Anti-mitotic agent and aurora kinase inhibitor combination as anti-cancer treatment

A method of treating or ameliorating cancer comprising administering sequentially to a mammal in need of such treatment an amount of at least one first compound, wherein said first compound is an anti-mitotic agent selected from the group consisting of a taxane, paclitaxel, docetaxel, a Cenp-E Inhibitor, Abraxane, Epothilone, Monastrol, a KSP inhibitor, Ispinesib, and a compound of Formulas A-D shown in paragraphs a-d below:

• a. A compound represented by the structural Formula A:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 6-membered aryl or a 5- or 6-membered heteroaryl fused as shown in Formula A, wherein in said aryl and heteroaryl each substitutable ring carbon is independently substituted with R2 and each substitutable ring nitrogen is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7. —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —SCF3, —C(═NR7)NR4R5, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10C(O)OR11, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally independently substituted with 1-3 moieties selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)OR10, —C(O)NR10R11, —CF3, OCF2, —NR10)C(O)OR11, and —NR10C(O)R40;
• or two R8 groups, when attached to the same carbon atom, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H or alkyl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6-OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-4SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• and
• R40 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally independently substituted with 1-3 moieties independently selected from the group consisting of —CN, —OH, halo, alkyl, haloalkyl, alkoxy, and —NR10R11;
• b. A compound represented by the structural Formula B:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 7-membered ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl fused as shown in Formula B, wherein in each of said 5- to 7-membered ring, each substitutable ring carbon is independently substituted with 1-2 R2 moieties and each substitutable ring heteroatom is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• wherein m is 0 to 2;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkylsilyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, and —C(S)NR7(CH2)1-10OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• or two R2s on the same carbon atom are optionally taken together with the carbon atom to which they are attached to form a C═O, a C═S or an ethylenedioxy group;
• R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —C(═NR7)NR4R5, —C(O)N(R7)—(CR40R41)1-5—C(NR7)NR4R5, —C(O)N(R7)(CR40R41)1-5—NR4R5, —C(O)N(R7)(CR40R41)1-5—C(O)—NR4R5, —C(O)N(R7)(CR40R41)1-5—OR7, —C(S)NR7(CH2)1-5NR4R5, and —C(S)NR7(CH2)1-5OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• each of R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,
• —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10 NR10R11, and —NR10)C(O)OR11;
• wherein said each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-4 R42 moieties;
• wherein when each of said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms anywhere within said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, such radicals may optionally and independently in each occurrence, be taken together with the carbon atoms to which they are attached, to form a five- or six-membered carbocyclic or heterocyclic ring;
• or two R8 groups, when attached to the same carbon, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H, alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• wherein each of said R11 alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl is independently optionally substituted with 1-3 moieties selected from the group consisting of —CN, —OH, —NH2, —N(H)alkyl, —N(alkyl)2, halo, haloalkyl, CF3, alkyl, hydroxyalkyl, alkoxy, aryl, aryloxy, and heteroaryl;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7,
• —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• R40 and R41 can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkyl and cycloalkenyl;
• each R42 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —(C1-C6 alkyl)-OR10,
• —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3,
• —N(R10)C(O)R11, and —NR10C(O)OR11;
• with the proviso that when W is C(R12), R12 and R3 are optionally taken together, with the two ring carbon atoms to which they are attached to form a 6-membered ring selected from the group consisting of cycloalkenyl, aryl, heteroaryl, heterocyclyl and heterocyclenyl, wherein said 6-membered ring is optionally substituted with 1-3 moieties independently selected from oxo, thioxo, —OR11, —NR10R11, —C(O)R11, —C(O)OR11, —C(O)N(R10)(R11), or —N(R10)C(O)R11;
• c.
• or a pharmaceutically acceptable salt, solvate, or ester thereof;
• and
• d. A compound of Formula D
• or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
• R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NHC(═O)alkyl, —C(═O)NH2, —C(═O)NH(alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(alkyl)2, —C(═O)OH, —C(═O)Oalkyl, —C(═O)heterocyclyl, —C(═O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the “heterocyclyl” and “aryl” portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the “alkyl”, “cycloalkyl”, “heterocyclyl”, and “aryl” portions of said R groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, —C(O)OH, —C(═O)Oalkyl, and —C(O)NH2;
• R1 is selected from the group consisting of alkyl, heterocyclyl, —C(═O)aryl, —NH2, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)(cycloalkyl), —NH(heterocyclyl), —N(alkyl)(heterocyclyl), N(alkyl)2, —NH(aryl), —N(alkyl)(aryl), —N(aryl)2, —NH(heteroaryl), —N(alkyl)(heteroaryl), —NHC(═O)-alkyl, —N(alkyl)C(═O)-alkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the “alkyl”, “cycloalkyl”, “aryl”, and “heteroaryl” portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, —NH2, —NH(alkyl), —N(alkyl)2, alkoxy, —NHC(═O)alkyl, —C(═O)H, —C(═O)alkyl, —C(═O)aryl —C(═O)heteroaryl, —C(═O)Oalkyl, —C(═O)NH2, —C(O)NHalkyl, —C(═O)N(alkyl)2;
• wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• R2 and R3 independently are H or alkyl, or —C(R2)(R3)— is absent;
• R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —S(═O)2alkyl, —S(═O)2NH2, —S(═O)2NH(alkyl), —S(═O)2N(alkyl)2, —S-alkyl, —S-haloalkyl, —C(═O)OH, —NH2, —NH(alkyl), —N(alkyl)2, and —C(═O)Oalkyl;
• followed by administering one or more of a second compound, wherein said second compound is an aurora kinase inhibitor selected from the group consisting of compounds represented by Formulas E-K shown below in paragraphs e-k:
• e. A compound represented by the structural Formula E:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl, —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said
• —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl, —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
• said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, alkoxy, heteroaryl, and —NR5R6;
• said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alkyl, —OR5, —N(R5R6) and
• —S(O2)R5;
• and
• said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, —OR5, alkyl, —CHO, —NR5R6, —S(O2)N(R5R6), —C(O)N(R5R6), —SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
• R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring;
• f. A compound represented by the structural formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is selected from the group consisting of H, halogen, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl,
• —C(O)R7,
• wherein each of said aryl, heteroaryl, cycloalkyl, arylalkyl, alkenyl, heterocyclyl and the heterocyclyl moieties whose structures are shown immediately above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF3, CN, —OCF3, —OR6, —C(O)R7, —NR5R6, —C(O2)R6, —C(O)NR5R6, —(CHR5)nOR6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R1 is H, halogen or alkyl;
• R2 is alkyl;
• R3 is selected from the group consisting of H, aryl, heteroaryl, heterocyclyl, —(CHR5)n-aryl, —(CHR5)n-heteroaryl, —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —(CH2)m—NR8, —(CHR5)n—CH(aryl)2,
• and
• wherein each of said aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H or alkyl;
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6, —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• n is 1-4;
• and
• p is 0-3;
• g. A compound selected from the compounds of the formulas:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
• h. A compound of the formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• L is selected from the group consisting of S, S(O) and S(O2);
• G is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl, wherein each of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which are independently selected from the group consisting of —OR5, halo, —CN, —C(O)NR5R6, —N(H)—C(O)R5, —N(H)—C(O)—NR5R6, —S(O2)NR5R6, —NR5R6, —C(O)R5, —C(O2)R5, —SR5, —S(O)R5, —S(O2)R5;
