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:

R1 is N(R 1A ) 2 ;

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

R 2 is fluoro or OR 2A ;

R 2A is 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 R6 A , 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.

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

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

4. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R 1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle.

5. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R 1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle.

6. 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 ;

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

7. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted aryl, cycloalkyl, 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 8 is hydrogen or C(O)R 8A ;

R 8A is hydrogen or optionally substituted alkyl, alkoxy or aryl;

R 9A and R 9B are each independently OR 9C or SR 9C , or are taken together to provide O, S or NR 9C ; and

each R 9C is independently optionally substituted alkyl, aryl or heterocycle.

8. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted aryl, cycloalkyl, 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;

R 8 is hydrogen or C(O)R 8A ;

R 8A is hydrogen or optionally substituted alkyl, alkoxy or aryl;

R 9A and R 9B are each independently OR 9C or SR 9C , or are taken together to provide O, S or NR 9C ; and

each R 9C is independently optionally substituted alkyl, aryl or heterocycle.

9. A pharmaceutical formulation comprising a compound of claim 4 and a pharmaceutically acceptable diluent or excipient.

10. 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 4 .

11. A method of decreasing blood glucose in a patient, which comprises administering to the patient an effective amount of a compound of claim 4 .

12. 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 4 .

13. 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 4 .

14. A method of treating or managing 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 4 , wherein the disease or disorder is atherosclerosis, cardiovascular disease, diabetes (Type 1 or 2), hyperglycemia, hypertension, lipid disorders, obesity, or Syndrome X.

15. The method of claim 14 , wherein the disease or disorder is type 2 diabetes.

16. A pharmaceutical formulation comprising a compound of claim 5 and a pharmaceutically acceptable diluent or excipient.

17. 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 5 .

18. A method of decreasing blood glucose in a patient, which comprises administering to the patient an effective amount of a compound of claim 5 .

19. 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 5 .

20. 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 5 .

21. A method of treating or managing 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 5 , wherein the disease or disorder is atherosclerosis, cardiovascular disease, diabetes (Type 1 or 2), hyperglycemia, hypertension, lipid disorders, obesity, or Syndrome X.

22. The method of claim 21 , wherein the disease or disorder is type 2 diabetes.

23. The compound of claim 4 , wherein R 1A is lower alkyl.

24. The compound of claim 5 , wherein R 1A is lower alkyl.

25. (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical formulation comprising (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or excipient.

27. A method of treating type 2 diabetes in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol or a pharmaceutically acceptable salt thereof.