AMPK-activating heterocyclic compounds and methods for using the same

1. A process for providing a compound in substantially enantiomerically pure form, the compound having the formula

wherein

R 1 is H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) or —C(O)O—C 1 -C 4 alkyl);

G is —CH 2 —, —C(O)—, —S(O) 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —O—, —C(O)—NH—, —C(O)—NH—CH 2 —, —CH 2 CH 2 —, a single bond, —OCH 2 —, CH 2 CH 2 O—, —CH(COOMe)- or —CH(COOEt)-;

R 17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-L-R 7 —(C 0 -C 6 alkyl)-NR 8 R 9 , —(C 0 -C 6 alkyl)-OR 10 , —(C 0 -C 6 alkyl)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —N 3 , —SF 5 , —NO 2 and —CN;

each R 3 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-L-R 7 ,—(C 0 -C 6 alkyl)-NR 8 R 9 , —(C 0 -C 6 alkyl)-OR 10 , —(C 0 -C 6 alkyl)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

w is 0 or 1;

each R 4 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-L-R 7 , —(C 0 -C 6 alkyl)-NR 8 R 9 , —(C 0 -C 6 alkyl)-OR 10 , —(C 0 -C 6 alkyl)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 4 on the same carbon optionally combine to form oxo, and two R 4 on different carbons optionally combine to form a —(C 0 -C 4 alkylene)-bridge;

x is 0, 1 or 2;

Q is a single bond, —CH 2 —, —CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 —, —O—, —CHF—, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O) 2 —;

each R 5 is independently selected from —(C 1 -C 6 alkyl), —(C 1 -C 6 haloalkyl), —(C 0 -C 6 alkyl)-L-R 7 , —(C 0 -C 6 alkyl)-NR 8 R 9 , —(C 0 -C 6 alkyl)-OR 10 , —(C 0 -C 6 alkyl)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —N 3 , —SF 5 , —NO 2 and —CN; and

y is 0, 1, 2, 3 or 4;

in which

each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —NR 9 C(S)—, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 — and —NR 9 SO 2 NR 9 —,

each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl), —(C 1 -C 2 haloalkyl), —(C 0 -C 2 alkyl)-L-(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-NR 9 (C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 -C 2 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl), and

each R 9 is independently selected from —H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl),

the compound having trans-substitution on the fluoropiperidine ring, the process comprising

providing the compound as a substantial mixture of enantiomers having trans-substitution on the fluoropiperidine ring; and

subjecting the substantial mixture of diastereomers to chiral high pressure liquid chromatography using a stationary phase and a mobile phase to separate the substantially enantiomerically pure compound.

2. The process according to claim 1 , wherein the mobile phase is a methanol-supercritical carbon dioxide mixture.

3. The process according to claim 2 , wherein the methanol-supercritical carbon dioxide mixture includes diethylamine.

4. The process according to claim 1 , wherein the mobile phase is a methanol-supercritical carbon dioxide mixture that includes 50% methanol and 0.1% diethylamine.

5. The process according to claim 1 , wherein elution is performed isocratically.

6. The process according to claim 1 , wherein the stereochemistry of the fluoro on the piperidine is (R).

7. The process according to claim 1 , wherein the stereochemistry of the fluoro on the piperidine is (S).

8. The process according to claim 1 , wherein Y 1 is CH and Q is —C(O)—.

9. The process according to claim 1 , wherein Y 1 is CH and Q is —O—.

10. The process according to claim 1 , wherein Y 1 is N and Q is —CH 2 —.

11. The process according to claim 1 , wherein G is —CH 2 —, —C(O)—, or —S(O) 2 —.

12. The process according to claim 1 , wherein w is 0.

13. The process according to claim 1 , wherein x is 0.

14. The process according to claim 1 , wherein

each R 3 is independently selected from the group consisting of —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;

each R 4 is independently selected from the group consisting of —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R4 optionally combine to form oxo;

each R 5 is independently selected from the group consisting of —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —N 3 , —SF 5 , —NO 2 and —CN,

R 17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen —NO 2 and —CN,

wherein each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl), —(C 1 -C 2 haloalkyl), —(C 0 -C 2 alkyl)-L-(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-NR 9 (C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 -C 2 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl).

15. The process according to claim 1 , wherein

R 1 is H;

y is 0, 1 or 2;

each R 5 is independently selected from halogen, unsubstituted (C 1 -C 6 alkoxy), —(C 1 -C 6 haloalkoxy), —SH, —S(unsubstituted C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), —N(unsubstituted C 1 -C 4 alkyl) 2 , —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(unsubstituted C 1 -C 4 alkyl), C(O)N(unsubstituted C 1 -C 4 alkyl) 2 , —C(O)OH, C(O)O(unsubstituted C 1 -C 6 alkyl), —(NH) 0-1 SO 2 R 33 and —(NH) 0-1 COR 33 , in which each R 33 is (unsubstituted C 1 -C 6 alkyl) or (C 1 -C 6 haloalkyl); and

R 17 is phenyl substituted with 0, 1 or 2 substituents each independently selected from halogen, unsubstituted (C 1 -C 6 alkoxy), —(C 1 -C 6 haloalkoxy), —SH, —S(unsubstituted C 1 -C 6 alkyl), —S(C 1 -C 6 haloalkyl), —OH, —CN, —NO 2 , —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), —N(unsubstituted C 1 -C 4 alkyl) 2 , —N 3 , —SF 5 , —C(O)—NH 2 , C(O)NH(unsubstituted C 1 -C 4 alkyl), C(O)N(unsubstituted C 1 -C 4 alkyl) 2 , —C(O)OH, C(O)O(unsubstituted C 1 -C 6 alkyl), —(NH) 0-1 SO 2 R 33 and —(NH) 0-1 COR 33 , in which each R 33 is (unsubstituted C 1 -C 6 alkyl) or (C 1 -C 6 haloalkyl);

each R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, trfluoromethyl, pentafluoroethyl, acetyl, —NH 2 , —OH, methoxy, ethoxy, trifluoromethoxy, —SO 2 Me, -halogen, —NO 2 and —CN;

each R 4 is independently methyl, ethyl, n-propyl, isopropyl, trfluoromethyl, pentafluoroethyl, acetyl, —NH 2 , —OH, methoxy, ethoxy, trifluoromethoxy, —SO 2 Me, -halogen, —NO 2 or —CN, and two R 4 optionally come together to form oxo.

16. The process according to claim 15 , wherein w is 0 and x is 0.

17. The process according to claim 16 , wherein Y 1 is CH and Q is —C(O)—.

18. The process according to claim 1 , wherein the compound is N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.