• R1 is H, halo, alkyl, aryl or heteroaryl, wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)NR5R6 and —OR5;
• R2 is selected from the group consisting of H, R9, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —CF3, —C(O)R7
• alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected,
• wherein each of the above-said aryl, heteroaryl, cycloalkyl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CF3, CN, —OCF3, —OR6, —C(O)R7, —NR5R6, —C(O2)R6, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R3 is selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl,
• —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —CH(heteroaryl)2, —(CH2)m—NR8, and
• wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H, alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• and
• p is 0-3;
• i. A compound of Formula I:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl, —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl, —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is heterocyclyl-(CR7R8)n—X, heterocyclenyl-(CR7R8)n—X, heteroaryl-(CR7R8)n—X or aryl-(CR7R8)n—X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl-moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of —CONR5R6, —OR5 and alkyl, n is 1-6,
• X is selected from the group consisting of, —NR5R6, —OR5, —SO—R5 and —SR5, R7 and R8 are each independently hydrogen or alkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, —SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, —S-alkyl, —CO2-alkyl, —CO2-alkenyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cycloalkenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, and heterocyclenyl;
• j. A compound having the formula:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein the dashed lines indicate an optional and additional bond, and wherein:
• R1 is nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl, wherein R1 is joined to the rest of the compound of formula (I) via a ring nitrogen atom, and wherein one or more ring carbon atoms of a nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl group can be substituted with up to 5 substituents, which may be the same or different, and are independently selected from alkyl, aryl, halo, —OH, —O-alkyl, —O-aryl, —N(R8)2, —CF3, —NO2, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —OC(O)R8 or —NHC(O)R8;
• R2 is —H, -alkyl, —NH2 or —CH2NH2;
• R3 is —H, -alkyl, —NH2 or —CH2NH2;
• each occurrence of R4 is independently —H, -alkyl, —NH2, —OH, -alkylene-OH, —CH2NH2, —C(O)R5, —C(O)NH2, —C(O)NH-alkyl, —C(O)N(alkyl)2, —NHC(O)R6 or —NHS(O)2R6;
• R5 is —H, -alkyl, -aryl, -heteroaryl, —NHOH;
• R6 is —H, -alkyl or —CF3;
• R7 is —H, —OH, —C1-C6 alkyl, —O—(C1-C6 alkyl), or —CF3;
• R8 is —H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;
• Ar is -arylene- or -heteroarylene-, wherein the arylene or heteroarylene is joined via 2 of its adjacent ring carbon atoms, and wherein the -arylene- or -heteroarylene- can be substituted with up to 4 substituents, which may be the same or different, and are independently selected from -halo, alkyl, alkoxy, aryloxy, —SR8, —S(O)R8, —S(O)2R8, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —NHC(O)R8, —CF3, —CN or NO2, and such that when Ar is tetrahydronaphthylene, R1 and R2 cannot both be hydrogen
• W is —NH— or —C(R4)2—, wherein both R4 groups and the carbon atom to which they are attached can combine to form a five to seven membered heterocyclyl or heteroaryl group;
• Y is —H, -halo, -alkyl or —CN;
• Z is —CR7— or —N—, when the optional additional bond is absent, and —C— when the optional additional bond is present;
• n is an integer ranging from 0 to 2;
• and
• (k) A compound of Formula K:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
• R is H, halo or alkyl;
• R3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
• A is -aryl-, -heteroaryl-, —N(R1)-aryl- or —N(R1)-heteroaryl-, wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, —NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino;
• RA is —(CH2)14-heteroaryl,
• wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino;
• R1 is H or alkyl;
• R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or —SO2NH2;
• said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and —NO2;
• and said cycloalkyl is unsubstituted or substituted with hydroxyl;
• or
• R1 and R2 together with the N to which each is attached, form a heterocyclic group selected from the group consisting of
• wherein
• Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y′ is hydroxyl;
• wherein the amounts of the first compound and the second compound result in a therapeutic effect.

A method of inducing endoreduplication in cancer cells comprising pretreatment of cancer cells with at least one anti-mitotic agent, wherein said anti-mitotic agent is selected from the group consisting of a Taxane, paclitaxel, docetaxel, a Cenp-E Inhibitor, Abraxane, Epothilone, Monastrol, and a KSP inhibitor, Ispinesib and compounds of Formulas A-D shown in paragraphs a-d below:

• a. A compound represented by the structural Formula A:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 6-membered aryl or a 5- or 6-membered heteroaryl fused as shown in Formula A, wherein in said aryl and heteroaryl each substitutable ring carbon is independently substituted with R2 and each substitutable ring nitrogen is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4R5, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10C(O)OR11, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally independently substituted with 1-3 moieties selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —NR C(O)OR11, and —NR10)C(O)R40;
• or two R8 groups, when attached to the same carbon atom, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H or alkyl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• and
• R40 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally independently substituted with 1-3 moieties independently selected from the group consisting of —CN, —OH, halo, alkyl, haloalkyl, alkoxy, and —NR10R11;
• b. A compound represented by the structural Formula B:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 7-membered ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl fused as shown in Formula B, wherein in each of said 5- to 7-membered ring, each substitutable ring carbon is independently substituted with 1-2 R2 moieties and each substitutable ring heteroatom is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• wherein m is 0 to 2;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkylsilyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, and —C(S)NR7(CH2)1-10OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• or two R2s on the same carbon atom are optionally taken together with the carbon atom to which they are attached to form a C═O, a C═S or an ethylenedioxy group;
• R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —C(═NR7)NR4R5, —C(O)N(R7)—(CR40R41)1-5—C(═NR7)NR4R5, —C(O)N(R7)(CR40R41)1-5—NR4R5, —C(O)N(R7)(CR40R41)1-5—C(O)—NR4R5,
• —C(O)N(R7)(CR40R41)1-5—OR7, —C(S)NR7(CH2)1-5NR4R5, and
• —C(S)NR7(CH2)1-5OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• each of R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10 NR10R11, and —NR10)C(O)OR11;
• wherein said each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-4 R42 moieties;
• wherein when each of said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms anywhere within said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, such radicals may optionally and independently in each occurrence, be taken together with the carbon atoms to which they are attached, to form a five- or six-membered carbocyclic or heterocyclic ring;
• or two R8 groups, when attached to the same carbon, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H, alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• wherein each of said R11 alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl is independently optionally substituted with 1-3 moieties selected from the group consisting of —CN, —OH, —NH2, —N(H)alkyl, —N(alkyl)2, halo, haloalkyl, CF3, alkyl, hydroxyalkyl, alkoxy, aryl, aryloxy, and heteroaryl;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7,
• —C(S)R7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• R40 and R41 can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkyl and cycloalkenyl;
• each R42 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10,
• —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3,
• —N(R10)C(O)R11, and —NR10C(O)OR11;
• with the proviso that when W is C(R12), R12 and R3 are optionally taken together, with the two ring carbon atoms to which they are attached to form a 6-membered ring selected from the group consisting of cycloalkenyl, aryl, heteroaryl, heterocyclyl and heterocyclenyl, wherein said 6-membered ring is optionally substituted with 1-3 moieties independently selected from oxo, thioxo, —OR11, —NR10R11, —C(O)R11, —C(O)OR11, —C(O)N(R10)(R11), or —N(R10)C(O)R11;
• c.
