Fused heterocyclic compounds and their use as sirtuin modulators

1. A compound represented by Structural Formula (Ia):

wherein:

R 10 is selected from —CH 2 -piperazinyl, —CH 2 -methylpiperazinyl, —CH 2 -pyrrolidyl, —CH 2 -piperidyl, —CH 2 -morpholino, —CH 2 —N(CH 3 ) 2 , —C(O)—NH—(CH 2 ) n -piperazinyl, —C(O)—NH—(CH 2 ) n -methylpiperazinyl, —C(O)—NH—(CH 2 ) n -pyrrolidyl —C(O)—NH—(CH 2 ) n -morpholino, —C(O)—NH—(CH 2 ) n -piperidyl, or —C(O)—NH—(CH 2 ) n —N(CH 3 ) 2 , wherein n is 1 or 2;

R 11 is selected from —C 1 -C 3 straight or branched alkylene or —C(O)—; and

each of ring K and ring E is independently substituted with up to three substituents independently selected from halo, —CF 3 , —O—(C 1 -C 3 straight or branched alkyl), —S—(C 1 -C 3 straight or branched alkyl), —N(R 40 )(R 50 ), —S(O) 2 —N(R 40 )(R 50 ), heterocyclyl, —(C 1 -C 3 straight or branched alkyl)-heterocyclyl, —O—(C 1 -C 3 straight or branched alkyl) -heterocyclyl, and —S—(C 1 -C 3 straight or branched alkyl)-heterocyclyl, or is optionally fused to a 5-6 membered heterocyclyl or heteroaryl, wherein any heterocyclyl or heteroaryl is optionally substituted with —C 1 -C 3 straight or branched alkyl.

2. A compound represented by Structural Formula (Ib):

wherein:

Z is selected from O or S;

R 10 is selected from —H, —C(O)—N(R 40 )(R 50 ), —S(O) 2 N(R 40 )(R 50 ), or —CH 2 —N(R 40 )(R 50 );

wherein each of R 40 and R 50 is independently selected from —H, —C 1 -C 3 straight or branched alkyl, —(C 1 -C 3 straight or branched alkyl)—N(CH 3 ) 2 , —(C 1 -C 3 straight or branched alkyl)-heterocyclyl, and —(C 1 -C 3 straight or branched alkyl)-alkylheterocyclyl, or wherein R 40 and R 50 taken together with the N atom to which they are bound form a 5-6 membered heterocyclic ring that is optionally substituted with —(C 1 -C 3 straight or branched alkyl), and wherein at least one of R 40 or R 50 is not H;

R 11 is selected from —C 1 -C 3 straight or branched alkylene or —C(O)—;

each of R 12 and R 13 is independently selected from —H or —(C 1 -C 3 straight or branched alkyl), or R 12 and R 13 are taken together to form a benzene ring that is substituted with up to two substituents independently selected from —(C 1 -C 3 straight or branched alkyl), —CF 3 or halo; and

ring K is substituted with up to three substituents independently selected from halo, —CF 3 , —O—(C 1 -C 3 straight or branched alkyl), —S—(C 1 -C 3 straight or branched alkyl), —N(R 40 )(R 50 ), —S(O) 2 —N(R 40 )(R 50 ), heterocyclyl, (C 1 -C 3 straight or branched alkyl)-heterocyclyl, —O—(C 1 -C 3 straight or branched alkyl)-heterocyclyl, —S—(C 1 -C 3 straight or branched alkyl)-heterocyclyl, or is optionally fused to a 5-6 membered heterocyclyl or heteroaryl, wherein any heterocyclyl or heteroaryl is optionally substituted with —C 1 -C 3 straight or branched alkyl.

3. A compound represented by Structural Formula (IVa):

or a salt thereof, wherein:

Ring E is optionally substituted; and

R 4 and R 5 are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

4. A compound represented by Structural Formula (V):

or a salt thereof, wherein:

R 4 , R 5 and R 9 are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

5. The compound of claim 4 , wherein the compound is represented by Structural Formula (VI):

or a salt thereof, wherein:

R 4 , R 5 and R 9 are independently —H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted non-aromatic heterocyclic group.

6. A composition comprising a compound of any of claims 1 , 2 , 3 , 4 and 5 , wherein the composition is pyrogen-free.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of any of claims 1 , 2 , 3 , 4 and 5 .

8. A packaged pharmaceutical comprising a compound of any of claims 1 , 2 , 3 , 4 and 5 and instructions for using the compound to modulate a sirtuin.

9. The compound of claim 1 , wherein one of R 40 or R 50 is H.

10. The compound of claim 1 , wherein ring K is substituted with up to 3 substituents independently selected from methyl, —O-methyl, —N(CH 3 ) 2 , or —CF 3 , and wherein ring K is unsubstituted in the positions ortho to the attachment to the rest of the molecule.

11. The compound according to claim 1 , wherein ring E is substituted with up to 2 substituents independently selected from methyl, —O-methyl, —S(O) 2 —N(CH 3 ) 2 , —O-methyl-morpholino, —O-ethyl-morpholino, fluoro, —CF 3 , piperidyl, methylpiperidyl, pyrrolidyl, or methylpyrrolidyl.

12. The compound according to claim 1 , wherein:

ring K is substituted with up to 3 substituents independently selected from methyl, O-methyl, N(CH 3 ) 2 , CF 3 , and wherein ring K is unsubstituted in the positions ortho to the attachment to the rest of the molecule;

ring E is substituted with up to 2 substituent independently selected from methyl, O-methyl, —S(O) 2 —N(CH 3 ) 2 , —O-methyl-morpholino, —O-ethyl-morpholino, fluoro, —CF 3 , methylpiperidyl, or pyrrolidyl; and

R 10 is selected from —CH 2 -piperazinyl, —C(O)—NH—(CH 2 ) 2 -piperazinyl, —C(O)—NH—(CH 2 ) 2 -methylpiperazinyl , —C(O)—NH—(CH 2 ) 2 -pyrrolidyl, or —C(O)—NH—(CH 2 ) 2 —N(CH 3 ) 2 .

13. The compound of claim 2 , wherein R 10 is —H.

14. The compound of claim 2 , wherein ring K is substituted with up to 3 substituents independently selected from methyl, O-methyl, N(CH 3 ) 2 , CF 3 , and wherein ring K is unsubstituted in the positions ortho to the attachment to the rest of the molecule.

15. The compound according to claim 2 , wherein each of R 12 and R 13 is independently selected from —H, methyl, —O-methyl, —S(O) 2 —N(CH 3 ) 2 , —O-methyl-morpholino, —O-ethyl-morpholino, fluoro, —CF 3 , piperidyl, methylpiperidyl, pyrrolidyl, or methylpyrrolidyl.

16. The compound according to claim 14 , wherein each of R 12 and R 13 is methyl.