c-MET MODULATORS AND METHOD OF USE

A compound for modulating kinase activity according to Formula I,

• or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
• each of J1, J2, and J3 is independently selected from ═N—, ═C(R1)—, —N(R1)—, —O— and —S(O)0-2—;
• each R1 is independently selected from —H, halogen, trihalomethyl, —CN, —NO2, —OR20, —N(R20)R20—S(O)0-2R20, —SO2N(R20)R20, —CO2R20, —C(O)N(R20)R20, —N(R20)SO2R20, —N(R20)C(O)R20, —NCO2R20, —C(O)R20, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-6alkyl and -D-R50;
• R2 is selected from —H, halogen, —OR20, —S(O)0-2R20, —NO2, —N(R20)R20, and optionally substituted C1-6alkyl;
• J4 is selected from ═N—, ═C(H)—, and ═C(CN)—;
• Ar is either a five- or six-membered arylene or a five- or six-membered heteroarylene containing between one and three heteroatoms;
• each R3 is independently selected from —H, halogen, trihalomethyl, —CN, —NO2, —OR20, —N(R20)R20, —S(O)0-2R20, —SO2N(R20)R20, —CO2R20, —C(O)N(R20)R20, —N(R20)SO2R20, —N(R20)C(O)R20, —NCO2R20, —C(O)R20, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-6alkyl and a group —B-L-T, wherein
• B is selected from absent, —N(R13)—, —N(SO2R13)—, —O—, —S(O)0-2—, and —C(═O)—;
• L is selected from absent, —C(═S)N(R13)—, —C(═NR14)N(R13)—, —SO2N(R13)—, —SO2—, —C(═O)N(R13)—, —N(R13)—, —C(═O)C1-2alkylN(R13)—, —N(R13)C1-2alkylC(═O)—, —C(═O)C0-1alkylC(═O)N(R13)—, —C0-4alkylene-, —C(═O)C0-1alkylC(═O)OR3—, —C(═NR14)C0-1alkylC(═O)—, —C(═O)—, —C(═O)C0-1alkylC(═O)—, and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen;
• and
• T is selected from —H, —R13, —C0-4alkyl, —C0-4alkylQ, —OC0-4alkylQ, —C0-4alkylOQ, —N(R13)C0-4alkylQ, —SO2C0-4alkylQ, —C(═O)C0-4alkylQ, —C0-4alkylN(R13)Q, and —C(═O)N(R13)C0-4alkylQ,
• wherein each of the aforementioned alkyls and alkylenes of —B-L-T is optionally substituted with one or two of R60;
• Z is selected from, —S(O)0-2—, —O—, and —NR4—;
• R4 is either —H or optionally substituted C1-6alkyl;
• each D is independently selected from —O—, —S(O)0-2—, and —NR5—;
• each R5 is independently —H or optionally substituted C1-6alkyl;
• each R13 is independently selected from —H, —C(═O)R20, —C(═O)OR20, —C(═O)SR20, —SO2R20—C(═O)N(R20)R20, and optionally substituted C1-4alkyl;
• two of R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, said heteroalicyclic can comprise up to four annular heteroatoms, and said heteroalicyclic can comprise an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R60;
• each R14 is independently selected from —H, —NO2, —N(R20)R20, —CN, —OR20, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-6alkyl;
• Q is a five- to ten-membered annular system, optionally substituted with between zero and four of R20;
• each R50 is independently either R20, or according to formula II;
• wherein X1, X2, and optionally X3, represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X1, X2, and X3;
• wherein,
• each X1 is independently selected from —C(R6)R7—, —O—, —S(O)0-2—, and —NR8—;
• each X2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen;
• each X3 is independently selected from —C(R6)R7—, —O—, —S(O)0-2—, and —NR8—;
• Y is either:
• an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X2 when X2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R6 or R7;
• provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R6 or R7;
• or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is —SO2—, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system;
• m and p are each independently one to four;
• n is zero to two, when n equals zero there is a single bond between the two bridgehead X2 's;
• R6 and R7 are each independently selected from —H, halogen, trihalomethyl, —CN, —NO2, —OR20, —N(R20)R20, —S(O)0-2R20, —SO2N(R20)R20, —CO2R20, —C(O)N(R20)R20, —N(R20)SO2R20, —N(R20)C(O)R20, —NCO2R20, —C(O)R20, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-6alkyl, and a bond to either Y or D;
• or
• R6 and R7, when taken together are oxo;
• or
• R6 and R7, when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
• each R8 is independently selected from —R20, Y, —SO2N(R20)R20, —CO2R20, —C(O)N(R20)R20, —SO2R20, and —C(O)R20;
• each R20 is independently selected from —H, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C1-6alkyl;
• or two of R20, when taken together with a common nitrogen to which they are attached, can form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
• each R60 is independently selected from —H, halogen, trihalomethyl, —CN, —NO2, —OR20, —N(R20)R20, —S(O)0-2R20, —SO2N(R20)R20, —CO2R20, —C(O)N(R20)R20, —N(R20)SO2R20, —N(R20)C(O)R20, —N(R20)CO2R20, —C(O)R20, optionally substituted C1-6alkyl, optionally substituted aryl, optionally substituted aryl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-6alkyl;
• two of R60, when taken together with a common carbon to which they are attached, can form an optionally substituted three- to seven-membered alicyclic or heteroalicyclic;
• and
• two of R60, when taken together can be oxo.