• or a pharmaceutically acceptable salt, solvate, or ester thereof;
• and
• d. A compound of Formula D
• or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
• R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, —SH, —S-alkyl, —S-haloalkyl, —S(═OD)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NHC(═O)alkyl, —C(═O)NH2, —C(═O)NH(alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(alkyl)2, —C(═O)OH, —C(═O)Oalkyl, —C(═O)heterocyclyl, —C(═O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the “heterocyclyl” and “aryl” portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the “alkyl”, “cycloalkyl”, “heterocyclyl”, and “aryl” portions of said R groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, —C(O)OH, —C(═O)Oalkyl, and —C(O)NH2;
• R1 is selected from the group consisting of alkyl, heterocyclyl, —C(═O)aryl, —NH2, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)(cycloalkyl), —NH(heterocyclyl), —N(alkyl)(heterocyclyl), N(alkyl)2, —NH(aryl), —N(alkyl)(aryl), —N(aryl)2, —NH(heteroaryl), —N(alkyl)(heteroaryl), —NHC(═O)-alkyl, —N(alkyl)C(═O)alkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the “alkyl”, “cycloalkyl”, “aryl”, and “heteroaryl” portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, —NH2, —NH(alkyl), alkoxy, —NHC(═O)alkyl, —C(═O)H, —C(═O)alkyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)Oalkyl, —C(═O)NH2, —C(O)NHalkyl, —C(═O)N(alkyl)2;
• wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• R2 and R3 independently are H or alkyl, or —C(R2)(R3)— is absent;
• R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —S(═O)2alkyl, —S(═O)2NH2, —S(═O)2NH(alkyl), —S(═O)2N(alkyl)2, —S-alkyl, —S-haloalkyl, —C(═O)OH, —NH2, —NH(alkyl), —N(alkyl)2, and —C(═O)Oalkyl;
• followed by administering one or more of a second compound, wherein said second compound is an aurora kinase inhibitor selected from the group consisting of compounds represented by Formulas E-K shown below in paragraphs e-k:
• e. A compound represented by the structural Formula E:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl,
• —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2,
• —NR5R6 (wherein the R5 and R6, together with the N of said
• —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl,
• —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
• said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, alkoxy, heteroaryl, and —NR5R6;
• said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alkyl, —OR5, —N(R5R6) and
• —S(O2)R5;
• and
• said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, —OR5, alkyl, —CHO, —NR5R6, —S(O2)N(R5R6), —C(O)N(R5R6), —SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
• R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring;
• f. A compound represented by the structural formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is selected from the group consisting of H, halogen, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl,
• —C(O)R7,
• wherein each of said aryl, heteroaryl, cycloalkyl, arylalkyl, alkenyl, heterocyclyl and the heterocyclyl moieties whose structures are shown immediately above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF3, CN, —OCF3,
• —OR6, —C(O)R7, —NR5R6, —C(O2)R6, —C(O)NR5R6, —(CHR5)nOR6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R1 is H, halogen or alkyl;
• R2 is alkyl;
• R3 is selected from the group consisting of H, aryl, heteroaryl, heterocyclyl, —(CHR5)n-aryl, —(CHR5)n-heteroaryl, —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —(CH2)m—NR8, —(CHR5)n—CH(aryl)2,
• and
• wherein each of said aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5,
• —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H or alkyl;
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and
• —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7,
• —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• n is 1-4;
• and
• p is 0-3;
• g. A compound selected from the compounds of the formulas:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
• h. A compound of the formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• L is selected from the group consisting of S, S(O) and S(O2);
• G is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl, wherein each of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which are independently selected from the group consisting of —OR5, halo, —CN, —C(O)NR5R6, —N(H)—C(O)R5, —N(H)—C(O)—NR5R6, —S(O2)NR5R6, —NR5R6, —C(O)R5, —C(O2)R5, —SR5, —S(O)R5, —S(O2)R5;
• R1 is H, halo, alkyl, aryl or heteroaryl, wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)NR5R6 and —OR5;
• R2 is selected from the group consisting of H, R9, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —CF3, —C(O)R7,
• alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected,
• wherein each of the above-said aryl, heteroaryl, cycloalkyl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CF3, CN, —OCF3, —OR6, —C(O)R7, —NR5R6, —C(O2)R6,
• —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7,
• —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R3 is selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl,
• —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —CH(heteroaryl)2, —(CH2)n—NR8, and
• wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H, alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• and
• p is 0-3;
• i. A compound of Formula I:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl, —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl, —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is heterocyclyl-(CR7R8)n—X, heterocyclenyl-(CR7R8)n—X, heteroaryl-(CR7R8)n—X or aryl-(CR7R8)n—X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl-moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of —CONR5R6, —OR5 and alkyl, n is 1-6,
• X is selected from the group consisting of, —NR5R6, —OR5, —SO—R5 and —SR5, R7 and R8 are each independently hydrogen or alkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, —SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, —S-alkyl, —CO2-alkyl, —CO2-alkenyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cycloalkenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, and heterocyclenyl;
• j. A compound having the formula:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein the dashed lines indicate an optional and additional bond, and wherein:
• R1 is nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl, wherein R1 is joined to the rest of the compound of formula (I) via a ring nitrogen atom, and wherein one or more ring carbon atoms of a nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl group can be substituted with up to 5 substituents, which may be the same or different, and are independently selected from alkyl, aryl, halo, —OH, —O-alkyl, —O-aryl, —N(R8)2, —CF3, —NO2, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —OC(O)R8 or —NHC(O)R8;
• R2 is —H, -alkyl, —NH2 or —CH2NH2;
• R3 is —H, -alkyl, —NH2 or —CH2NH2;
• each occurrence of R4 is independently —H, -alkyl, —NH2, —OH, -alkylene-OH, —CH2NH2, —C(O)R5, —C(O)NH2, —C(O)NH-alkyl, —C(O)N(alkyl)2, —NHC(O)R6 or —NHS(O)2R6;
• R5 is —H, -alkyl, -aryl, -heteroaryl, —NHOH;
• R6 is —H, -alkyl or —CF3;
• R7 is —H, —OH, —C1-C6 alkyl, —O—(C1-C6 alkyl), or —CF3;
• R8 is —H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;
• Ar is -arylene- or -heteroarylene-, wherein the arylene or heteroarylene is joined via 2 of its adjacent ring carbon atoms, and wherein the -arylene- or -heteroarylene- can be substituted with up to 4 substituents, which may be the same or different, and are independently selected from -halo, alkyl, alkoxy, aryloxy, —SR8, —S(O)R8, —S(O)2R8, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —NHC(O)R8, —CF3, —CN or NO2, and such that when Ar is tetrahydronaphthylene, R1 and R2 cannot both be hydrogen
• W is —NH— or —C(R4)2—, wherein both R4 groups and the carbon atom to which they are attached can combine to form a five to seven membered heterocyclyl or heteroaryl group;
• Y is —H, -halo, -alkyl or —CN;
• Z is —CR7— or —N—, when the optional additional bond is absent, and —C— when the optional additional bond is present;
• n is an integer ranging from 0 to 2;
• and
• (k) A compound of Formula K:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
• R is H, halo or alkyl;
• R3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
• A is -aryl-, -heteroaryl-, —N(R1)-aryl- or —N(R1)-heteroaryl-, wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, —NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino;
• RA is —(CH2)1-4-heteroaryl,
• wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino;
• R1 is H or alkyl;
• R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or —SO2NH2;
• said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and —NO2;
• and said cycloalkyl is unsubstituted or substituted with hydroxyl;
• or
• R1 and R2 together with the N to which each is attached, form a heterocyclic group selected from the group consisting of
• wherein
• Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y′ is hydroxyl.

