Sulfanyl-tetrahydropyran-based compounds and methods of their use

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted aryl, cycloalkyl, or heterocycle;

B is optionally substituted aryl, cycloalkyl, or heterocycle;

Y is O, S, SO, SO 2 , NR 4 , (C(R 5 ) 2 ) p , (C(R 5 ) 2 ) q —C(O)—(C(R 5 ) 2 ) q , (C(R 5 ) 2 ) q —C(O)O—(C(R 5 ) 2 ) q , (C(R 5 ) 2 ) q —OC(O)—(C(R 5 ) 2 ) q , (C(R 5 ) 2 ) q —C(O)NR 4 —(C(R 5 ) 2 ) q , (C(R 5 ) 2 ) q —NR 4 C(O)—(C(R 5 ) 2 ) q , or (C(R 5 ) 2 ) q —NR 4 C(O)NR 4 —(C(R 5 ) 2 ) q ;

R 1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle;

R 2 is fluoro or OR 2A ;

each of R 2A , R 2B , and R 2C is independently hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl;

each R 4 is independently hydrogen or optionally substituted alkyl;

each R 5 is independently hydrogen, hydroxyl, halogen, amino, cyano, OR 5A , SR 5A , or optionally substituted alkyl;

each R 5A is independently optionally substituted alkyl;

p is 0-3; and

each q is independently 0-2.

2. The compound of claim 1 , which is of the formula:

3. The compound of claim 2 , which is of the formula:

wherein:

each R 6 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 6A , OR 6A , SR 6A , SOR 6A , SO 2 R 6A , C(O)R 6A , CO 2 R 6A , CO 2 H, CON(R 6A )(R 6A ), CONH(R 6A ), CONH 2 , NHC(O)R 6A , NHSO 2 R 6A , or optionally substituted alkyl, aryl or heterocycle;

each R 6A is independently optionally substituted alkyl, aryl or heterocycle;

each R 7 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 7A , OR 7A , SR 7A , SOR 7A , SO 2 R 7A , C(O)R 7A , CO 2 R 7A , CO 2 H, CON(R 7A )(R 7A ), CONH(R 7A ), CONH 2 , NHC(O)R 7A , NHSO 2 R 7A , or optionally substituted alkyl, aryl or heterocycle;

each R 7A is independently optionally substituted alkyl, aryl or heterocycle;

m is 1-3; and

n is 1-3.

4. The compound of claim 3 , which is of the formula:

5. The compound of claim 4 , wherein Y is (C(R 4 ) 2 ) p .

6. The compound of claim 5 , wherein p is 1.

7. The compound of claim 4 , wherein Y is (C(R 5 ) 2 ) q —C(O)—(C(R 5 ) 2 ) q .

8. The compound of claim 7 , wherein each q is independently 0 or 1.

9. The compound of claim 4 , wherein R 1A is hydrogen.

10. The compound of claim 4 , wherein R 1A is optionally substituted alkyl.

11. The compound of claim 4 , wherein R 6 is hydrogen, hydroxyl, halogen, OR 6A , or optionally substituted lower alkyl.

12. The compound of claim 11 , wherein R 6 is hydrogen.

13. The compound of claim 11 , wherein R 6 is halogen.

14. The compound of claim 11 , wherein R 6 is hydroxyl.

15. The compound of claim 11 , wherein R 6 is OR 6A .

16. The compound of claim 11 , wherein R 6 is optionally substituted methyl.

17. The compound of claim 4 , wherein R 7 is hydrogen, C≡CR 7A , OR 7A , or optionally substituted lower alkyl.

18. The compound of claim 17 , wherein R 7 is hydrogen.

19. The compound of claim 17 , wherein R 7 is C≡CR 7A .

20. The compound of claim 19 , wherein R 7A is optionally substituted monocyclic aryl or heterocycle.

21. The compound of claim 17 , wherein R 7 is OR 7A .

22. The compound of claim 17 , wherein R 7 is acetylenyl or optionally substituted methyl or ethyl.

23. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle;

R 2 is fluoro or OR 2A ;

each of R 2A , R 2B , and R 2C is independently hydrogen, optionally substituted alkyl, C(O)alkyl, C(O)aryl, or aryl;

each R 6 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 6A , OR 6A , SR 6A , SOR 6A , SO 2 R 6A , C(O)R 6A , CO 2 R 6A , CO 2 H, CON(R 6A )(R 6A ), CONH(R 6A ), CONH 2 , NHC(O)R 6A , NHSO 2 R 6A , or optionally substituted alkyl, aryl or heterocycle;

each R 6A is independently optionally substituted alkyl, aryl or heterocycle;

each R 7 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 7A , OR 7A , SR 7A , SOR 7A , SO 2 R 7A , C(O)R 7A , CO 2 R 7A , CO 2 H, CON(R 7A )(R 7A ), CONH(R 7A ), CONH 2 , NHC(O)R 7A , NHSO 2 R 7A , or optionally substituted alkyl, aryl or heterocycle;

each R 7A is independently optionally substituted alkyl, aryl or heterocycle;

m is 1-3; and

n is 1-3.

24. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle;

each R 6 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 6A , OR 6A , SR 6A , SOR 6A , SO 2 R 6A , C(O)R 6A , CO 2 R 6A , CO 2 H, CON(R 6A )(R 6A ), CONH(R 6A ), CONH 2 , NHC(O)R 6A , NHSO 2 R 6A , or optionally substituted alkyl, aryl or heterocycle;

each R 6A is independently optionally substituted alkyl, aryl or heterocycle;

each R 7 is independently hydrogen, hydroxyl, halogen, amino, cyano, nitro, C≡CR 7A , OR 7A , SR 7A , SOR 7A , SO 2 R 7A , C(O)R 7A , CO 2 R 7A , CO 2 H, CON(R 7A )(R 7A ), CONH(R 7A ), CONH 2 , NHC(O)R 7A , NHSO 2 R 7A , or optionally substituted alkyl, aryl or heterocycle;

each R 7A is independently optionally substituted alkyl, aryl or heterocycle;

m is 1-3; and

n is 1-3.

25. A pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable diluent or excipient.

26. A method of inhibiting sodium glucose co-transporter 2 activity, which comprises contacting sodium glucose co-transporter 2 with an effective amount of a compound of claim 1 .

27. A method of decreasing blood glucose in a patient, which comprises administering to the patient an effective amount of a compound of claim 1 .

28. A method of increasing the excretion of glucose in the urine of a patient, which comprises administering to the patient an effective amount of a compound of claim 1 .

29. A method of restoring insulin sensitivity in a patient, which comprises administering to a patient in need thereof an effective amount of a compound of claim 1 .

30. A method of treating a disease or disorder in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , wherein the disease or disorder is atherosclerosis, cardiovascular disease, diabetes (type 1 or 2), hyperglycemia, hypertension, lipid disorders, obesity, or Syndrome X.

31. The method of claim 30 , wherein the disease or disorder is type 2 diabetes.