Hydroxamates as therapeutic agents

1. A compound of Formula (I):

wherein:

R 1 is hydrogen or alkyl;

X is —O—

Y is alkylene;

Ar 1 is phenylene wherein said Ar 1 is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl;

R 3 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

Ar 2 is heteroaryl, wherein said Ar 2 is optionally substituted with one or two groups independently selected from alkyl, halo, haloalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, haloalkoxy, haloalkoxyalkyl, optionally substituted phenylalkyl, optionally substituted phenyloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, -alkylene-S(O) n R a , where n is 0 to 2 and R a is hydroxyalkyl or optionally substituted phenyl, -alkylene-NR e -alkyleneCONR c R d , where R c is hydroxyl and R d and R e are independently hydrogen or alkyl, or carboxyalkylaminoalkyl; and

one of R 4 and R 5 is hydrogen or alkyl and the other is —CH 2 R 6 where R 6 is aryl, heteroaryl, heterocycloalkyl, hydroxyalkyloxy, alkoxyalkyloxy, aminoalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkoxyalkyl-S(O) n —, hydroxyalkyl-S(O) n —, —S(O) n -aryl, aralkyl-S(O) n —, —S(O) n -heteroaryl, heteroaralkyl-S(O) n —, S(O) n —, heterocycloalkyl, heterocycloalkylalkyl-S(O) n —, where n is 0, 1, or 2, —NR 7 R 8 , where R 7 is hydrogen or alkyl and R 8 is alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, —NR 9 SO 2 R 10 , where R 9 is hydrogen or alkyl and R 10 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, or —NR 11 COR 12 , where R 11 is hydrogen or alkyl and R 12 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 , R 3 , and R 4 are hydrogen.

3. The compound of claim 1 wherein R 1 , R 3 , and R 5 are hydrogen.

4. The compound of claim 1 wherein R 1 , R 3 , and R 4 are hydrogen and R 5 is —CH 2 NR 7 R 8 , where R 7 is hydrogen or alkyl and R 8 is alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl.

5. The compound of claim 1 wherein R 1 , R 3 , and R 4 are hydrogen and R 5 is —CH 2 -heterocycloalkyl.

6. The compound of claim 1 wherein R 1 , R 3 , and R 4 are hydrogen, and R 5 is —CH 2 R 6 where R 6 is hydroxyalkyloxy, alkoxyalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkoxyalkyl-S(O) n —, hydroxyalkyl-S(O) n —, —S(O) n -aryl, aralkyl-S(O) n —, —S(O) n -heteroaryl, heteroaralkyl-S(O) n —, —S(O) n -heterocycloalkyl, heterocycloalkylalkyl-S(O) n —, where n is 0, 1, or 2.

7. The compound of claim 1 wherein Y is ethylene, R 1 , R 3 , and R 4 are hydrogen, and R 5 is —CH 2 NR 7 R 8 , where R 7 is hydrogen or alkyl and R 8 is alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl.

8. The compound of claim 1 wherein Y is ethylene, R 1 , R 3 , and R 4 are hydrogen, and R 5 is —CH 2 -heterocycloalkyl.

9. The compound of claim 1 wherein Y is ethylene, R 1 , R 3 , and R 4 are hydrogen, and R 5 is —CH 2 R 6 where R 6 is hydroxyalkyloxy, alkoxyalkyloxy, aryloxy, aralkyloxy, heteroaryloxy, heteroaralkyloxy, heterocycloalkyloxy, heterocycloalkylalkyloxy, alkoxyalkyl-S(O) n —, hydroxyalkyl-S(O) n —, —S(O) n -aryl, aralkyl-S(O) n —, —S(O) n -heteroaryl, heteroaralkyl-S(O) n —, —S(O) n -heterocycloalkyl, heterocycloalkylalkyl-S(O) n —, where n is 0,1, or 2.

10. The compound of claim 7 wherein the heteroaryl of Ar 2 is benzofuran-2-yl optionally substituted with a substituent selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-[1,2,4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-ylmethyl, 4-methylpiperazin-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); and

the —CONHOH and X groups are at the 1 and 4 position of the phenylene ring.

11. The compound of claim 8 wherein the heteroaryl of Ar 2 is benzofuran-2-yl optionally substituted with a substituent selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-[1,2,4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-ylmethyl, 4-methylpiperazin-ylmethyl, 3,3,3-trifluoropropyloxy-methyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonyl-methyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, Ar-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); and

the —CONHOH and X groups are at the 1 and 4 position of the phenylene ring.

12. The compound of claim 9 wherein the heteroaryl of Ar 2 is benzofuran-2-yl optionally substituted with a substituent selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, 1-cyclopropylpiperidin-4-yloxy, 1-(2,2,2-trifluoroethyl)piperidin-4-yloxy, N,N-dimethylamino-methyl, N,N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N,N-dimethylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 4-[1,2,4-triazin-1-yl-phenoxy-methyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethyl-piperidin-ylmethyl, 4-methylpiperazin-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluoro-phenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethyl-aminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropyl-sulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3-trifluoromethoxyphenyl)ethyl, AT-hydroxyaminocarbonyl-methylaminomethyl, or 3-(2-carboxyethylamino-methyl); and

the —CONHOH and X groups are at the 1 and 4 position of the phenylene ring.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.