Thiazole benzamide derivatives and pharmaceutical compositions for inhibiting cell proliferation, and methods for their use

A compound represented by Formula (I):

• 659
• wherein:
• R1and R2 are each independently hydrogen, or an alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, amino alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —NO2, —NH2, —N—OH, N—ORc, —CN, —(CH2)z—CN where z is 0-4, halogen, —OH, —O—Ra—O—, —ORb, —CO—Rc, O—CO—Rc, —CO—ORc, —O—CO—ORc, —O—CO—O—CO—Rc, —O—ORc, ═O, ═S, SO2—Rc, —SO—Rc, —NRdRe, —CO—NRdRe, —O—CO—NRdRe, —NRc—CO—NRdRe, —NRc—CO—Re, NRc—CO—ORc, —CO—NRc—CO—Rd, —O—SO2—Rc, —O—SO—Rc, —O—S—Rc, —S—CO—Rc, —SO—CO—ORc, —SO2—CO—ORc, —O—SO3, —NRc—SRd, —NRc—SO—Rd, NRc—SO2—Rd, —CO—SRc, —CO—SO—Rc, CO—SO2—Rc, —CS—Rc, —CSO—Rc, —CSO2—Rc, —NRc—CS—Rd, —O—CS—Rc, —O—CSO—Rc, O—CSO2—Rc, —SO2—NRdRe, —SO—NRdRe, —S—NRdRe, —NRd—CSO2—Rd, —NRc—CSO—Rd, NRc—CS—Rd, —SH, —S—Rb, and —PO2—ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, —CO—Rc, —CO—ORc, —O—CO—O—Rc, —O—CO—Rc, —NRc—CO—Rd, —CO—NRdRe, —OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, —CORf, —COORf, —O—CO—O—Rf, —O—CO—Rf, —OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, —NH2, —CN, —(CH2)z—CN where z is 0-4, halogen, haloalkyl, haloaryl, —OH, ═O, —N—OH, N—ORc—NRdRe, —CO—NRdRe, —CO—ORc, —CO—Rc, —NRc—CO—NRdRe, —C—CO—ORc, —NRc—CO—Rd, —O—CO—O—Rc, O—CO—NRdRe, —SH, —O—Rb, —O—Ra—O—, —S—Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above, where R1and R2 are not both hydrogen;
• or
• R1 or R2, together with the
• 660
• and two adjacent carbon atoms of the phenyl ring of Formula (I), forms a 5- or 6-membered ring structure fused to the phenyl ring of Formula (I) and unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —NO2, —NH2, —N—OH, N—ORc, —CN, —(CH2), —CN where z is 0-4, halogen, —OH, —O—Ra—O—, —ORb, —CO—Rc, O—CO—Rc, —CO—ORc, —O—CO—ORc, —O—CO—O—CO—Rc, —O—ORc, ═O, ═S, —SO2—Rc, —SO—Rc, —NRdRe, —CO—NRdRe, —O—CO—NRdRe, —NRc—CO—NRdRe, —NRc—CO—Rc, —NRc—CO—ORe, —CO—NRc—CO—Rd, —O—SO2—Rc, —O—SO—Rc, —O—S—Rc, —S—CO—Rc, —SO—CO—ORc, —SO2—CO—ORc, —O—SO3, —NRc—SRd, —NRc-SO—Rd, NRc—SO2—Rd, —CO—SRc, —CO—SO—Rc, —CO—SO2—Rc, —CS—Rc, —CSO—Rc, —CSO2—Rc, —NRc—CS—Rd, —O—CS—Rc, —O—CSO—Rc, —O—CSO2—Rc, —SO2—NRdRe, —SO—NRdRe, —S—NRdRe, —NRd—CSO2—Rd, —NRc—CSO—Rd, —NRc—CS—Rd, —SH, —S—Rb, and —PO2—ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, —CO—Rc, —CO—ORc, —O—CO—O—Rc, —O—CO—Rc, —NRc—CO—Rd, —CO—NRdRc, —OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, and Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, —CORf, —COORf, —O—CO—O—Rf, —O—CO—Rf, —OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, —NH2, —CN, —(CH2)z—CN where z is 0-4, halogen, haloalkyl, haloaryl, —OH, ═O, —N—OH, N—ORc, —NRdRe, —CO—NRdRe, —CO—ORc, —CO—Rc, —NRc—CO—NRdRe, —C—CO—ORc, —NRc—CO—Rd, —O—CO—O—Rc, O—CO—NRdRe, —SH, —O—Rb, —O—Ra—O—, —S—Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are as defined above;
• or
• R1and R2, taken together with the nitrogen atom to which they are bonded, form a monocyclic or fused or non-fused polycyclic structure which may contain one to three additional heteroatoms, the structure being unsubstituted or substituted with one or more substituents selected from the group consisting alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —NO2, —NH2, —N—OH, N—ORc, —CN, —(CH2)z—CN where z is 0-4, halogen, —OH, —O—Ra—O—, —ORb, —CO—Rc, —O—CO—Rc, CO—ORc, —O—CO—ORc, —O—CO—O—CO—Rc, —ORc, ═O, ═S, —SO2—Rc, —SO—Rc, —NRdRe, —CO—NRdRe, —O—CO—NRdRe, —NRc—CO—NRdRe, —NRc—CO—Re, —NRc—CO—ORe, —CO—NRc—CO—Rd, —O—SO2—Rc, —O—SO—Rc, —O—S—Rc, —S—CO—Rc, —SO—CO—ORc, —SO2—CO—ORc, —O—SO3, —NRc—SRd, —NRc—SO—Rd, NRc—SO2—Rd, —CO—SRc, —CO—SO—Rc, —CO—SO2—Rc, —CS—Rc, —CSO—Rc, —CSO2—Rc, —NRc—CS—Rd, —O—CS—Rc, —O—CSO—Rc, —O—CSO2—Rc, —SO2—NRdRe, —SO—NRdRe, —S—NRdRe, —NRd—CSO2—Rd, —NRc—CSO—Rd, —NRc—CS—Rd, —SH, —S—Rb, and —PO2—ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, —CO—Rc, —CO—ORc, —O—CO—O—Rc, —O—CO—Rc, —NRc—CO—Rd, —CO—NRdRe, —OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, —CORf, —COORf, —O—CO—O—Rf, —O—CO—Rf, —OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, —NH2, —CN, —(CH2)z—CN where z is 0-4, halogen, haloalkyl, haloaryl, —OH, ═O, —N—OH, N—ORc, —NRdRe, —CO—NRdRe, —CO—ORc, —CO—Rc, —NRc—CO—NRdRe, —C—CO—ORc, —NRc—CO—Rd, —O—CO—O—Rc, O—CO—NRdRe, —SH, —O—Rb, —O—Ra—O—, —S—Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above;
• R3 is an aryl, heteroaryl, alkyl, or cycloalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —NO2, —NH2, —N—OH, N—ORc, —CN, —(CH2)z—CN where z is 0-4, halogen, —OH, —O—Ra—O—, —ORb, —CO—Rc, —O—CO—Rc, —CO—ORc, —O—CO—ORc, —O—CO—O—CO—Rc, —O—ORc, ═O, ═S, —SO2—Rc, —SO—Rc, —NRdRe, —CO—NRdRe, —CO—NRdRe, —NRc—CO—NRdRe, —NRc—CO—Rc, —NRc—CO—ORc, —CO—NRc—CO—Rd, —O—SO2—Rc, —O—SO—Rc, —O—S—Rc, —S—CO—Rc, —SO—CO—ORc, —SO2—CO—ORc, —O—SO3, —NRc—SRd, —NRc—SO—Rd, NRc—SO2—Rd, —CO—SRc, —CO—SO—Rc, —CO—SO2—Rc, —CS—Rc, —CSO—Rc, —CSO2—Rc, —NRc, —CS—Rd, —O—CS—Rc, —O—CSO—Rc, —O—CSO2—Rc, —SO2—NRdRe, —SO—NRdRe, —S—NRdRe, —NRd—CSO2—Rd, —NRc—CSO—Rd, —NRc—CS—Rd, —SH, —S—Rb, and —PO2—ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, —CO—Rc, —CO—ORc, —O—CO—O—Rc, —O—CO—Rc, —NRc—CO—Rd, —CO—NRcRe, —OH, Ar, heteroaryl, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, —CORf, —COORf, —O—CO—O—Rf, —O—CO—Rf, —OH, Ar, heteroaryl, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl, and where any of the alkyl, heteroalkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents may be further substituted with one or more substituents independently selected from the group consisting of NO2, —NH2, —CN, —(CH2)z—CN where z is 0-4, halogen, haloalkyl, haloaryl, —OH, ═O, —N—OH, N—ORc, —NRdRe, —CO—NRdRe, —CO—ORc, —CO—Rc, —NRc—CO—NRdRe, —C—CO—ORc, —NRc—CO—Rd, —O—CO—O—Rc, O—CO—NRdRe, —SH, —O—Rb, —O—Ra—O—, —S—Rb, and unsubstituted alkyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, where Ra, Rb, Rc, Rd, and Re are defined above;
• and
• Y is hydrogen, alkyl, heteroalkyl, haloalkyl, halocycloalkyl, haloheterocycloalkyl, cycloalkyl, heterocycloalkyl, —NO2, —NH2, —N—OH, N—ORc, —CN, —(CH2)z—CN where z is 0-4, halogen, —OH, —O—Ra—O—, —ORb, —CO—Rc, —O—CO—Rc, —CO—ORc, —O—CO—ORc, —O—ORc, ═O, ═S, —NRdRe, —CO—NRdRe, —O—CO—NRdRe, —NRc—CO—Re, —NRc—O—ORc, —CO—NRc—CO—Rd, —O—SO2—Rc, —O—SO—Rc, —O—S—Rc, —S—CO—Rc, —SO—CO—ORc, —SO—CO—ORc, —O—SO3, —NRc—SRd, —NRc—SO—Rd, NRc—SO2—Rd, —CO—SRc, —CO—SO—Rc, —CO—SO2—Rc, —CS—Rc, —CSO—Rc, —CSO2—Rc, —NRc—CS—Rd, —O—CS—Rc, —O—CSO—Rc, —O—SO2—Rc, —SO2—NRdRe, —SO—NRdRe, —S—NRdRe, —NRc—CSO2—Rd, —NRc—CSO—Rd, —NR, —CS—Rd, —SH, —S—Rb, and —PO2—ORc, where Ra is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and alkynyl, Rb is selected from the group consisting of alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, halogen, —CO—Rc, —CO—ORc, —O—CO—O—Rc, O—CO—Rc, —NRc—CO—Rd, —CO—NRdRe, —OH, heterocycloalkyl, and cycloalkyl, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, —CORf, —COORf, —O—CO—O—Rf, —O—CO—Rf, —OH, cycloalkyl, and heterocycloalkyl, where Rd and Re can cyclize to form a heteroaryl or heterocycloalkyl group, and Rf is selected from the group consisting of hydrogen, alkyl, and heteroalkyl;
• or a pharmaceutically acceptable salt of said compound, pharmaceutically acceptable prodrug of said compound, pharmaceutically active metabolite of said compound, or pharmaceutically acceptable salt of said metabolite.