Urea compounds and methods of uses

A method of inhibiting cell proliferation which comprises administering an effective amount of a compound of Formula I

• 290
• wherein each of A1-A6 is selected from CH2, CH, C, O, S, NH and N;
• wherein A1-A6 together form a ring A selected from
• additionally substituted or unsubstituted 5- or 6-membered heterocyclyl,
• additionally substituted or unsubstituted 5- or 6-membered heteroaryl fused with a phenyl group,
• additionally substituted or unsubstituted 5- or 6-membered cycloalkenyl, and additionally substituted or unsubstituted phenyl, wherein the ring A is additionally substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3—NR3R3—SO2NR3R3, —NR3C(OR3, —NR3C(O)R cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein X and Z taken together form a nitrogen containing ring selected from unsubstituted 5-6 membered heterocyclyl, unsubstituted 5-6 membered heterocyclyl fused with a phenyl group,
• 5-6 membered heterocyclyl substituted with one or more substituents independently selected from R1, and
• 5-6 membered nitrogen-containing heterocyclyl, fused with a phenyl group, substituted with one or more substituents independently selected from R1;
• wherein R1 is independently selected from H, halo, —OR, —SR, —CO2R3, —CO2NR3R3, —COR3—CONR3, R3, —NR3R3, —C(S)NR3R3, —SO2NR3R3, —NR3C(O)oR3, —NR3C(O) R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, optionally substituted phenyl, optionally substituted phenoxy, lower alkyl, lower cyano, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein Y is selected from, in either orientation,
• 291
• wherein R2 is selected from lower alkylaminoalkynyl,
• substituted or unsubstituted phenyl,
• substituted or unsubstituted 5-6 membered heterocyclyl, and
• substituted or unsubstituted 5-6 membered heterocyclyl bridged with a phenyl group;
• wherein substituted R2 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —C(O) NR3, R3, —S2NR3, R3, —NR3C(O)OR3, —NHC(O) R3, —SO2NHC(O)R3, —C(S)NR3R3, nitro, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted heterocyclylalkylenyl, optionally substituted phenyl, optionally substituted phenoxyalkylenyl, optionally substituted heterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, lower alkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower (hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy, lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower ((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lower cyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R6is selected from H, alkyl, 5-6 membered heterocyclylalkylenyl and alkylamino;
• wherein p is 1 or 2;
• wherein q is 0 or 1;
• and
• wherein r is 0-3;
• and pharmaceutically acceptable salts thereof;
• provided A is not thiazol-2-yl when Y is ureido.

A method of treating cancer which comprises administering an effective amount of a compound of Formula I

• 292
• wherein each of A1-A6 is selected from CH2, CH, C, O, S, NH and N;
• wherein A1-A6 together form a ring A selected from
• additionally substituted or unsubstituted 5- or 6-membered heterocyclyl,
• additionally substituted or unsubstituted 5- or 6-membered heteroaryl fused with a phenyl group,
• additionally substituted or unsubstituted 5- or 6-membered cycloalkenyl, and
• additionally substituted or unsubstituted phenyl, wherein the ring A is additionally substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)R3, —NR3C(O) R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein X and Z taken together form a nitrogen containing ring selected from unsubstituted 5-6 membered heterocyclyl, unsubstituted 5-6 membered heterocyclyl fused with a phenyl group,
• 5-6 membered heterocyclyl substituted with one or more substituents independently selected from R1, and
• 5-6 membered nitrogen-containing heterocyclyl, fused with a phenyl group, substituted with one or more substituents independently selected from R1;
• wherein R1 is independently selected from H, halo, —OR, —SR3, —CO2R3, —CO2NR3R3, —COR3, —CONR3R3, —NR3R3, —C(S)NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, optionally substituted phenyl, optionally substituted phenoxy, lower alkyl, lower cyano, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein Y is selected from, in either orientation,
• 293
• wherein R2 is selected from lower alkylaminoalkynyl, substituted or unsubstituted phenyl,
• substituted or unsubstituted 5-6 membered heterocyclyl, and
• substituted or unsubstituted 5-6 membered heterocyclyl bridged with a phenyl group;
• wherein substituted R2 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —C(O)NR3R3, —SO2NR3R3, —NR3C(O) OR3, —NHC(O)R3, —SO2NHC(O)R3, —C(S)NR3R3, nitro, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted heterocyclylalkylenyl, optionally substituted phenyl, optionally substituted phenoxyalkylenyl, optionally substituted heterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, lower alkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower (hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy, lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower ((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lower cyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R6is selected from H, alkyl, 5-6 membered heterocyclylalkylenyl and alkylamino;
• wherein p is 1 or 2;
• wherein q is 0 or 1;
• and
• wherein r is 0-3;
• and pharmaceutically acceptable salts thereof;
• provided A is not thiazol-2-yl when Y is ureido.

