Methods of Treatment

A method of treating a warm-blooded animal having acute myeloid leukemia (AML), comprising administering to said animal a therapeutically effective amount of a compound according to formula (III):

• or pharmaceutically acceptable salts thereof, wherein
• R1 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C10 cycloalkyl, which R1 may be unsubstituted or substituted;
• R2 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl which R2 may be unsubstituted or substituted;
• R3 is H, CF3, C2F5, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CH2—Z or R2 and R3 taken together with the nitrogen atom to which they are attached form a heterocyclic ring, which alkyl, alkenyl, alkynyl or het ring may be unsubstituted or substituted;
• Z is H, OH, F, Cl, CH3, CH2Cl, CH2F or CH2OH;
• R4 is C0-10 alkyl, C3-C10 cycloalkyl, wherein the C0-10 alkyl, or cycloalkyl group is unsubstituted or substituted;
• A is het, which may be substituted or unsubstituted;
• D is C1-C7 alkylene or C2-C9 alkenylene, C(O), O, NR7, S(O)r, C(O)—C1-C10 alkyl, O—C1-C10 alkyl, S(O)r-C1-C10 alkyl, C(O)C0-C10 arylalkyl OC0-C10 arylalkyl, or S(O)r C0-C10 arylalkyl, which alkyl and aryl groups may be unsubstituted or substituted;
• r is 0, 1, or 2;
• A1 is a substituted aryl or unsubstituted or substituted het which substituents on aryl and het are halo, lower alkoxy, NR5R6, CN, NO2 or SR5;
• each Q is independently H, C1-C10 alkyl, C1-C10 alkoxy, aryl C1-C10 alkoxy, OH, O—C1-C10-alkyl, (CH2)0-6—C3-C7 cycloalkyl, aryl, aryl C1-C10 alkyl, O—(CH2)0-6 aryl, (CH2)1-6het, het, O—(CH2)1-6het, —OR11, C(O)R11, —C(O)N(R11)(R12), N(R11)(R12), SR11, S(O)R11, S(O)2R11, S(O)2—N(R11)(R12), or NR11—S(O)2—(R12), wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted;
• n is 0, 1, 2 or 3, 4, 5, 6 or 7;
• het is a 5-7 membered monocyclic heterocyclic ring containing 1-4 heteroring atoms selected from N, O and S or an 8-12 membered fused ring system that includes one 5-7 membered monocyclic heterocyclic ring containing 1, 2, or 3 heteroring atoms selected from N, O and S, which het is unsubstituted or substituted;
• R11 and R12 are independently H, C1-C10 alkyl, (CH2)0-6—C3-C7cycloalkyl, (CH2)0-6—(CH)0-1(aryl)1-2, C(O)—C1-C10alkyl, —C(O)—(CH2)1-6—C3-C7cycloalkyl, —C(O)—O—(CH2)0-6-aryl, —C(O)—(CH2)0-6—O-fluorenyl, C(O)—NH—(CH2)0-6-aryl, C(O)—(CH2)0-6-aryl, C(O)—(CH2)1-6-het, —C(S)—C1-C10alkyl, —C(S)—(CH2)1-6—C3-C7cycloalkyl, —C(S)—O—(CH2)0-6-aryl, —C(S)—(CH2)0-6—O-fluorenyl, C(S)—NH—(CH2)0-6-aryl, —C(S)—(CH2)0-6-aryl or C(S)—(CH2)1-6-het, C(O)R11, C(O)NR11R12, C(O)OR11, S(O)nR11, S(O)mNR11R12, m=1 or 2, C(S)R11, C(S)NR11R12, C(S)OR11, wherein alkyl, cycloalkyl and aryl are unsubstituted or substituted;
• or R11 and R12 are a substituent that facilitates transport of the molecule across a cell membrane;
• or R11 and R12 together with the nitrogen atom form het;
• wherein the alkyl substituents of R11 and R12 may be unsubstituted or substituted by one or more substituents selected from C1-C10alkyl, halogen, OH, O—C1-C6alkyl, —S—C1-C6alkyl, CF3 or NR11R12;
• substituted cycloalkyl substituents of R11 and R12 are substituted by one or more substituents selected from a C2-C10 alkene;
• C1-C6alkyl;
• halogen;
• OH;
• O—C1-C6alkyl;
• S—C1-C6alkyl, CF3;
• or NR11R12 and
• substituted het or substituted aryl of R11 and R12 are substituted by one or more substituents selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN O—C(O)—C1-C4alkyl and C(O)—O—C1-C4-alkyl;
• R5, R6 and R7 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, and
• wherein the substituents on R1, R2, R3, R4, Q, and A and A1 groups are independently halo, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower alkoxy, aryl, aryl lower alkyl, amino, amino lower alkyl, diloweralkylamino, lower alkanoyl, amino lower alkoxy, nitro, cyano, cyano lower alkyl, carboxy, lower carbalkoxy, lower alkanoyl, aryloyl, lower arylalkanoyl, carbamoyl, N-mono- or N,N-dilower alkyl carbamoyl, lower alkyl carbamic acid ester, amidino, guanidine, ureido, mercapto, sulfo, lower alkylthio, sulfoamino, sulfonamide, benzosulfonamide, sulfonate, sulfanyl lower alkyl, aryl sulfonamide, halogen substituted aryl sulfonate, lower alkylsulfinyl, arylsulfinyl;
• aryl-lower alkylsulfinyl, lower alkylarylsulfinyl, lower alkylsulfonyl, arylsulfonyl, aryl-lower alkylsulfonyl, lower aryl alkyl lower alkylarylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, phosphono(—P(═O)(OH)2), hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, (R9)NC(O)—NR10R13, lower alkyl carbamic acid ester or carbamates or —NR8R14, wherein R8 and R14 can be the same or different and are independently H or lower alkyl, or R8 and R14 together with the N atom form a 3- to 8-membered heterocyclic ring containing a nitrogen heteroring atoms and may optionally contain one or two additional heteroring atoms selected from nitrogen, oxygen and sulfur, which heterocyclic ring may be unsubstituted or substituted with lower alkyl, halo, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, nitro, amino, lower alkyl, amino, diloweralkyl amino, cyano, carboxy, lower carbalkoxy, formyl, lower alkanoyl, oxo, carbarmoyl, N-lower or N,N-dilower alkyl carbamoyl, mercapto, or lower alkylthio, and
• R9, R10, and R13 are independently hydrogen, lower alkyl, halogen substituted lower alkyl, aryl, aryl lower alkyl, halogen substituted aryl, halogen substituted aryl lower alkyl.