Heterocyclic compounds and methods of use

1. A compound of Formula I

wherein W is NR 4 ;

X is O;

wherein Y 1 is N, Y 2 is O, dashed line “a” is absent and dashed line “b” indicates a bond;

wherein ring A is phenyl;

wherein R is selected from

a) substituted or unsubstituted 6-10 membered aryl, or

b) substituted or unsubstituted cycloalkyl

wherein substituted R is substituted with one or more substituents independently selected from halo, —OR 3 , —SR 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —C(O)R 3 , —NR 3 R 3 , oxo, —OC(O)R 3 , —SO 2 R 3 , —SO 2 NR 3 R 3 , —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , —NR 3 C(O)NR 3 R 3 , optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, and lower alkyl substituted with R 5 ;

wherein R 1 is substituted or unsubstituted quinolinyl,

wherein R 2 is optionally substituted cycloalkyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro, lower alkyl substituted with R 5 , lower alkenyl substituted with R 5 , and lower alkynyl substituted with R 5 ;

wherein R 3 is independently selected from H, lower alkyl, lower aminoalkyl, lower alkylaminoalkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 3 -C 6 -cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl, and lower haloalkyl;

wherein R 4 is independently selected from H, and lower alkyl; and

wherein R 5 is one or more substituents independently selected from H, halo, optionally substituted cycloalkyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, and nitro;

and enantiomers, diastereomers, pharmaceutically acceptable salts and solvates thereof.

2. Compound of claim 1 wherein R is selected from substituted or unsubstituted aryl selected from phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl, and C 3-6 -cycloalkyl, wherein substituted R is substituted with one or more substituents independently selected from halo, —OR 3 , oxo, —SR 3 , —SO 2 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —C(O)R 3 , —NR 3 R 3 , —NH(C 1 -C 4 alkylenylR 3 ), —(C 1 -C 4 alkylenyl)NR 3 R 3 , —SO 2 NR 3 R 3 , —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , amino-C 1 C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, optionally substituted 5-6 membered heterocyclylcarbonylalkyl, C 1-4 -alkoxycarbonylaxnino-C 1-6 -alkyl,

optionally substituted C 4-6 -cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, optionally substituted phenyl-C 1-6 -alkylenyl, optionally substituted 5-6 membered heterocyclyl-C 1 -C 6 -alkylenyl, 5-6 membered heterocyclyl-C 2 -C 6 -alkenylenyl, C 1-4 -alkyl, cyano, C 1-4 -hydroxyalkyl, nitro and C 1-4 -haloalkyl; wherein R e and R f are independently selected from H and C 1-2 -haloalkyl; wherein R 7 is selected from H, C 1-3 -alkyl, optionally substituted phenyl-C 1-3 -alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C 1 -C 3 -alkyl, C 1-3 -alkoxy-C 1-2 -alkyl and C 1-3 -alkoxy-C 1-3 -alkoxy-C 1-3 -alkyl.

3. Compound of claim 1 wherein R is a substituted or unsubstituted ring selected from phenyl, indanyl, tetrahydronaphthyl, naphthyl, and cyclohexyl, wherein substituted R is substituted with 1-3 substituents independently selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, axninosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholinylmethyl, methylpiperazinylmethyl, isopropyl-piperazinylmethyl, methylpiperazinylpropyl, morpholinylpropyl, methylpiperidinylmethyl, morpholinylethyl, 1-(4morpholinyl)-2,2-dimethylpropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, 1-methylpyrrolidinylmethyl, pyrrolidinylpropyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxybutyl, difluoromethoxy, trifluoromethoxy, 1-aminoethyl, 2-axninoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, dimethylaminopropyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, 1-methylpiperdin-4-yloxy, piperdin-4-yloxy, piperidinylethoxy, morpholinylethyloxy, 4-methylpiperazinylethoxy, 4-isopropylpiperazinylethoxy, piperdin-4-methoxy, 4-methylpiperdin-1-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, 3-(dimethylaxnino)pyrrolidin-1-ylethoxy, isopropoxy, methoxy and ethoxy.

4. Compound of claim 1 wherein R is

wherein R x is selected from bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1,1-di(trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and ethoxy; and wherein R y is selected from 4-methylpiperazinylsulfonyl, morpholinylmethyl, 4-methylpiperazinylmethyl, 4-methylpiperazinylpropyl, 4-isopropylpiperazinylmethyl, 4-methylpiperidinylmethyl, 4-aminopiperidinylmethyl, 4-methylamino-piperidinylmethyl, 4-dimethylamino-piperidinylmethyl, 3-dimethylaminopyrrolidin-1-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, morpholinylethyloxy, 4-methylpiperazinylethoxy, 4-isopropylpiperazinylmethoxy, piperdin-4-methoxy, 4-methylpiperdin-1-ylmethoxy, l-methylpyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, l-isopropylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3- (dimethylamino)pyrrolidin-1-ylethoxy, 2-(N,N-dimethylamino)acetylamino and 2-(N,N-dimethylaxnino) ethylamino.

