AZA spiro alkane derivatives as inhibitors of metalloproteases

1. A compound having the formula:

or an enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof, wherein:

V is heterocyclyl substituted with 0-5 R e ;

V′ is C 3-13 carbocyclyl substituted with 0-5 R e ;

R e is H, T, C 1-8 alkylene-T, C 2-8 alkenylene-T, C 2-6 alkynylene-T, C(O)NR a ′(CR b ′R c ′) r -T, C(O)O(CR b ′R c ′) r -T, S(O) p (CR b ′R c ′) r -T, (CR b ′R c ′) r —O—(CR b ′R c ′) r -T, OH, Cl, F, Br, I, CN, NO 2 , NR I R II , COR III , COOR IV , OR IV , CONR I R II , NR I CONR I R II , OCONR I R II , NR I COR II , SO 2 NR I R II , NR I SO 2 R II , NR I SO 2 NR I R II , OSO 2 NR I R II , SO p R V , C 1-8 haloalkyl, C 3-13 carbocyclyl, heterocyclyl, carbocyclylalkyl, or heterocyclylalkyl, wherein each of said carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocylcylalkyl groups is optionally substituted by one or more C 1-8 alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester, carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl or arylsulfonyl;

T is H, C 1-10 alkyl substituted with 0 to 5 R b ′; C 2-10 alkenyl substituted with 0 to 5 R b ′, C 2-10 alkynyl substituted with 0 to 5 R b ′, C 3-13 carbocyclyl substituted with 0-3 R b ′, heterocyclyl substituted with 0-5 R b ′;

R a ′, R b ′ and R c ′ are each, independently, H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, Cl, F, Br, I, CN, NO 2 , NR I R II , COR III , COOR IV , OR IV , CONR I R II , R I NCONR I R II , OCONR I R II , R I NCOR II , SO 2 NR I R II , NR I SO 2 R II , NR I SO 2 NR I R II , OSO 2 NR I R II , SO p R V , C 1-8 haloalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, carbocyclyloxy or heterocarbocyclyloxy, wherein each of said carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, carbocyclyloxy or heterocarbocyclyloxy groups is optionally substituted by one or more C 1-8 alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, carboxy alkyl ester, carboxy aryl ester, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, sulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylsulfonyl, arylsulfinyl, alkylsulfonyl or arylsulfonyl;

R I and R II are each, independently, H, C 1-6 alkyl or C 3-13 carbocyclyl;

R III and R IV are each, independently, H, C 1-6 alkyl, haloalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl or heterocyclylalkyl, wherein said carbocyclyl, heterocyclyl, carbocyclylalkyl or heterocyclylalkyl are each optionally substituted by one or more halo, C 1-4 alkyl or C 1-4 alkoxy;

R V is C 1-6 alkyl, haloalkyl, carbocyclyl or heterocyclyl;

p=1 or 2; and

r=0, 1, 2, 3, 4 or 5;

with the proviso that the spiro ring is a stable chemical entity.

2. The compound of claim 1 wherein V is azetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl, piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl, pyridin-1-yl, 3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl, 1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl, 3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl, 1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a] quinolin-3-yl, pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl, 1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl, 1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl, 3,3 a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, or 2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl.

3. The compound of claim 1 wherein V′ is phenyl substituted with 0-5 T, C 1-8 alkylene-T, (CR b ′R c ′) r —O—(CR b ′R c ′) r -T, OH, Cl, F, Br, I, CN, NO 2 , OR IV , CONR I R II or NR I COR II .

4. The compound of claim 1 wherein V′ is phenyl.

5. The compound of claim 1 wherein:

V is piperindin-1yl, piperazin-1-yl, pyrrolidin-1-yl, pyridin-1-yl or 3,6-dihydropyridin-1-yl and

V′ is phenyl substituted with 0-3 R e .

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

7. A method for treating breast cancer in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1 .

8. A method for treating a cancer associated with activity of Her-2 sheddase in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein said cancer is breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, colon cancer, gastric cancer, pancreatic cancer or glioma.

9. The compound of claim 1 , selected from:

(5,6-trans)-N-hydroxy-6-{[4-(3-methylphenyl)piperazin-1-yl]carbonyl}spiro[-2.5]octane-5-carboxamide;

(5,6-trans)-N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide;

(5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5) octane-5-carboxamide;

(6S)—N-hydroxy-6-(((3R)-3-phenylpyrrolidin-1-yl)-carbonyl)spiro[2.5]octane-5-carboxamide;

(5S,6S)—N-hydroxy-6-{[4-(2-methyl-4-nitrophenyl)piperazin-1-yl]carbonyl}spiro[2.5]octane-5-carboxamide; and

(5S,6S)—N-hydroxy-6-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]spiro[2.5]octane-5-carboxamide,

or an enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof.

10. The compound of claim 1 wherein:

V is piperazin-1-yl, pyrrolidin-1-yl, or 3,6-dihydropyridin-1-yl and

V′ is phenyl substituted with 0-3 R e .