A method of retarding the growth of a tumor in vivo comprising the steps of (a) first administering to tumor in vivo at least one anti-mitotic agent selected from the group consisting of a taxane, paclitaxel, docetaxel, a Cenp-E Inhibitor, Abraxane, Epothilone, Monastrol, a KSP inhibitor, Ispinesib and compounds represented by Formulas A-D shown in paragraphs a-d below:

• a. A compound represented by the structural Formula A:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 6-membered aryl or a 5- or 6-membered heteroaryl fused as shown in Formula A, wherein in said aryl and heteroaryl each substitutable ring carbon is independently substituted with R2 and each substitutable ring nitrogen is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m;
• alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4R5, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10C(O)OR11, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally independently substituted with 1-3 moieties selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —NR10C(O)OR11, and —NR10C(O)R40;
• or two R8 groups, when attached to the same carbon atom, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H or alkyl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• and
• R40 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally independently substituted with 1-3 moieties independently selected from the group consisting of —CN, —OH, halo, alkyl, haloalkyl, alkoxy, and —NR10R11;
• b. A compound represented by the structural Formula B:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 7-membered ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl fused as shown in Formula B, wherein in each of said 5- to 7-membered ring, each substitutable ring carbon is independently substituted with 1-2 R2 moieties and each substitutable ring heteroatom is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• wherein m is 0 to 2;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkylsilyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, and —C(S)NR7(CH2)1-10OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• or two R2s on the same carbon atom are optionally taken together with the carbon atom to which they are attached to form a C═O, a C═S or an ethylenedioxy group;
• R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —C(═NR7)NR4R5, —C(O)N(R7)—(CR40R41)1-5—C(═NR7)NR4R5, —C(O)N(R7)(CR40R41)1-5—NR4R5, —C(O)N(R7)(CR40R41)1-5—C(O)—NR4R5,
• —C(O)N(R7)(CR40R41)1-5—OR7, —C(S)NR7(CH2)1-5NR4R5, and
• —C(S)NR7(CH2)1-5OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• each of R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl,
• —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10C(O)OR11;
• wherein said each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-4 R42 moieties;
• wherein when each of said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms anywhere within said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, such radicals may optionally and independently in each occurrence, be taken together with the carbon atoms to which they are attached, to form a five- or six-membered carbocyclic or heterocyclic ring;
• or two R8 groups, when attached to the same carbon, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H, alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• wherein each of said R11 alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl is independently optionally substituted with 1-3 moieties selected from the group consisting of —CN, —OH, —NH2, —N(H)alkyl, —N(alkyl)2, halo, haloalkyl, CF3, alkyl, hydroxyalkyl, alkoxy, aryl, aryloxy, and heteroaryl;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7,
• —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• R40 and R41 can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkyl and cycloalkenyl;
• each R42 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10,
• —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3,
• —N(R10)C(O)R11, and —NR10C(O)OR11;
• with the proviso that when W is C(R12), R12 and R3 are optionally taken together, with the two ring carbon atoms to which they are attached to form a 6-membered ring selected from the group consisting of cycloalkenyl, aryl, heteroaryl, heterocyclyl and heterocyclenyl, wherein said 6-membered ring is optionally substituted with 1-3 moieties independently selected from oxo, thioxo, —OR11, —NR10R11, —C(O)R11, —C(O)OR11, —C(O)N(R10 (R11), or —N(R10)C(O)R11;
• c.
