Human ADAM-10 inhibitors

1. A compound of structural formula I:

and pharmaceutically acceptable salts thereof wherein -L 1 -R 1 is selected from:

and

wherein each R 14 is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and

R 2 is selected from:

and

2. A compound of structural formula I:

and pharmaceutically acceptable salts thereof wherein L 1 is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —;

R 1 is C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy;

R 2 is —R 21 -L 2 -R 22 ;

R 21 is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50 substituents;

L 2 is —O—, —C(O)—, —CH 2 —, —NH—, —S(O 2 )— or a direct bond;

R 22 is saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three R 50 substituents; and

R 50 is R 51 -L 3 -(CH 2 ) n —;

L 3 is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond;

R 51 is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents;

wherein n is 0, 1, 2, or 3;

provided that an O or S is not singly bonded to another O or S.

3. The compound according to claim 2 , wherein R 1 is methoxyethoxy.

4. The compound according to claim 2 , wherein L 2 is —O—.

5. The compound according to claim 4 , wherein, R 2 is phenoxyphenyl wherein each phenyl is optionally substituted with one or two R 50 substituents.

6. The compound according to claim 5 , wherein the saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring containing one or two annular heteroatoms per ring is selected from the group consisting of morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyranyl, isobenzofuranyl, chromenyl, pyrrolyl, imidazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, carbazolyl, acrydinyl, and furazanyl, optionally substituted with one or two R 50 substituents.

7. The compound according to claim 1 , having the absolute stereochemistry of structural formula II:

8. The compound according to claim 1 , having the absolute stereochemistry of structural formula III:

9. A compound selected from:

and

or a pharmaceutically acceptable salt of any of the above compounds.

10. A compound according to formula IV,

and pharmaceutically acceptable salts thereof wherein,

Z is —C(R 15 )═, —C(H)═, or —N═;

Ar is aryl or heteroaryl, each optionally substituted;

R 15 is fluoro;

p is 1, 2, or 3;

L 1 is —C(O)—, —S(O) 2 —, or —(CH 2 ) n —;

L 4 is nothing or —O—;

R 1 is —H, —OR 11 , —(CH 2 ) n R 11 , —C(O)R 11 , or —NR 12 R 13 ;

R 11 , R 12 , and R 13 independently are

j) R 50 ;

k) saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one or two R 50 substituents;

l) C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, or —C(O)H, each of which is optionally substituted with one, two or three substituents independently selected from R 50 and saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two or three R 50 substituents;

or R 12 and R 13 together with the N to which they are covalently bound, a C 5 -C 6 heterocycle optionally containing a second annular heteroatom and optionally substituted with one or two R 50 substituents; and

R 50 is R 51 -L 3 -(CH 2 ) n —;

L 3 is —O—, —NH—, —S(O) 0-2 —, —C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NHC(O)—, —C 6 H 4 —, or a direct bond;

R 51 is —H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, —CF 3 , —OCF 3 , —OH, —NH 2 , mono-C 1 -C 6 alkyl amino, di-C 1 -C 6 alkyl amino, —SH, —CO 2 H, —CN, —NO 2 , —SO 3 H, or a saturated or mono- or poly-unsaturated C 5 -C 14 -mono- or fused poly-cyclic ring, optionally containing one or two annular heteroatoms per ring and optionally substituted with one, two, or three substituents;

wherein n is 0, 1, 2, or 3;

provided that an O or S is not singly bonded to another O or S.

11. The compound according to claim 10 , wherein -L 1 -R 1 is selected from:

and

wherein each R 14 is independently selected from —H, —(CH 2 ) 1-3 CO 2 H, alkyl, alkoxy, alkenyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.

12. The compound according to claim 11 , wherein Z is —C(R 15 )═ or —C(H)═; L 4 is —O—; and p is at least one.

13. The compound according to claim 12 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted.

14. The compound according to claim 13 , wherein Ar is phenyl, optionally substituted, with at least one halogen.

15. The compound according to claim 14 , wherein p is at least two.

16. The compound according to claim 15 , wherein -L 1 -R 1 is —C(═O)OR 14 or —(CH 2 ) 2 OR 14 .

17. The compound according to claim 9 , having the structure:

18. The compound according to claim 11 , wherein Z is —N═; and L 4 is —O—.

19. The compound according to claim 18 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted.

20. The compound according to claim 19 , wherein Ar is optionally substituted tetrahydro-naphthalene.

21. The compound according to claim 20 , wherein -L 1 -R 1 is —C(═O)OR 14 or —(CH 2 ) 2-3 OR 14 .

22. The compound according to claim 9 , having the structure:

23. The compound according to claim 11 , wherein Z is —N═; and L 4 is nothing.

24. The compound according to claim 23 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted.

25. The compound according to claim 24 , wherein Ar is optionally substituted phenyl.

26. The compound according to claim 25 , wherein -L 1 -R 1 is —C(═O)OR 14 or —(CH 2 ) 2-3 OR 14 .

27. The compound according to claim 9 , having the structure:

28. The compound according to claim 11 , of formula V,

29. The compound according to claim 28 , wherein Ar is selected from the group consisting of phenyl, biphenyl, napthyl, tetrahydronaphthalene, chromen-2-one, dibenzofuran, pyryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl, each optionally substituted.

30. The compound according to claim 29 , wherein Ar is phenyl, optionally substituted, with at least one halogen.

31. The compound according to claim 29 , wherein Ar is selected from,

32. The compound according to claim 30 , wherein the absolute stereochemistry is according to formula VI,

33. The compound according to claim 32 , wherein -L 1 -R 1 is —C(═O)OR 14 or —(CH 2 ) 2-3 OR 14 .

34. A pharmaceutical composition comprising a compound as described in claim 1 , and a pharmaceutically acceptable carrier.