Nitrogen heterocycle biaryls for osteoporosis and other diseases

1. A compound of formula:

wherein

Y is chosen from the group consisting of —O—, —S—, —SO 2 —, —CH 2 — and —N(loweralkyl)-;

L is a linker, said linker comprising from one to eight carbons and from zero to three nitrogens, sulfurs and oxygens, wherein at least two atoms are interposed between ring B and carbon β, said linker being straight chain, branched or cyclic, and, when cyclic, attached either at carbons a and b of ring B or, when R 1 is methylene, at R 1 ;

Q is NR 9 ;

E is hydroxy, or E is a biolabile residue such that E and the carboxyl to which it is attached together form an ester or amide cleavable in vivo to provide a compound in which E is hydroxy;

R 1 is chosen from the group consisting of hydrogen, aryl, heteroaryl, (C 1 to C 6 ) hydrocarbon, substituted aryl, (C 1 to C 3 )alkylaryl, —NHCOOR 10 , —NHSO 2 R 10 and —NHCOR 10 ;

R 2 is chosen from the group consisting of hydrogen, aryl, heteroaryl, (C 1 to C 6 ) hydrocarbon, substituted aryl, (C 1 to C 3 )alkylaryl, —NHCOOR 10 , —NHSO 2 R 10 and —NHCOR 10 , and R 2a is hydrogen; or taken together R 2 and R 2a form a carbonyl;

R 3 and R 4 are independently chosen from the group consisting of hydrogen, (C 1 to C 4 ) hydrocarbon, loweralkoxy, halogen and fluoro(loweralkyl);

R 5 , R 6 and R 7 are independently chosen from the group consisting of hydrogen, halogen and fluoro(loweralkyl);

R 8 is chosen from hydrogen and lower alkyl; and

R 9 is chosen from hydrogen, alkyl, substituted alkyl, aryl and (C 1 to C 3 ) akylaryl; or

taken together R 8 and R 9 represent a two to four carbon chain forming a five to seven membered cyclic structure, which may contain one degree of unsaturation; and

R 10 is chosen from the group consisting of alkyl, substituted alkyl, aryl and (C 1 to C 3 )alkylaryl.

2. A compound according to claim 1 of formula:

wherein L is a cyclic linker forming a five-, six or seven-membered ring, optionally substituted with one or two substituents chosen from lower alkyl and oxo.

3. A compound according to claim 2 of formula:

wherein

U is chosen from the group consisting of CH, C(CH 3 ) and N;

V is chosen from the group consisting of C═O, CH 2 and O;

W is chosen from the group consisting of (CH 2 ) n C═O, C(=O)(CH 2 ) n , (CH 2 ) n CH 2 , O(CH 2 ) n and (CH 2 ) n O; and

n is zero, one or two.

4. A compound according to claim 3 of formula:

wherein p is one, two or three;

wherein R 11 hydrogen or methyl;

5. A compound according to claim 1 of formula:

6. A compound according to claim 5 of formula:

wherein n is zero, one or two.

7. A compound according to claim 1 of formula:

wherein L is a linker comprising from one to four carbons and from zero to three nitrogens, sulfurs and oxygens, in a straight or branched chain.

8. A compound according to claim 1 of formula:

wherein L is a linker comprising from one to eight carbons and from zero to three nitrogens, sulfurs and oxygens, in a straight or branched chain.

9. A compound according to claim 1 of formula:

wherein Q a is NR 9 , and R 9 is chosen from hydrogen, alkyl, aryl, (C 1 to C 3 )alkylaryl and alkyl substituted with methoxy, fluoro or hydroxy.

10. A compound according to claim 1 of formula:

wherein R 9 is chosen from hydrogen, lower alkyl, and fluoro(loweralkyl).

11. A compound according to claim 1 of formula

wherein m is one or two.

12. A compound according to claim 9 of formula:

wherein m is one or two.

13. A compound according to any of claims 1 to 12 wherein E is hydroxy.

14. A compound according to claim 1 wherein R 2 and R 2a are hydrogen and R 1 is chosen from hydrogen, —NHCOOR 10 , —NHCOR 10 and —NHSO 2 R 10 .

15. A compound according to claim 1 wherein R 1 is other than hydrogen and the carbon to which R 1 is attached is of the configuration shown:

16. A compound according to claim 1 wherein R 2 is hydrogen, C 1 -C 6 hydrocarbon, aryl, substituted aryl or heteroaryl.

17. A compound according to claim 1 wherein R 1 is hydrogen, R 2a is hydrogen and R 2 is other than hydrogen, and the carbon to which R 2 is attached is of the configuration shown:

18. A compound according to claim 1 wherein R 3 and R 4 are chosen from hydrogen, methyl, methoxy, halogen and trifluoromethyl.

19. A compound according to claim 1 wherein R 5 and R 7 are hydrogen.

20. A compound according to claim 1 wherein R 8 chosen from hydrogen and methyl.

21. A compound according to claim 1 wherein L is chosen from —C(═O)NH—, —CH═CH— and —CH 2 CH 2 —.

22. A compound according to any of claims 1 to 12 wherein Y is —O—.

23. A compound according to claim 22 wherein

E is hydroxy

R 1 hydrogen, —NHCOOR 10 or —NHCOR 10 ;

R 2 is hydrogen, aryl, heteroaryl or substituted aryl;

R 3 R 4 are chosen from hydrogen, methyl, methoxy, halogen and trifluoromethyl;

R 5 R 7 are hydrogen; and

R 8 is chosen from hydrogen and methyl.

24. A compound according to claim 13 wherein Y is —O—.

25. A pharmaceutical composition comprising a compound according to claim 1 and pharmaceutically acceptable carrier.