• or a pharmaceutically acceptable salt, solvate, or ester thereof;
• and
• d. A compound of Formula D
• or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
• R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NHC(═O)alkyl, —C(═O)NH2, —C(═O)NH(alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(alkyl)2, —C(═O)OH, —C(═O)Oalkyl, —C(═O)heterocyclyl, —C(═O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the “heterocyclyl” and “aryl” portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the “alkyl”, “cycloalkyl”, “heterocyclyl”, and “aryl” portions of said R groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, —C(O)OH, —C(═O)Oalkyl, and —C(O)NH2;
• R1 is selected from the group consisting of alkyl, heterocyclyl, —C(═O)aryl, —NH2, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)(cycloalkyl), —NH(heterocyclyl), —N(alkyl)(heterocyclyl), N(alkyl)2, —NH(aryl), —N(alkyl)(aryl), —N(aryl)2, —NH(heteroaryl), —N(alkyl)(heteroaryl), —NHC(═O)-alkyl, —N(alkyl)C(═O)-alkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the “alkyl”, “cycloalkyl”, “aryl”, and “heteroaryl” portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, —NH2, —NH(alkyl), —N(alkyl)2, alkoxy, —NHC(═O)alkyl, —C(═O)H, —C(═O)alkyl, —C(═O)aryl, —C(═O)heteroaryl;
• —C(═O)Oalkyl, —C(═O)NH2, —C(O)NHalkyl, —C(═O)N(alkyl)2;
• wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• R2 and R3 independently are H or alkyl, or —C(R2)(R3)— is absent;
• R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —S(═O)2NH2, —S(═O)2NH(alkyl), —S(═O)2N(alkyl)2, —S-alkyl, —S-haloalkyl, —C(═O)OH, —NH2, —NH(alkyl), —N(alkyl)2, and —C(═O)Oalkyl;
• and (b) subsequently administering to said tumor at least one aurora kinase inhibitor, wherein said aurora kinase inhibitor is selected from the group consisting of a compound represented by Formulas E-K shown below in paragraphs e-k:
• e. A compound represented by the structural Formula E:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl,
• —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2,
• —NR5R6 (wherein the R5 and R6, together with the N of said
• —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl,
• —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
• said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, alkoxy, heteroaryl, and —NR5R6;
• said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alkyl, —OR5, —N(R5R6) and
• —S(O2)R5;
• and
• said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, —OR5, alkyl, —CHO, —NR5R6, —S(O2)N(R5R6), —C(O)N(R5R6), —SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
• R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring;
• f. A compound represented by the structural formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is selected from the group consisting of H, halogen, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl,
• —C(O)R7,
• wherein each of said aryl, heteroaryl, cycloalkyl, arylalkyl, alkenyl, heterocyclyl and the heterocyclyl moieties whose structures are shown immediately above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF3, CN, —OCF3,
• —OR6, —C(O)R7, —NR5R6, —C(O2)R6, —C(O)NR5R6, —(CHR5)nOR6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R1 is H, halogen or alkyl;
• R2 is alkyl;
• R3 is selected from the group consisting of H, aryl, heteroaryl, heterocyclyl, —(CHR5)n-aryl, —(CHR5)n-heteroaryl, —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —(CH2)n—NR8, —(CHR5)n—CH(aryl)2,
• and
• wherein each of said aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5,
• —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H or alkyl;
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and
• —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7,
• —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• n is 1-4;
• and
• p is 0-3;
• g. A compound selected from the compounds of the formulas:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
• h. A compound of the formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• L is selected from the group consisting of S, S(O) and S(O2);
• G is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl, wherein each of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which are independently selected from the group consisting of —OR5, halo, —CN, —C(O)NR5R6, —N(H)—C(O)R5, —N(H)—C(O)—NR5R6, —S(O2)NR5R6, —NR5R6, —C(O)R5, —C(O2)R5, —SR5, —S(O)R5, —S(O2)R5;
• R1 is H, halo, alkyl, aryl or heteroaryl, wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)NR5R6 and —OR5;
• R2 is selected from the group consisting of H, R9, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —CF3, —C(O)R7,
• alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected,
• wherein each of the above-said aryl, heteroaryl, cycloalkyl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CF3, CN, —OCF3, —OR6, —C(O)R7, —NR5R6, —C(O2)R6,
• —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7,
• —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R3 is selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl,
• —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —CH(heteroaryl)2, —(CH2)m—NR8, and
• wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H, alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• and
• p is 0-3;
• i. A compound of Formula I:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl, —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl, —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is heterocyclyl-(CR7R8)n—X, heterocyclenyl-(CR7R8)n—X, heteroaryl-(CR7R8)n—X or aryl-(CR7R8)n—X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl-moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of —CONR5R6, —OR5 and alkyl, n is 1-6,
• X is selected from the group consisting of, —NR5R6, —OR5, —SO—R5 and —SR5, R7 and R8 are each independently hydrogen or alkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkylSH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, —SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, —S-alkyl, —CO2-alkyl, —CO2-alkenyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cycloalkenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, and heterocyclenyl;
• j. A compound having the formula:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein the dashed lines indicate an optional and additional bond, and wherein:
• R1 is nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl, wherein R1 is joined to the rest of the compound of formula (I) via a ring nitrogen atom, and wherein one or more ring carbon atoms of a nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl group can be substituted with up to 5 substituents, which may be the same or different, and are independently selected from alkyl, aryl, halo, —OH, —O-alkyl, —O-aryl, —N(R8)2, —CF3, —NO2, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —OC(O)R8 or —NHC(O)R8;
• R2 is —H, -alkyl, —NH2 or —CH2NH2;
• R3 is —H, -alkyl, —NH2 or —CH2NH2;
• each occurrence of R4 is independently —H, -alkyl, —NH2, —OH, -alkylene-OH, —CH2NH2, —C(O)R5, —C(O)NH2, —C(O)NH-alkyl, —C(O)N(alkyl)2, —NHC(O)R6 or —NHS(O)2R6;
• R5 is —H, -alkyl, -aryl, -heteroaryl, —NHOH;
• R6 is —H, -alkyl or —CF3;
• R7 is —H, —OH, —C1-C6 alkyl, —O—(C1-C6 alkyl), or —CF3;
• R8 is —H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;
• Ar is -arylene- or -heteroarylene-, wherein the arylene or heteroarylene is joined via 2 of its adjacent ring carbon atoms, and wherein the -arylene- or -heteroarylene- can be substituted with up to 4 substituents, which may be the same or different, and are independently selected from -halo, alkyl, alkoxy, aryloxy, —SR8, —S(O)R8, —S(O)2R8, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —NHC(O)R8, —CF3, —CN or NO2, and such that when Ar is tetrahydronaphthylene, R1 and R2 cannot both be hydrogen
• W is —NH— or —C(R4)2—, wherein both R4 groups and the carbon atom to which they are attached can combine to form a five to seven membered heterocyclyl or heteroaryl group;
• Y is —H, -halo, -alkyl or —CN;
• Z is —CR7— or —N—, when the optional additional bond is absent, and —C— when the optional additional bond is present;
• n is an integer ranging from 0 to 2;
• and
• (k) A compound of Formula K:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
• R is H, halo or alkyl;
• R3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
• A is -aryl-, -heteroaryl-, —N(R1)-aryl- or —N(R1)-heteroaryl-, wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, —NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino;
• RA is —(CH2)1-4-heteroaryl,
• wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino;
• R1 is H or alkyl;
• R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or —SO2NH2;
• said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and —NO2;
• and said cycloalkyl is unsubstituted or substituted with hydroxyl;
• or
• R1 and R2 together with the N to which each is attached, form a heterocyclic group selected from the group consisting of
• wherein
• Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y′ is hydroxyl.