A method of inhibiting a tyrosine kinase which comprises administering an effective amount of a compound of Formula I

• 294
• wherein each of A1-A6is selected from CH2, CH, C, O, S, NH and N;
• wherein A1-A6 together form a ring A selected from
• additionally substituted or unsubstituted 5- or 6-membered heterocyclyl,
• additionally substituted or unsubstituted 5- or 6-membered heteroaryl fused with a phenyl group,
• additionally substituted or unsubstituted 5- or 6-membered cycloalkenyl, and
• additionally substituted or unsubstituted phenyl, wherein the ring A is additionally substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O) R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein X and Z taken together form a nitrogen containing ring selected from
• unsubstituted 5-6 membered heterocyclyl,
• unsubstituted 5-6 membered heterocyclyl fused with a phenyl group,
• 5-6 membered heterocyclyl substituted with one or more substituents independently selected from R1, and
• 5-6 membered nitrogen-containing heterocyclyl, fused with a phenyl group, substituted with one or more substituents independently selected from R1;
• wherein R1 is independently selected from H, halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —CONR3R3, —NR3, R3, —C(S)NR3R3, —SO2NR3R3, —NR3C(O) oR3, —NR3C(O) R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, optionally substituted phenyl, optionally substituted phenoxy, lower alkyl, lower cyano, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein Y is selected from, in either orientation,
• 295
• wherein R2 is selected from lower alkylaminoalkynyl,
• substituted or unsubstituted phenyl,
• substituted or unsubstituted 5-6 membered heterocyclyl, and
• substituted or unsubstituted 5-6 membered heterocyclyl bridged with a phenyl group;
• wherein substituted R2 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3—COR3, —NR3R3, —C(O)NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NHC(O)R3, —SO2NHC(O)R3, —C(S)NR3R3, nitro, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted heterocyclylalkylenyl, optionally substituted phenyl, optionally substituted phenoxyalkylenyl, optionally substituted heterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, lower alkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower (hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy, lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower ((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lower cyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R6 is selected from H, alkyl, 5-6 membered heterocyclylalkylenyl and alkylamino;
• wherein p is 1 or 2;
• wherein q is 0 or 1;
• and
• wherein r is 0-3;
• and pharmaceutically acceptable salts thereof;
• provided A is not thiazol-2-yl when Y is ureido.

A method of treating a neurological disorder which comprises administering an effective amount of a compound of Formula 1

• 296
• wherein each of A1-A6 is selected from CH2, CH, C, O, S, NH and N;
• wherein A1-A6 together form a ring A selected from
• additionally substituted or unsubstituted 5- or 6-membered heterocyclyl,
• additionally substituted or unsubstituted 5- or 6-membered heteroaryl fused with a phenyl group,
• additionally substituted or unsubstituted 5- or 6-membered cycloalkenyl, and
• additionally substituted or unsubstituted phenyl, wherein the ring A is additionally substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —SO2NR3R3, —NR3 C(O)OR3, —NR3C(O) R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein X and Z taken together form a nitrogen containing ring selected from
• unsubstituted 5-6 membered heterocyclyl,
• unsubstituted 5-6 membered heterocyclyl fused with a phenyl group,
• 5-6 membered heterocyclyl substituted with one or more substituents independently selected from R1, and
• 5-6 membered nitrogen-containing heterocyclyl, fused with a phenyl group, substituted with one or more substituents independently selected from R1;
• wherein R1 is independently selected from H, halo, —OR3, —SR, —CO2R3, —CO2NR3R3, —COR3, —CONR3R3, —NR3R3, —C(S)NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NR3C(O)R3, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, optionally substituted phenyl, optionally substituted phenoxy, lower alkyl, lower cyano, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein Y is selected from, in either orientation,
• 297
• wherein R2 is selected from lower alkylaminoalkynyl,
• substituted or unsubstituted phenyl,
• substituted or unsubstituted 5-6 membered heterocyclyl, and
• substituted or unsubstituted 5-6 membered heterocyclyl bridged with a phenyl group;
• wherein substituted R2 is substituted with one or more substituents independently selected from halo, —OR3, —SR3, —CO2R3, —CO2NR3R3, —COR3, —NR3R3, —C(O)NR3R3, —SO2NR3R3, —NR3C(O)OR3, —NHC(O)R3, —SO2NHC(O)R3, —C(S)NR3R3, nitro, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 4-7 membered heterocyclyl, optionally substituted heterocyclylalkylenyl, optionally substituted phenyl, optionally substituted phenoxyalkylenyl, optionally substituted heterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, lower alkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower (hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy, lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower ((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lower cyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl;
• wherein R3 is selected from H, lower alkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, C3-C6 cycloalkyl, and lower haloalkyl;
• wherein R is selected from H, alkyl, 5-6 membered heterocyclylalkylenyl and alkylamino;
• wherein p is 1 or 2;
• wherein q is 0 or 1;
• and
• wherein r is 0-3;
• and pharmaceutically acceptable salts thereof;
• provided A is not thiazol-2-yl when Y is ureido.