Piperdine-based inhibitors of sodium glucose co-transporter 2 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 1 is OR 1A , SR 1A , SOR 1A , SO 2 R 1A , or R 1A ;

each 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;

R 3 is hydrogen or optionally substituted alkyl, aryl or heterocycle;

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;

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;

n is 1-3;

p is 0-3; and

each q is independently 0-2;

with the proviso that at least one of R 6 and R 7 is not hydrogen.

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

3. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is OR 1A , SR 1A , SOR 1A , SO 2 R 1A , or R 1A ;

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

R 2 is fluoro or OR 2A ;

each R 2A 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.

4. The compound of claim 3 , wherein R 1 is OR 1A .

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

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

7. The compound of claim 3 , wherein R 1 is SR 1A .

8. The compound of claim 7 , wherein R 1A is hydrogen.

9. The compound of claim 7 , wherein R 1A is optionally substituted alkyl.

10. The compound of claim 3 , wherein R 1 is SOR 1A .

11. The compound of claim 10 , wherein R 1A is hydrogen.

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

13. The compound of claim 3 , wherein R 1 is SO 2 R 1A .

14. The compound of claim 13 , wherein R 1A is hydrogen.

15. The compound of claim 13 , wherein R 1A is optionally substituted alkyl.

16. The compound of claim 3 , wherein R 1 is N(R 1A ) 2 .

17. The compound of claim 16 , wherein at least one R 1A is hydrogen.

18. The compound of claim 16 , wherein at least one R 1A is optionally substituted alkyl.

19. The compound of claim 3 , wherein R 1 is R 1A .

20. The compound of claim 19 , wherein R 1A is hydrogen.

21. The compound of claim 19 , wherein R 1A is optionally substituted alkyl.

22. The compound of claim 3 , wherein R 6 is hydrogen, hydroxyl, halogen, OR 6A , or optionally substituted lower alkyl.

23. The compound of claim 22 , wherein R 6 is hydrogen.

24. The compound of claim 22 , wherein R 6 is halogen.

25. The compound of claim 22 , wherein R 6 is hydroxyl.

26. The compound of claim 22 , wherein R 6 is OR 6A .

27. The compound of claim 22 , wherein R 6 is optionally substituted methyl.

28. The compound of claim 3 , wherein R 7 is hydrogen, C≡CR 7A , OR 7A , or optionally substituted lower alkyl.

29. The compound of claim 26 , wherein R 7 is hydrogen.

30. The compound of claim 26 , wherein R 7 is C≡CR 7A .

31. The compound of claim 26 , wherein R 7 is OR 7A .

32. 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 the formula:

or a pharmaceutically acceptable salt thereof, wherein:

the disease or disorder is atherosclerosis, cardiovascular disease, diabetes, hyperglycemia, hypertension, lipid disorders, obesity, or Syndrome X;

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 1 is OR 1A , SR 1A , SOR 1A , SO 2 R 1A , or R 1A ;

each 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;

R 3 is hydrogen or optionally substituted alkyl, aryl or heterocycle;

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.

33. The method of claim 32 , wherein the disease or disorder is type 2 diabetes.