A method of inducing polyploidy in cancer cells comprising the steps of first administering to a cancer cell in vivo at least one anti-mitotic agent selected from the group consisting of a taxane, paclitaxel, docetaxel, a Cenp-E Inhibitor, Abraxane, Epothilone, Monastrol, KSP inhibitors including Ispinesib SB-715992 (Cytokinetics), and compounds represented by Formulas A-D shown in paragraphs a-d below:

• a. A compound represented by the structural Formula A:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 6-membered aryl or a 5- or 6-membered heteroaryl fused as shown in Formula A, wherein in said aryl and heteroaryl each substitutable ring carbon is independently substituted with R2 and each substitutable ring nitrogen is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4R5, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• each R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR'°, —C(O)NR'° R11, —CF3, —OCF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10C(O)OR11, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally independently substituted with 1-3 moieties selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3, —NR10)C(O)OR11, and —NR10C(O)R40;
• or two R8 groups, when attached to the same carbon atom, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H or alkyl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• and
• R40 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally independently substituted with 1-3 moieties independently selected from the group consisting of —CN, —OH, halo, alkyl, haloalkyl, alkoxy, and —NR10R11;
• b. A compound represented by the structural Formula B:
• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• ring Y is a 5- to 7-membered ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl fused as shown in Formula B, wherein in each of said 5- to 7-membered ring, each substitutable ring carbon is independently substituted with 1-2 R2 moieties and each substitutable ring heteroatom is independently substituted with R6;
• W is N or C(R12);
• X is N or N-oxide;
• Z is S, S(═O) or S(═O)2;
• R1 is H, alkyl, alkoxy, hydroxy, halo, —CN, —S(O)m-alkyl, —C(O)NR9R10, —(CR9R10)1-6OH, or —NR4(CR9R10)1-2OR9;
• wherein m is 0 to 2;
• each R2 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, alkylsilyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, and —C(S)NR7(CH2)1-10OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• or two R2s on the same carbon atom are optionally taken together with the carbon atom to which they are attached to form a C═O, a C═S or an ethylenedioxy group;
• R3 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7, —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —C(═NR7)NR4R5, —C(O)N(R7)—(CR40R41)1-5—C(═NR7)NR4R5, —C(O)N(R7)(CR40R41)1-5—NR4R5, —C(O)N(R7)(CR40R41)1-5—C(O)—NR4R5,
• —C(O)N(R7)(CR40R41)1-5—OR7, —C(S)NR7(CH2)1-5NR4R5, and
• —C(S)NR7(CH2)1-5OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-5 R9 moieties;
• each of R4 and R5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —OR7, —C(O)R7, and —C(O)OR7, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, is optionally substituted with 1-4 R8 moieties;
• or R4 and R5, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, —(CH2)1-6CF3, —C(O)R7, —C(O)OR7 and —SO2R7;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl, wherein each member of R7 except H is optionally substituted with 1-4 R8 moieties;
• each R8 is independently selected from the group consisting of halo, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, —NO2, -Ore, —(C1-C6 alkyl)-OR10, —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —CF2CF3, —C(═NOH)R10, —N(R10)C(O)R11, —C(═NR10)NR10R11, and —NR10)C(O)OR11;
• wherein said each of said alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl is independently optionally substituted with 1-4 R42 moieties;
• wherein when each of said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl contains two radicals on adjacent carbon atoms anywhere within said cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl, such radicals may optionally and independently in each occurrence, be taken together with the carbon atoms to which they are attached, to form a five- or six-membered carbocyclic or heterocyclic ring;
• or two R8 groups, when attached to the same carbon, are optionally taken together with the carbon atom to which they are attached to form a C═O or a C═S group;
• each R9 is independently selected from the group consisting of H, alkyl, alkoxy, OH, CN, halo, —(CR10R11)0-4NR4R5, haloalkyl, hydroxyalkyl, alkoxyalkyl, —C(O)NR4R5, —C(O)OR7, —OC(O)NR4R5, —NR4C(O)R5, and —NR4C(O)NR4R5;
• each R10 is independently H or alkyl;
• or R9 and R10, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• each R11 is independently H, alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl;
• or R10 and R11, when attached to the same nitrogen atom, are optionally taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring having 0-2 additional heteroatoms selected from N, O or S;
• wherein each of said R11 alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl is independently optionally substituted with 1-3 moieties selected from the group consisting of —CN, —OH, —NH2, —N(H)alkyl, —N(alkyl)2, halo, haloalkyl, CF3, alkyl, hydroxyalkyl, alkoxy, aryl, aryloxy, and heteroaryl;
• each R12 is independently selected from the group consisting of H, halo, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —(CR10R11)0-6—OR7, —C(O)R4, —C(S)R4, —C(O)OR7,
• —C(S)OR7, —OC(O)R7, —OC(S)R7, —C(O)NR4R5, —C(S)NR4R5, —C(O)NR4OR7, —C(S)NR4OR7, —C(O)NR7NR4R5, —C(S)NR7NR4R5, —C(S)NR4OR7, —C(O)SR7, —NR4R5, —NR4C(O)R5, —NR4C(S)R5, —NR4C(O)OR7, —NR4C(S)OR7, —OC(O)NR4R5, —OC(S)NR4R5, —NR4C(O)NR4R5, —NR4C(S)NR4R5, —NR4C(O)NR4OR7, —NR4C(S)NR4OR7, —(CR10R11)0-6SR7, SO2R7, —S(O)1-2NR4R5, —N(R7)SO2R7, —S(O)1-2NR5OR7, —CN, —OCF3, —SCF3, —C(═NR7)NR4, —C(O)NR7(CH2)1-10NR4R5, —C(O)NR7(CH2)1-10OR7, —C(S)NR7(CH2)1-10NR4R5, —C(S)NR7(CH2)1-10OR7, haloalkyl and alkylsilyl, wherein each of said alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl is independently optionally substituted with 1-5 R9 moieties;
• R40 and R41 can be the same or different, each being independently selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, cycloalkyl and cycloalkenyl;
• each R42 is independently selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —NO2, —OR10, —(C1-C6 alkyl)-OR10,
• —CN, —NR10R11, —C(O)R10, —C(O)OR10, —C(O)NR10R11, —CF3, —OCF3,
• —N(R10)C(O)R11, and —NR10C(O)OR11;
• with the proviso that when W is C(R12), R12 and R3 are optionally taken together, with the two ring carbon atoms to which they are attached to form a 6-membered ring selected from the group consisting of cycloalkenyl, aryl, heteroaryl, heterocyclyl and heterocyclenyl, wherein said 6-membered ring is optionally substituted with 1-3 moieties independently selected from oxo, thioxo, —OR11, —NR10R11, —C(O)R11, —C(O)OR11, —C(O)N(R10(R11), or —N(R10)C(O)R11;
• c.
