Antiproliferative 2-(sulfo-phenyl)-aminothiazole derivatives and pharmaceutical compositions, and methods for their use

A compound of Formula (II):

• 763
• wherein:
• R4 is a moiety selected from the group consisting of C2-C14 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl and 3-10 membered heteroaryl, wherein R4 is unsubstituted or substituted with 1 to 4 R10 groups;
• R5 is a moiety selected from the group consisting of hydroxyl, halo, C1-14 alkyl, C1-C14 alkoxyl, acyl, amide and nitro;
• R5′ and R5″ are independently selected from hydrogen, hydroxyl, halo, C1-14 alkyl, C1-C14 alkoxyl, acyl, amide, amino, acetamido and nitro;
• R6 is a group selected from the following formulae:
• 764
• wherein:
• R8 is hydrogen, C1-3 alkyl, C3-C10 cycloalkyl, or C1-C14 alkoxyl;
• R8′ is an C3-C14 alkyl, 2-9 membered heteroalkyl, acyl, C1-C3 alkyl-nitrile, C1-C3 alkyl-carboxamide, C1-C4 alkyl-heterocycloalkyl, C1-C4 alkyl-aryl, C1-C4 alkyl-heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl or 3-10 membered heteroaryl, or together with R8 cyclizes to form a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl or 3-10 membered heteroaryl, with the proviso that R6 is not
• 765
• and wherein R8′ is unsubstituted or substituted with 1 to 4 R10 groups;
• R9 is hydrogen, or a moiety selected from the group consisting of an C1-C9 alkyl, C2-C9 alkenyl, 2-9 membered heteroalkenyl, C1-C9 alkylamide, C1-C9 alkyl-carboxamide, 2-9 membered heteroalkyl, C1-C4 alkyl-cycloalkyl, C1-C4 alkyl-heterocycloalkyl, C1-C4 alkyl-aryl, C1-C4 alkyl-heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl and 3-10 membered heteroaryl, with the proviso that R6 is not
• 766
• wherein R9 is unsubstituted or substituted with 1 to 4 R10 groups;
• R7 is a moiety selected from the group consisting of hydrogen, hydroxyl, halo, C1-C14 alkyl, C1-C14 alkoxyl, acyl, amide and nitro;
• wherein each R10 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxyl, C1-C6 alkoxyl, C, C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)Ra, —C(O)ORb, —OC(O)Rb, —NRbC(O)Rc, —C(O)NRbRc, —NRbRc, —NRbORc, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)t(4-10 membered heteroaryl), —(CRdRe)qC(O)(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)qC(O)(CRdRe)t(aryl), —(CRdRe)qC(O)(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)qC(O)(CRdRe)t(4-10 membered heteroaryl), —(CRdRe)tO(CRdRe)q(C3-C10 cycloalkyl), —(CRdRe)tO(CRdRe)q(aryl), —(CRdRe)tO(CRdRe)q(4-10 membered heterocycloalkyl), —(CRdRe)tO(CRdRe)q(4-10 membered heteroaryl), —(CRdRe)qSO2(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)qSO2(CRdRe)t(aryl), and —(CRdRe)qSO2(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)qSO2(CRdRe)t(4-10 membered heteroaryl), wherein Ra is selected from the group consisting of halo, hydroxyl, —NRdRe C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxyl, and trifluoromethoxy, Rb and Rc are independently selected from H, C1-C6 alkyl, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), and
• —(CRdRe)t(4-10 membered heteroaryl), wherein q and t are each independently an integer from 0 to 5, Rd and Re are independently H or C1-C6 alkyl, wherein 1 or 2 ring carbon atoms of the heterocyclic and heteroaryl moieties of the foregoing R10 groups are unsubstituted or substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic and heteroaryl moieties of the foregoing R10 groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —ORb, —C(O)Rb, —C(O)ORb, —NRbC(O)Rc, —C(O)NRbRc, —NRbRc, —NRbORc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), and
• —(CRdRe)t(4-10 membered heteroaryl);
• wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methane) group which is not attached to a halogeno, SO or SO2 group or to a N, O, or S is unsubstituted or substituted with a substituent from the group selected from hydroxyl, halo, C1-C4 alkyl, C1-C4 alkoxy and —NRdRe wherein Rd and Re are as defined above;
• and wherein Ph means phenyl;
• or a pharmaceutically acceptable salt of a compound of the Formula (I), or a multimer, prodrug or pharmaceutically active metabolite of a compound of the Formula (I) or pharmaceutically acceptable salt thereof.