5. Compound of claim 1 wherein R 1 is a substituted or unsubstituted quinolinyl ring wherein substituted R 1 is substituted with one or more substituents independently selected from halo, hydroxy, C 1-3 -alkyl, C 1-2 -alkoxy, C 1-2 -alkoxy-C 1-2 -alkoxy, optionally substituted 5-6 membered heterocyclyl-C 1-2 -alkoxy, amino, C 1-2 -alkylainino, aminosulfonyl, —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, nitro, cyano, C 1-2 -alkylamino-C 1-2 -alkoxy, C 1-2 -alkylamino-C 1-2 -alkyl, C 1-2 -alkylaxnino-C 2-3 -alkylamino, C 1-2 -hydroxyalkyl, C 1-2 -aminoalkyl, and C 1-2 -haloalkyl.

6. Compound of claim 1 wherein R 1 is a substituted or unsubstituted quinolyl ring wherein substituted R 1 is substituted with one or more substituents independently selected from chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, methoxyethoxy, amino, methylamino, ethylamino, 1-methylpiperidinylmethoxy, aminosulfonyl, dimethylaminoethoxy, piperdinylmethoxy, piperdin-1-ylethoxy, morpholinoethoxy, pyrrolidin-1-ylethoxy, 4-methylpiperazin-1-ylethoxy, dimethylaminoethylamino, dimethylaminopropylamino, methyl, ethyl, propyl, cyano, hydroxymethyl, aminomethyl, aminocarbonyl, nitro, trifluoromethyl, optionally substituted piperidinyl, morpholinyl, optionally substituted piperazinyl, and optionally substituted phenyl.

7. Compound of claim 1 wherein R 2 is one or more substituents independently selected from H, chloro, fluoro, bromo, cyclopropyl, optionally substituted phenyl, methyl, ethyl, propyl, cyano, and, nitro.

8. Compound of claim 1 wherein R 2 is H; wherein R 3 is selected from H, C 1-4 -alkyl, phenyl, phenyl-C 1-4 -alkyl, 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C 1-3 -alkyl, C 3 -C 6 cycloalkyl and C 1-2 -haloalkyl.

9. Compound of claim 1 wherein R 4 is independently selected from H, C 1-3 -alkyl, phenyl, 5-6 membered heterocyclyl, C 5 -C 6 cycloalkyl, and C 1-3 -haloalkl.

10. Compound of Formula III

wherein W 1 is NH, and X is O;

wherein R is selected from

a) substituted or unsubstituted 6-10 membered aryl, or

d) substituted or unsubstituted cycloalkyl,

wherein substituted R is substituted with one or more substituents independently selected from halo, —OR 3 , —SR 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —C(O)R 3 , —NR 3 R 3 , —SO 2 R 3 , —SO 2 NR 3 R 3 , —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , —NR 3 C(O)NR 3 R 3 , oxo, —OC(O)R 3 , optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, alkylaminoalkoxyalkoxy, nitro and lower alkyl substituted with R 6 ;

wherein R 1a is selected from unsubstituted or substituted quinolinyl, and where substituted R 1a is substituted with one or more substituents selected from halo, —OR 3 , —SR 3 , —SO 2 R 3 , —CO 2 R 3 , —C(O)R 3 , —NR 3 R 3 , SO 2 NR 3 R 3 , —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , optionally substituted 3-6 membered heterocyclyl, optionally substituted phenyl, nitro, cyano, oxo, and lower alkyl substituted with R 6 ;

wherein R 2 is one or more substituents independently selected from H, halo, —OR 3 , —SR 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —C(O)R 3 , —NR 3 R 3 , —SO 2 R 3 , —SO 2 NR 3 R 3 , —NR 3 C(O)OR 3 , —NR 3 C(O)R 3 , —NR 3 C(O)NR 3 R 3 , optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, cyano, alkylaminoalkoxy, nitro, and lower alkyl substituted with R 6 ;

wherein R 3 is independently selected from H, lower alkyl, optionally substituted phenyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted C 3 -C 6 -cycloalkyl, optionally substituted phenylalkyl, optionally substituted 3-6 membered heterocyclylalkyl, optionally substituted C 3 -C 6 cycloalkylalkyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl; and

wherein R 6 is one or more substituents independently selected from H, halo, optionally substituted cycloalkyl, optionally substituted phenyl, cyano, alkylaminoalkoxy and nitro;

enantiomers, diastereomers and pharmaceutically acceptable salts and solvates thereof.