• or a pharmaceutically acceptable salt, solvate, or ester thereof;
• and
• d. A compound of Formula D
• or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
• R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, —SH, —S-alkyl, —S-haloalkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NHC(═O)alkyl, —C(═O)NH2, —C(═O)NH(alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(alkyl)2, —C(═O)OH, —C(═O)Oalkyl, —C(═O)heterocyclyl, —C(═O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the “heterocyclyl” and “aryl” portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the “alkyl”, “cycloalkyl”, “heterocyclyl”, and “aryl” portions of said R groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, —C(O)OH, —C(═O)Oalkyl, and —C(O)NH2;
• R1 is selected from the group consisting of alkyl, heterocyclyl, —C(═O)aryl, —NH2, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)(cycloalkyl), —NH(heterocyclyl), —N(alkyl)(heterocyclyl), N(alkyl)2, —NH(aryl), —N(alkyl)(aryl), —N(aryl)2, —NH(heteroaryl), —N(alkyl)(heteroaryl), —NHC(═O)-alkyl, —N(alkyl)C(═O)-alkyl, —NHC(═O)Oalkyl, —N(alkyl)C(═O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the “alkyl”, “cycloalkyl”, “aryl”, and “heteroaryl” portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, —SH, —S-alkyl, —S(═O)2alkyl, —S(═O)2OH, —S(═O)2NH2, —S(═O)2NH(alkyl), S(═O)2NH(cycloalkyl), —S(═O)2N(alkyl)2, —S(═O)2heterocyclyl, —S(═O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, —NH2, —NH(alkyl), —N(alkyl)2, alkoxy, —NHC(═O)alkyl, —C(═O)H, —C(═O)alkyl, —C(═O)aryl, —C(═O)heteroaryl, —C(═O)Oalkyl, —C(═O)NH2, —C(O)NHalkyl, —C(═O)N(alkyl)2;
• wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• R2 and R3 independently are H or alkyl, or —C(R2)(R3)— is absent;
• R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
• wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —S(═O)2alkyl, —S(═O)2NH2, —S(═O)2NH(alkyl), —S(═O)2N(alkyl)2, —S-alkyl, —S-haloalkyl, —C(═O)OH, —NH2, —NH(alkyl), —N(alkyl)2, and —C(═O)Oalkyl;
• subsequently administering to said cancer cell at least one aurora kinase inhibitor, wherein said aurora kinase inhibitor is selected from the group consisting of a compound represented by Formulas E-K shown below in paragraphs e-k:
• e. A compound represented by the structural Formula E:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl,
• —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2,
• —NR5R6 (wherein the R5 and R6, together with the N of said
• —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl,
• —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein:
• said alkyl shown above for R3 can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, alkoxy, heteroaryl, and —NR5R6;
• said aryl shown above for R3 is unsubstituted, or optionally substituted, or optionally fused, with halo, heteroaryl, heterocyclyl, cycloalkyl or heteroarylalkyl, wherein each of said heteroaryl, heterocyclyl, cycloalkyl and heteroarylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different each moiety being independently selected from alkyl, —OR5, —N(R5R6) and
• —S(O2)R5;
• and
• said heteroaryl shown above for R3 can be unsubstituted or optionally substituted, or optionally fused, with one or more moieties which can be the same or different with each moiety being independently selected from the group consisting of halo, amino, alkoxycarbonyl, —OR5, alkyl, —CHO, —NR5R6, —S(O2)N(R5R6), —C(O)N(R5R6), —SR5, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclenyl, and heterocyclyl;
• R5 is H, alkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is H, alkyl, aryl, arylalkyl, heteroaryl, heterocyclyl or cycloalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring;
• f. A compound represented by the structural formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is selected from the group consisting of H, halogen, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl,
• —C(O)R7,
• wherein each of said aryl, heteroaryl, cycloalkyl, arylalkyl, alkenyl, heterocyclyl and the heterocyclyl moieties whose structures are shown immediately above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF3, CN, —OCF3,
• —OR6, —C(O)R7, —NR5R6, —C(O2)R6, —C(O)NR5R6, —(CHR5)nOR6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R1 is H, halogen or alkyl;
• R2 is alkyl;
• R3 is selected from the group consisting of H, aryl, heteroaryl, heterocyclyl, —(CHR5)n-aryl, —(CHR5)n-heteroaryl, —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —(CH2)m—NR8, —(CHR5)n—CH(aryl)2,
• and
• wherein each of said aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5,
• —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H or alkyl;
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and
• —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7,
• —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6,
• —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• n is 1-4;
• and
• p is 0-3;
• g. A compound selected from the compounds of the formulas:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof;
• h. A compound of the formula:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• L is selected from the group consisting of S, S(O) and S(O2);
• G is alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl, wherein each of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which are independently selected from the group consisting of —OR5, halo, —CN, —C(O)NR5R6, —N(H)—C(O)R5, —N(H)—C(O)—NR5R6, —S(O2)NR5R6, —NR5R6, —C(O)R5, —C(O2)R5, —SR5, —S(O)R5, —S(O2)R5;
• R1 is H, halo, alkyl, aryl or heteroaryl, wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)NR5R6 and —OR5;
• R2 is selected from the group consisting of H, R9, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, —CF3, —C(O)R7,
• alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected,
• wherein each of the above-said aryl, heteroaryl, cycloalkyl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, CF3, CN, —OCF3, —OR6, —C(O)R7, —NR5R6, —C(O2)R6,
• —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7,
• —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R3 is selected from the group consisting of H, alkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl,
• —(CHR5)n—OR6, —S(O2)R6, —C(O)R6, —S(O2)NR5R6, —C(O)OR6, —C(O)NR5R6, cycloalkyl, —CH(aryl)2, —CH(heteroaryl)2, —(CH2)n—NR8, and
• wherein each of said alkyl, aryl, heteroaryl and heterocyclyl can be substituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF3, CN, —OCF3, —OR5, —NR5R6, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R6, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R5 is H, alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;
• and
• R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R7 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, —OR5, —NR5R6, —CH2OR5, —C(O2)R5, —C(O)NR5R6, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• R8 is selected from the group consisting of R6, —C(O)NR5R6,
• —S(O2)NR5R6, —C(O)R7, —C(O2)R6, —S(O2)R7 and —(CH2)-aryl;
• R9 is selected from the group consisting of halogen, CN, NR5R6,
• —C(O2)R6, —C(O)NR5R6, —OR6, —C(O)R7, —SR6, —S(O2)R7, —S(O2)NR5R6, —N(R5)S(O2)R7, —N(R5)C(O)R7 and —N(R5)C(O)NR5R6;
• m is 0 to 4;
• and
• p is 0-3;
• i. A compound of Formula I:
