

W is —N(C 1 -C 4 alkyl)-;

wherein:

each R 6 is independently selected from hydrogen, halogen, C 1 -C 4 alkyl and fluoro-substituted C 1 -C 4 alkyl, or two R 6 bound to the same carbon atom are taken together to form ═O,

R 1 is substituted with a spiro bicycle;

wherein:

R 1 is optionally further substituted with one or more substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 2 alkyl, —O—R 3 , —S—R 3 , —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ); and

when R 1 is phenyl, R 1 is also optionally further substituted with —O-(saturated heterocycle), —O-(fluoro-substituted saturated heterocycle), C 1 -C 4 alkyl-substituted saturated heterocycle, 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy;

R 2 is selected from a carbocycle and a heterocycle;

wherein:

R 2 is optionally substituted with one or more 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 3 , —S—R 3 , —SO 2 —R 3 , ═O, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), —(C 1 -C 4 alkyl)-C(O)—N(R 3 )(R 3 ), —O-phenyl, phenyl, and a second heterocycle;

when R 2 is phenyl, R 2 is also optionally substituted with —O-(saturated heterocycle), 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy;

wherein:

any phenyl, saturated heterocycle, or second heterocycle substituent of R 2 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;

each R 3 is independently selected from hydrogen and —C 1 -C 4 alkyl; or

two R 3 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 3 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 ;

when two R 3 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 hydrogen, —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;

p is 2;

X 2 is selected from —C(═O)-†, —C(═O)—O†, —S(═O) 2 -†, and —C(═O)—NH-†;

wherein:

† represents where X 2 is bound to R 1 ; or

a corresponding tautomer or pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 1 is a heterocycle.

4. The compound of claim 1 , wherein the compound is represented by the following Structural Formula:

and

wherein:

X 2 is as defined in claim 1 .

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

wherein:

R 1 is optionally substituted with one or more substituents independently selected from halo, C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), —N(R 3 )(R 3 ), —C(O)—N(R 3 )(R 3 ), ═O, and —O—R 3 .

6. The compound of claim 5 , wherein R 1 is substituted with one or more groups independently selected from —F, —Cl, —CH 3 , —OCH 3 ,

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

8. The compound of claim 1 , wherein R 1 is selected from

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

wherein:

R 2 is optionally substituted with one or more groups independently selected from halo, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-N(R 3 )(R 3 ), C 1 -C 2 fluoro-substituted alkyl, —O—R 3 , —SO 2 —R 3 , —N(R 3 )(R 3 ), and —O—(C 1 -C 4 alkyl)-N(R 3 )(R 3 ).

10. The compound of claim 1 , wherein R 2 is optionally substituted with one or more groups independently selected from ═O, —F, —Cl, —CN, —CH 3 , —OCH 3 , —CF 2 H, —N(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 ,

—CF 3 , —OCF 3 , —OCF 2 H,

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

12. The compound of claim 11 , wherein R 2 is selected from

13. The compound of claim 1 , wherein X 2 is C(═O)—NH-†.

14. A pharmaceutical composition comprising a compound of Formula (I) according to claim 1 and a pharmaceutically acceptable carrier or diluent.

15. 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 according to claim 14 to a subject in need thereof.

16. A compound which is:

TABLE 2

Compound No.

Structure

443

444

445

446

447

448

449

or

a pharmaceutically acceptable salt thereof.

17. 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 (I) according to claim 1 to a subject in need thereof.

18. 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 according to claim 16 to a subject in need thereof.