Heterocyclic N-Oxides as Hypoxic Selective Protein Kinase Inhibitors

A method for inhibiting the proliferation of cancer cells in a mammal, comprising administering to said mammal a therapeutically effective amount of a mono-N-oxide prodrug compound selected from the group consisting of compounds of the formulas I, II and III:

• Wherein:
• R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted, C1-C6 haloalkyl, C3-C10 cycloalkyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted, a 5- to 7-membered heterocyclic ring which is saturated or unsaturated and which may contain one or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom, C1-C6 alkoxy which is unsubstituted or substituted, C3-C10 cycloalkoxy which is unsubstituted or substituted, halogen, hydroxyl, —OR6, —SR6, —SO2R6, —SO2N(R6)2, —SO2N(R7)(R8), —N(R6)2, —N(R7)(R8), cyano, nitro, —COOR6, —C(O)N(R6)2, —C(O)N(R7)(R8), —N(R6)C(O)R6, —N(R6)COOR6, —N(R6)CON(R6)2, —N(R6)CON(R9)(R8), —N(R6)SO(R6), —N(R6)SO2(R6), —C(O)R6, —OCH2(CH2)pN(R6)2, —OCH2(CH2)pN(R7)(R8), —CH2(CH2)pN(R6)2, —CH2(CH2)pN(R7)(R8), C(O)NHCH2(CH2)pN(R6)2, —C(O)NHCH2(CH2)pN(R7)(R8), —NH(CH2)pN(R6)2, —NH(CH2)pN(R7)(R8), —NHC(O)CH2(CH2)pN(R7)(R8), —NHC(O)CH2(CH2)pN(R6)2, —(CH2)qC(O)R6, —OCH2CH2OR6, —O(CH2)qC(O)R6, —O(CH2)q(OCH2CH2)qOR6, XN(R6)2 or —X—N(R7)(R8)
• wherein X is a C1-C6 alkylidine group that is optionally interrupted by —O—, —S—, —C(O)— or —N(R6), and wherein
• R1 and R2 may form, together with the carbon atoms to which they are attached, a fused benzene ring or a fused 5- to 7-membered heterocyclic ring which is saturated or unsaturated and which may contain one or more heteroatoms selected from O, N, and S, the benzene ring or heterocyclic ring being unsubstituted or substituted;
• wherein R6 is H, C1-C6 alkyl which is unsubstituted or substituted, C3-C10 cycloalkyl which is unsubstituted or substituted, a 5- to 7-membered heterocyclic ring which is unsaturated or saturated and which contains one or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom, an aromatic or heteroaromatic ring optionally substituted by halogen, hydroxyl, —OR10, —SR10, —SO2R10, —SO2N(R10)2, —N(R10)2, —N(R7)(R8), cyano, nitro, —COOR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)COOR10, —N(R10)CON(R10)2, —N(R10)SO(R10), —N(R10)SO2(R10), —C(O)R10 and aromatic or heteroaromatic ring optionally substituted by two R10 that may be taken together to form a fused bicyclic system, and wherein more than one R6 attached to the same nitrogen atom is the same or different;
• R7 and R8 form, together with the N atom to which they are attached, a 3- to 9-membered N-containing heterocyclic ring which is unsaturated or saturated and which may contain one or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom;
• p is 0 or an integer from 1 to 5;
• q is an integer from 1 to 6;
• A and B are optionally and independently N or CR3
• wherein R3 is optionally H, NHR6, OR6, SR6, or selected from C1-C6 alkyl which is unsubstituted or substituted, C1-C6 alkoxy which is unsubstituted or substituted, C3-C10 cycloalkoxy which is unsubstituted or substituted, phenyl which is unsubstituted or substituted, halogen, hydroxyl, SOR6, SO2R6, SONHR6, NO2, cyano, N(R6)2, NHCON(R6)2 or NHCON(R7)(R8), COOR6, NR7R8 wherein each R6 is the same or different and wherein R3 groups on adjacent carbon atoms can, together with the carbon atoms to which they are attached, form an aromatic ring which may be substituted with one or more R6 groups;
• R4 is optionally H, NHR6, SR6, C1-C6 alkyl which is unsubstituted or substituted and which is optionally interrupted by —O—, —S—, —C(O)— or —N(R6)—, C3-C8 cycloalkyl which is unsubstituted or substituted, aryl which is unsubstituted or substituted or a 5- to 7-membered heterocyclic group which is unsaturated or saturated, which contains 1 or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom, or R4 and A, together with the C atoms to which they are attached, form a 5-membered N-containing heterocyclic ring, which is saturated or unsaturated and which may contain one or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom;
• and
• R10 is H or C1-C6 alkyl which is unsubstituted or substituted, C3-C10 cycloalkyl which is unsubstituted or substituted or a 5- to 7-membered heterocyclic ring which is unsaturated or saturated which contains one or more heteroatoms selected from O, N and S and which is unsubstituted or substituted on any ring carbon or ring heteroatom and wherein more than one R10 attached to the same nitrogen atom is the same or different;
• or a pharmaceutically acceptable salt of a compound of the Formulas (I), (II) or (III).