• or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:
• R is H, CN, —NR5R6, cycloalkyl, cycloalkenyl, heterocyclenyl, heteroaryl, —C(O)NR5R6, —N(R5)C(O)R6, heterocyclyl, heteroaryl substituted with (CH2)1-3NR5R6, unsubstituted alkyl, or alkyl substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of —OR5, heterocyclyl, —N(R5)C(O)N(R5R6), —N(R5)—C(O)OR6, —(CH2)1-3—N(R5R6) and —NR5R6;
• R1 is H, halo, aryl or heteroaryl, wherein each of said aryl and heteroaryl can be unsubstituted or substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —CH2OR5, —C(O)NR5R6, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5 and —OR5;
• R2 is H, halo, aryl, arylalkyl or heteroaryl, wherein each of said aryl, arylalkyl and heteroaryl can be unsubstituted or optionally independently be substituted with one or more moieties which can be the same or different each moiety being independently selected from the group consisting of halo, amide, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)OH, —C(O)NH2, —NR5R6 (wherein the R5 and R6, together with the N of said —NR5R6, form a heterocyclyl ring), —CN, arylalkyl, —CH2OR5, —S(O)R5, —S(O2)R5, —CN, —CHO, —SR5, —C(O)OR5, —C(O)R5, heteroaryl and heterocyclyl;
• R3 is heterocyclyl-(CR7R8)n—X, heterocyclenyl-(CR7R8)n—X, heteroaryl-(CR7R8)n—X or aryl-(CR7R8)n—X wherein each of the heterocyclyl-, heterocyclenyl-, heteroaryl- or aryl-moieties of said R3 can be unsubstituted or substituted with one or more moieties, independently selected from the group consisting of —CONR5R6, —OR5 and alkyl, n is 1-6,
• X is selected from the group consisting of, —NR5R6, —OR5, —SO—R5 and —SR5, R7 and R8 are each independently hydrogen or alkyl;
• R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, -alkyl-S-alkyl, aminoalkyl, aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl, alkylN(alkyl)2, alkylNH(alkyl), alkylN(alkenyl)2, -alkylN(alkoxyl)2, -alkyl-SH and hydroxyalkyl, wherein each of said aryl, heteroaryl, heterocyclenyl, heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxyl, —S-alkylheterocyclyl, heterocyclyl, heterocyclenyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl, wherein each of said aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of alkyl, alkyl, alkenyl, aryl, cycloalkenyl, cycloalkyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroaryl, heterocyclenyl, heterocyclyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, alkoxyalkyl, -alkyl-S-alkyl, -alkyl SH, alkoxyl, —S-alkyl, hydroxyalkyl, and aminoalkyl;
• further wherein in any —NR5R6 in Formula I, said R5 and R6 can optionally be joined together with the N of said —NR5R6 to form a cyclic ring or bridged cyclic ring, wherein each of said cyclic ring or bridged cyclic ring, can be unsubstituted or substituted with one or more moieties, which can be the same or different, independently selected from the group consisting of hydroxyl, —SH, alkyl, alkenyl, hydroxyalkyl, -alkyl-SH, alkoxyl, —S-alkyl, —CO2-alkyl, —CO2-alkenyl, arylalkyl, cycloalkenylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclenylalkyl, heterocycloalkylalkyl, heteroaryl, aryl, cycloalkenyl, cycloalkyl, spiroheterocyclyl, spiroheterocyclenyl, spiroheteroaryl, spirocyclyl, spirocyclenyl, spiroaryl, alkoxyalkyl, -alkyl-S-alkyl, heterocyclyl, and heterocyclenyl;
• j. A compound having the formula:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein the dashed lines indicate an optional and additional bond, and wherein:
• R1 is nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl, wherein R1 is joined to the rest of the compound of formula (I) via a ring nitrogen atom, and wherein one or more ring carbon atoms of a nitrogen-containing heteroaryl, nitrogen-containing heterocyclyl, nitrogen-containing benzofused heteroaryl or nitrogen-containing benzofused heterocyclyl group can be substituted with up to 5 substituents, which may be the same or different, and are independently selected from alkyl, aryl, halo, —OH, —O-alkyl, —O-aryl, —N(R8)2, —CF3, —NO2, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —OC(O)R8 or —NHC(O)R8;
• R2 is —H, -alkyl, —NH2 or —CH2NH2;
• R3 is —H, -alkyl, —NH2 or —CH2NH2;
• each occurrence of R4 is independently —H, -alkyl, —NH2, —OH, -alkylene-OH, —CH2NH2, —C(O)R5, —C(O)NH2, —C(O)NH-alkyl, —C(O)N(alkyl)2, —NHC(O)R6 or —NHS(O)2R6;
• R5 is —H, -alkyl, -aryl, -heteroaryl, —NHOH;
• R6 is —H, -alkyl or —CF3;
• R7 is —H, —OH, —C1-C6 alkyl, —O—(C1-C6 alkyl), or —CF3;
• R8 is —H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;
• Ar is -arylene- or -heteroarylene-, wherein the arylene or heteroarylene is joined via 2 of its adjacent ring carbon atoms, and wherein the -arylene- or -heteroarylene- can be substituted with up to 4 substituents, which may be the same or different, and are independently selected from -halo, alkyl, alkoxy, aryloxy, —SR8, —S(O)R8, —S(O)2R8, —C(O)R8, —C(O)OR8, —C(O)N(R8)2, —NHC(O)R8, —CF3, —CN or NO2, and such that when Ar is tetrahydronaphthylene, R1 and R2 cannot both be hydrogen
• W is —NH— or —C(R4)2—, wherein both R4 groups and the carbon atom to which they are attached can combine to form a five to seven membered heterocyclyl or heteroaryl group;
• Y is —H, -halo, -alkyl or —CN;
• Z is —CR7— or —N—, when the optional additional bond is absent, and —C— when the optional additional bond is present;
• n is an integer ranging from 0 to 2;
• and
• (k) A compound of Formula K:
• or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein:
• R is H, halo or alkyl;
• R3 is heteroaryl-X, wherein X is heterocyclylalkyl- wherein said heterocyclyl can be unsubstituted or optionally substituted with 1-4 alkyl moieties;
• A is -aryl-, -heteroaryl-, —N(R1)-aryl- or —N(R1)-heteroaryl-, wherein each of said aryl and heteroaryl can be independently unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, each substituent being independently selected from the group consisting of alkyl, —NO2, halo, hydroxy, trihaloalkyl, alkoxy, and dialkylamino;
• RA is —(CH2)1-4-heteroaryl,
• wherein said heteroaryl can optionally be fused with an aryl, wherein each of said aryl and heteroaryl can independently be optionally substituted with one or more moieties each moiety being independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl and dialkylamino;
• R1 is H or alkyl;
• R2 is H, hydroxyalkyl-, arylalkyl-, heteroaryl, aryl, heteroarylalkyl-, alkyl, dialkylaminoalkyl-, alkylaminoalkyl-, cycloalkylalkyl-, cycloalkyl, heterocyclylalkyl- or heterocyclyl, wherein said aryl and aryl of arylalkyl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of trihaloalkyl, —NO2, halo, hydroxyalkyl, alkoxyalkyl, dialkylamino and heterocyclylalkyl-, wherein said heterocyclylalkyl can be unsubstituted or substituted with alkyl or —SO2NH2;
• said heteroaryl and heteroaryl of heteroarylalkyl can be unsubstituted or substituted with one or more moieties, each moiety being independently selected from the group consisting of hydroxyalkyl, alkoxy, alkyl, halo, hydroxyl, and —NO2;
• and said cycloalkyl is unsubstituted or substituted with hydroxyl;
• or
• R1 and R2 together with the N to which each is attached, form a heterocyclic group selected from the group consisting of
• wherein
• Y is alkoxyalkyl, hydroxyalkyl, dialkylaminoalkyl or alkyl, further wherein Y′ is hydroxyl.