11. Compound of claim 10 wherein R is a substituted or unsubstituted ring selected from phenyl, indanyl, tetrahydronaphthyl, naphthyl, and cyclohexyl, wherein substituted R is substituted with 1-3 substituents independently selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, hydroxy, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, morpholin-4-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-isopropyl-piperazin-1-ylmethyl, 4-methylpiperazin-1-ylpropyl, morpholin-4-ylpropyl, methylpiperidinylmethyl, morpholin-4-ylethyl, 1-(4-morpholinyl) -2,2-dimethyipropyl, piperidinylethyl, piperidinylmethyl, piperidinylpropyl, 4-(dimethylaminoethyl)piperazin-1-ylmethyl, 1-methylpyrrolidinylmethyl, pyrrolidinylpropyl, methylsulfonyl, methylcarbonyl, piperidinylmethylcarbonyl, methylpiperazinylcarbonylethyl, methoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, 1,1-di(trifluoromethyl) -1-hydroxymethyl, 1,1-di(trifluoromethyl) -1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl) -1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxybutyl, difluoromethoxy, trifluoromethoxy, 1-amninoethyl, 2-aminoethyl, 1-(N-isopropylamino) ethyl, 2-(N-isopropylamino)ethyl, dimethylamninopropyl, dimethylaminoethoxy, diethylaminoethoxy, 4-chiorophenoxy, phenyloxy, 1-methylpiperdin-4-yloxy, piperdin-4-yloxy, piperidinylethoxy, morpholin-4-ylethyloxy, 4-methylpiperazin-l-ylethoxy, 4-isopropylpiperazinylethoxy, piperdin-4-ylmethoxy, 4-methylpiperdin-1-ylmethoxy, 1-methylpiperdin-4-ylmethoxy, 1-isopropylpiperdin-4-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 1-pyrrolidinylmethoxy, 1-pyrrolidinylethoxy, 1-methylpyrrolidin-3-ylmethoxy, 3-(dimethylamino)pyrrolidin-1-ylethoxy, 2-tetrahydrofurylmethoxy, isopropoxy, methoxy and ethoxy.

12. Compound of claim 10 wherein R is

wherein R x is selected from bromo, chloro, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, 1,1-di (trifluoromethyl) -1-hydroxymethyl, trifluoromethoxy, difluoromethoxy, isopropoxy, methoxy and ethoxy; and wherein R y is selected from H, 4-methylpiperazinylsulfonyl, trifluoromethyl, morpholinylmethyl, 4-methylpiperazinylmethyl, 3-dimethylaminopyrrolidin-1-ylmethyl, 4-methylpiperazinyipropyl, 4-isopropylpiperazinylmethyl, 4-methylpiperidinylmethyl, 4-aminopiperidinylmethyl, 4-methylamino-piperidinylmethyl, 4-dimethylamino-piperidinylmethyl, 1-methylpyrrolidin-2-ylmethyl, dimethylaminoethyl, dimethylaminoethoxy, piperidinylethoxy, morpholinylethyloxy, 4-methylpiperazin-1-ylethoxy, 4-(dimethylaminoethyl)piperazin-1-ylmethyl, 4-isopropylpiperazinylmethoxy, piperdin-4-ylmethoxy, 4-methylpiperdin-1-ylmethoxy, 1-methylpiperdin-4-ylmethoxy, 1-isopropylpiperdin-4-ylmethoxy, 1-pyrrolidinylmethoxy, 1-pyrrolidinylethoxy, 1-methylpyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-3-ylmethoxy, 1-isopropylpyrrolidin-2-ylmethoxy, 1-isopropylpyrrolidin-3-ylmethoxy, 3-(dimethylamino)pyrrolidin-1-ylethoxy, 2-tetrahydrofurylmethoxy, diethylamninoethoxy, 2-(N,N-dimethylamino) acetylainino and 2-(N,N-dimethylamino)ethylamino.

13. Compound of claim 10 wherein R 1a is a substituted or unsubstituted 4-quinolyl ring wherein substituted R 1a is substituted with one or more substituents independently selected from chioro, fluoro, bromo, hydroxy, methoxy, ethoxy, methoxyethoxy, amino, methylamino, ethylamino, 1-methylpiperidinylmethoxy, aminosulfonyl, dimethylaminoethoxy, piperdinylmethoxy, piperdin-1-ylethoxy, morpholinoethoxy, pyrrolidin-1-ylethoxy, 4methylpiperazin-1-ylethoxy, methylaminocarbonyl, 1-pyrrolidinylbutylaminocarbonyl, dimethylaminoethylamino, dimethylaminopropylamino, methyl, ethyl, propyl, cyano, hydroxyrnethyl, aminomethyl, aminocarbonyl, nitro, trifluoromethyl, optionally substituted piperidinyl, morpholinyl, optionally substituted piperazinyl, and optionally substituted phenyl.

14. Compound of claim 10 wherein R 2 is H or Cl.

15. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound as in claim 1 or 10 .