Compounds for the treatment of proliferative disorders

A method of treating leukemia, sarcoma, melanoma, or breast carcinoma, in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIIB):

• or a pharmaceutically acceptable salt thereof, wherein:
• one of Rk or R1 is —H and the other is
• ring E is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkylsulfanyl, an optionally substituted alkylamino, an optionally substituted dialkylamino, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, —C(O)NR34R35, —NR36C(O)R37, halo, —OR36, cyano, nitro, haloalkoxy, —C(O)R36, —NR34R35, —SR36, —C(O)OR36, —OC(O)R36, —NR36C(O)NR34R35, —NR36C(N—R38)NR34R35, —OC(O)NR34R35, —NR36C(O)OR37, —OP(O)(OR36)2, —SP(O)(OR36)2, —OS(O)2(OR36), —S(O)pR36, or —S(O)pNR34R35;
• R34 and R35, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R34 and R35 taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• R36 and R37 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R38 is H, an optionally substituted alkyl, —C(O)R36, —C(O)OR36, or an optionally substituted aralkyl;
• Rw is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR7)2, —SP(O)(OR7)2, nitro, an alkyl ester, or hydroxyl;
• and
• R7, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl.

A method of inhibiting tubulin polymerization in a cell, comprising contacting the cell with an effective amount of a compound represented by formula (VIIA):

• or a pharmaceutically acceptable salt thereof, wherein:
• one of Rk or R1 is —H and the other is
• Ring E is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkylsulfanyl, an optionally substituted alkylamino, an optionally substituted dialkylamino, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, —C(O)NR34R35, —NR36C(O)R37, halo, —OR36, cyano, nitro, haloalkoxy, —C(O)R36, —NR34R35, —SR36, —C(O)OR36, —OC(O)R36, —NR36C(O)NR34R35, —NR36C(N—R38)NR34R35, —OC(O)NR34R35, —NR36C(O)OR37, —OP(O)(OR36)2, —SP(O)(OR36)2, —OS(O)2(OR36), —S(O)pR36, or —S(O)pNR34R35;
• Rx is—(C(O)—CHR—NH)mH, —C(O)—CHR—NH—C(O)(CH2)nC(O)OH, —C(O)(CH2)—C(O)OH, —C(O)YRz, —C(O)NH—C(O)—CHR—NH2, or -(C(O)—CHR—NH)qC(O)(Y1);
• R is a side chain of a naturally-occurring amino acid;
• an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted aromatic group, or an optionally substituted heteroaromatic group;
• Ry is —H or lower alkyl;
• Rw is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR7)2, —SP(O)(OR7)2, nitro, an alkyl ester, or hydroxyl;
• R7, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R34 and R35, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R34 and R35 taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• R36 and R37 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R38 is H, an optionally substituted alkyl, —C(O)R36, —C(O)OR36, or an optionally substituted aralkyl;
• Y is CH2, O, or NH;
• Rz is Alk-NH2, Alk-C(O)OH, Het, or Y1;
• Alk is an optionally substituted alkylene;
• Het is an optionally substituted heteroalkyl;
• Y1 is polyethyleneglycol (PEG), hydroxypropyl methacrylate (HPMA) copolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or hydroxypropyl methacrylate (HPMA) copolymer-methacryloyl-Gly-Phe-Leu-Gly-OH;
• n is 1, 2, 3, or 4;
• m is an integer from 1 to 10;
• and
• q is 0 or 1.

A method of inhibiting tubulin polymerization in a subject, comprising administering to the subject an effective amount of a compound represented by formula (VIIA):

• or a pharmaceutically acceptable salt thereof, wherein:
• one of Rk or R1 is —H and the other is
• Ring E is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkylsulfanyl, an optionally substituted alkylamino, an optionally substituted dialkylamino, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, —C(O)NR34R35, —NR36C(O)R37, halo, —OR36, cyano, nitro, haloalkoxy, —C(O)R36, —NR34R35, —SR36, —C(O)OR36, —OC(O)R36, —NR36C(O)NR34R35, —NR36C(N—R38)NR34R35, —OC(O)NR34R35, —NR36C(O)OR37, —OP(O)(OR36)2, —SP(O)(OR36)2, —OS(O)2(OR36), —S(O)pR36, or —S(O)pNR34R35;
• Rx is—(C(O)—CHR—NH)mH, —C(O)—CHR—NH—C(O)(CH2)nC(O)OH, —C(O)(CH2)nC(O)OH, —C(O)YRz, —C(O)NH—C(O)—CHR—NH2, or -(C(O)—CHR—NH)qC(O)(Y1);
• R is a side chain of a naturally-occurring amino acid;
• an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted aromatic group, or an optionally substituted heteroaromatic group;
• Ry is —H or lower alkyl;
• Rw is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR7)2, —SP(O)(OR7)2, nitro, an alkyl ester, or hydroxyl;
• R7, for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R34 and R35, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• or R34 and R35 taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• R36 and R37 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
• R38 is H, an optionally substituted alkyl, —C(O)R36, —C(O)OR36, or an optionally substituted aralkyl;
• Y is CH2, O, or NH;
• Rz is Alk-NH2, Alk-C(O)OH, Het, or Y1;
• Alk is an optionally substituted alkylene;
• Het is an optionally substituted heteroalkyl;
• Y1 is polyethyleneglycol (PEG), hydroxypropyl methacrylate (HPMA) copolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or hydroxypropyl methacrylate (HPMA) copolymer-methacryloyl-Gly-Phe-Leu-Gly-OH;
• n is 1, 2, 3, or 4;
• m is an integer from 1 to 10;
• and
• q is 0 or 1.