Nitrogen-containing heterocyclic compounds as FXR modulators

1. A compound according to formula I

a stereoisomer thereof, a salt thereof, or a salt of the stereoisomer; wherein

L and M are both N;

Z is a substituted or unsubstituted C 1 -C 4 alkylene;

W is

X is

D is N or CR 9 ;

one of G 1 , G 2 , G 3 , and G 4 is CR 13 , one of G 1 , G 2 , G 3 , and G 4 is C bonded to R 4 , and the remaining two are selected from the group consisting of CH and CR 11 ;

Q is O, S, or NR 12 ;

R 1 and R 2 are independently H, OH, halo, CN, carboxyl, NR a R b , or a substituted or unsubstituted alkyl, alkoxy, or hydroxyalkyl group;

R 3 is a substituted or unsubstituted alkyl or cycloalkyl group;

R 4 is CN, SO 3 H, CONR a R b , SO 2 NR a R b , NHSO 2 R b , SO 2 NHCOR a , CO 2 R c , or a substituted or unsubstituted tetrazolyl or 1,2,4-oxadiazol-5(4H)-one-3-yl group;

R 9 and R 13 are independently H, halo, or a substituted or unsubstituted C 1 -C 6 alkyl, or O—(C 1 -C 6 alkyl) group;

R 10 at each occurrence is independently halo, CO 2 R c , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group;

R 11 at each occurrence OH, halo, CF 3 , CN, carboxyl, NR a R b , or a substituted or unsubstituted alkyl, alkoxy group, or phenyl group;

R 12 is H or a substituted or unsubstituted C 1 -C 6 alkyl group; and

R a at each occurrence is independently H, or a substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl, or SO 2 -alkyl group;

R b at each occurrence is H or a substituted or unsubstituted alkyl, or haloalkyl group;

R c is H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl group;

n is 1, 2, 3, or 4; and

r and t are each independently 1, 2, or 3.

2. The compound of claim 1 , wherein t is 2 or 3.

3. The compound of claim 1 , wherein R 4 is CO 2 H, CN, CONH 2 , SO 2 NH 2 , or a substituted or unsubstituted CO 2 —C 1 -C 6 alkyl, CO 2 —C 3 -C 6 cycloalkyl, CONH—C 1 -C 6 alkyl, CONH—C 3 -C 6 cycloalkyl, NH—SO 2 —C 1 -C 6 alkyl, or tetrazolyl group.

4. The compound of claim 3 , wherein R 4 is CO 2 H, CN, CONH 2 , or a substituted or unsubstituted CO 2 —C 1 -C 6 alkyl, CONH—C 1 -C 6 alkyl, or tetrazolyl group.

5. The compound of claim 3 , wherein R 4 is CO 2 H, CONH 2 , or a tetrazolyl group.

6. The compound of claim 1 having the structure of Formula IA3:

7. The compound of claim 1 , wherein Z is a substituted or unsubstituted methylene.

8. The compound of claim 1 , wherein W is

9. The compound of claim 1 , wherein R 1 and R 2 are independently halo, CN, CO 2 R e , NR e R f , or a substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 hydroxyalkyl group; and

wherein R e and R f at each occurrence are independently H or a substituted or unsubstituted C 1 -C 6 alkyl group.

10. The compound of claim 9 , wherein R 1 and R 2 are independently H, F, Cl, CN, CO 2 H, NR e R f , or a substituted or unsubstituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 1 -C 3 hydroxyalkyl group.

11. The compound of claim 1 , wherein R 1 and R 2 are independently H, F, Cl, CN, CO 2 H, NH 2 , CH 3 , CH 2 NH 2 , OCF 3 , or OCH 3 .

12. The compound of claim 1 , wherein R 1 and R 2 are both Cl.

13. The compound of claim 1 , wherein R 3 is a substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group.

14. The compound of claim 1 , wherein R 3 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 2 CH 3 ) 2 , CH(CH 2 CH 3 )(CH 3 ), C(CH 3 ) 3 , or cyclopropyl.

15. The compound of claim 1 , wherein R 3 is an isopropyl or cyclopropyl group.

16. The compound of claim 1 , wherein R 10 at each occurrence is independently halo, CO 2 R c , or a substituted or unsubstituted alkyl, alkoxy, hydroxyalkyl, cycloalkyl, or fluorinated cycloalkyl group.

17. The compound of claim 1 wherein X is

wherein q is 0, 1, or 2.

18. The compound of claim 1 , wherein R 11 at each occurrence is independently halo, CF 3 , or a substituted or unsubstituted alkyl, alkoxy, or phenyl group.

19. The compound of claim 1 , wherein R 13 is H, F, or a substituted or unsubstituted C 1 -C 3 alkyl, or O—(C 1 -C 3 alkyl) group.

20. The compound of claim 19 , wherein R 13 is H, F, CH 3 , or O—CH 3 .

21. The compound of claim 1 , wherein R 9 is H.

22. The compound of claim 17 , wherein q is 1 and R 11 is CH 3 or F.

23. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising an effective amount of the compound of claim 1 for treating an FXR-mediated disorder or condition selected from the group consisting of liver disease and diabetes.

25. The pharmaceutical composition of claim 24 wherein the liver disease is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis.

26. A method of treatment comprising administering an effective amount of a compound of claim 1 to a subject suffering from an FXR-mediated disorder or condition selected from the group consisting of liver disease and diabetes.

27. The method of claim 26 , wherein the disorder or condition is liver disease and is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, and liver cirrhosis.

28. The compound of claim 6 wherein Z is unsubstituted methylene.

29. The compound of claim 28 wherein X is

wherein q is 0.

30. The compound of claim 29 wherein W is

and R 1 and R 2 are both Cl.

31. The compound of claim 30 wherein R 3 is an isopropyl or cyclopropyl group.

32. The compound of claim 31 wherein R 4 is CO 2 H, CONH 2 , or a tetrazolyl group.

33. The compound of claim 32 wherein n is 1 or 2, and R 10 at each occurrence is independently an unsubstituted alkyl group.