A compound of Formula (IV):

• 770
• wherein:
• R3 is a monocycle selected from the group consisting of C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl and 3-10 membered heteroaryl;
• R4 is a moiety selected from the group consisting of substituted or unsubstituted C2-C14 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl and 3-10 membered heteroaryl;
• R5 is a moiety selected from the group consisting of hydroxyl, halo, C1-C14 alkyl, C1-C14alkoxyl, acyl, amide and nitro;
• R5′ and R5″ are independently selected from hydrogen, hydroxyl, halo, C1-14 alkyl, C1-C14 alkoxyl, acyl, amide, amino, acetamido and nitro;
• R7 is a moiety selected from the group consisting of hydrogen, hydroxyl, halo, C1-C14 alkyl, C1-C14 alkoxyl, acyl, amide and nitro;
• R8 is hydrogen, C1-C3 alkyl, C3-C10 cycloalkyl, or C1-C14 alkoxyl;
• R8′ is an C3-14 alkyl, 2-9 membered heteroalkyl, acyl, C1-3 alkyl-nitrile, C1-3 alkyl-carboxamide, C1-4 alkyl-heterocycloalkyl, C1-4 alkyl-aryl, CIA alkyl-heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl or 3-10 membered heteroaryl, or together with R8 cyclizes to form a C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl or 3-10 membered heteroaryl, with the proviso that R6 is not
• 771
• and wherein R is unsubstituted or substituted with 1 to 4 R10 groups;
• R9 is hydrogen, or a moiety selected from the group consisting of an C1-9 alkyl, C2-9 alkenyl, 2-9 membered heteroalkenyl, C1-9 alkylamide, C1-9 alkyl-carboxamide, 2-9 membered heteroalkyl, C1-4 alkyl-cycloalkyl, C1-4 alkyl-heterocycloalkyl, C1-4 alkyl-aryl, C1-4 alkyl-heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, aryl and 3-10 membered heteroaryl, with the proviso that R6 is not
• 772
• wherein R9 is unsubstituted or substituted with 1 to 4 R10 groups;
• R7 is a moiety selected from the group consisting of hydrogen, hydroxyl, halo, C1-C14 alkyl, C1-C14 alkoxyl, acyl, amide and nitro;
• wherein each R10 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxyl, C1-C6 alkoxyl, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —C(O)R8, —C(O)ORb, —OC(O)Rb, —NRbC(O)Rc, —C(O)NRbRc, —NRbRc, —NRbORc, —S(O)j(C1-C6 alkyl) wherein j is an integer from 0 to 2, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)t(4-10 membered heteroaryl), —(CRdRe)qC(O)(CRdRe)t(C3-C10 cycloalkyl), —(C RdRe)qC(O)(CRdRe)t(aryl), —(CRdRe)qC(O)(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)qC(O)(CRdRe)t(4-10 membered heteroaryl), —(CRdRe)tO(CRdRe)q(C3-C10 cycloalkyl), —(CRdRe)tO(CRdRe)q(aryl), —(CRdRe)tO(CRdRe)q(4-10 membered heterocycloalkyl), —(CRdRe)tO(CRdRe)q(4-10 membered heteroaryl), —(CRdRe)qSO2(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)qSO2(CRdRe)t(aryl), and —(CRdRe)qSO2(CRdRe)t(4-10 membered heterocycloalkyl), —(CRdRe)qSO2(CRdRe)t(4-10 membered heteroaryl), wherein Ra is selected from the group consisting of halo, hydroxyl, —NRdRe C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxyl, and trifluoromethoxy, Rb and Rc are independently selected from H, C1-C6 alkyl, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), and
• —(CRdRe)t(4-10 membered heteroaryl), wherein q and t are each independently an integer from 0 to 5, Rd and Re are independently H or C1-C6 alkyl, wherein 1 or 2 ring carbon atoms of the heterocyclic and heteroaryl moieties of the foregoing R10 groups are unsubstituted or substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic and heteroaryl moieties of the foregoing R10 groups are unsubstituted or substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —ORb, —C(O)Rb, —C(O)ORb, —NRbC(O)Rc, —C(O)NRbRc, —NRbRc, —NRbORc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CRdRe)t(C3-C10 cycloalkyl), —(CRdRe)t(aryl), —(CRdRe)t(4-10 membered heterocycloalkyl), and
• —(CRdRe)t(4-10 membered heteroaryl);
• and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methane) group which is not attached to a halogeno, SO or SO2 group or to a N, O, or S is unsubstituted or substituted with a substituent from the group selected from hydroxyl, halo, C1-C4 alkyl, C1-C4 alkoxy and —NRdRe wherein Rd and Re are as defined above;
• or a pharmaceutically acceptable salt of a compound of the Formula (I), or a multimer, prodrug or pharmaceutically active metabolite of a compound of the Formula (I) or pharmaceutically acceptable salt thereof.