Heterocyclic inhibitors of c-met and uses thereof

A compound having the formula:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• LA is selected from —C(O)NR4—, —C(S)NR4—, —S(O)2NR4—, —NR4C(O)—, —NR4C(S)—, —NR4S(O)2—, —NR4C(O)NR4—, —NR4C(S)NR4—, or —C(R4)2Q-, wherein Q is —NRS—, —O—, —S—, —S(O)—, or —S(O)2—;
• X is hydrogen, halogen, —OH, —OR5, —SR5, —CN, or —N(R5)2, or X together with C(R4)2 of LA forms a 5- or 6-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, or S;
• each of Y1 or Y2 is N or CH, wherein at least one of Y1 or Y2 must be N;
• Z is —S— or —CH═CH—;
• each R1 is, independently, hydrogen or C1-4 aliphatic, optionally substituted with substituents independently selected from halogen, —OH, —OR5, —SR5, —NO2, —CN, or —N(R5)2, or two R1 groups bonded to the same carbon form a 3-5 membered ring, optionally containing 1-2 atoms selected from N, O, or S;
• R2 is hydrogen, halogen, or C1-4 aliphatic, or R2 and R3, together with the carbons to which they are bonded, form a 6-membered aryl or 5-6 membered heteroaryl ring, wherein each ring is optionally substituted with up to two RAr1;
• R3 is a C1-8 aliphatic or C3-C8 cycloaliphatic group, optionally substituted with R;
• a 6 or 10 membered aryl;
• a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or a 3-10 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each of said aryl, heteroaryl, or heterocyclyl is optionally substituted with one to five RAr1, or R3 and R2, together form a 6-membered aryl or 5-6 membered heteroaryl ring, wherein each ring is optionally substituted with up to two RAr1;
• each R4 is, independently, hydrogen or a C1-4 aliphatic, optionally substituted with 1-5 groups independently selected from halogen, C1-4 aliphatic, halo(C1-4 aliphatic), OR5, O(halo(C1-4 aliphatic)), NO2, CN, CO2R5, C(O)N(R5)2, or N(R5)2;
• LB is a covalent bond between RB and the carbon to which LB is bonded, or is a saturated or unsaturated C1-4 alkylidene chain which is optionally substituted with 1-5 groups independently selected from halogen, C1-4 aliphatic, halo(C1-4 aliphatic), OR5, O(halo(C1-4 aliphatic)), NO2, CN, CO2R5, C(O)N(R5)2, or N(R5)2, wherein up to two saturated carbons of said alkylidene chain are replaced by —C(O)—, —C(O)N(R5)—, —C(O)N(R5)N(R5)—, —CO2—, —N(R5)—, —N(R5)C(O)—, —N(R5)CO2—, —N(R5)S(O)2—, —N(R5)C(O)N(R5)—, —N(R5)N(R5)—, —O—, —OC(O)—, —OC(O)N(R5)—, —S—, —SO—, —S(O)2—, or —S(O)2N(R5)—;
• RB is hydrogen, a C1-8 aliphatic, a C3-C8 cycloaliphatic group, optionally substituted with R;
• a 6 or 10 membered aryl ring;
• a 5-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or a 3-10 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein each of said aryl, heteroaryl, or heterocyclyl rings is optionally substituted with one to five RAr2;
• R is halogen, —R6, —OR6, —SR6, —OC(O)(C1-8 aliphatic), Ph optionally substituted with R6, —O(Ph) optionally substituted with R6, —CH2(Ph) optionally substituted with R6, —CH2CH2(Ph) optionally substituted with R6, —NO2, —CN, —N(R6)2, —NR6C(O)R6, —NR6C(O)N(R6)2, —NR6CO2R6, —NR6NR6C(O)R6, —NR6NR6C(O)N(R6)2, —NR6NR6CO2R6, —C(O)C(O)R6, —C(O)CH2C(O)R6, —OC2R6, —C(O)R6, —C(O)N(R6)2, —OC(O)N(R6)2, —S(O)2R6, —SO2N(R6)2, —S(O)R6, —NR6SO2N(R6)2, —NR6SO2R6, —C(═S)N(R6)2, —C(═NH)—N(R6)2, or —(CH2)yNHC(O)R6, wherein y is 1 to 4;
• or two R together on the same carbon atom are ═O, ═S, ═NNHR7, ═NN(R7)2, ═NNHC(O)R7, ═NNHCO2(C1-8 aliphatic), ═NNHSO2(C1-8 aliphatic), or ═NR7;
• each RAr1 or RAr2 is, independently, selected from halogen, —R6, —OR6, —SR6, Ph optionally substituted with one to five R6, —O(Ph) optionally substituted with one or more R6, —(CH2)y(Ph) optionally substituted with one to five R6, —NO2, —CN, —N(R6)2, —NR6C(O)R6, —NR6C(O)N(R6)2, —NR6NR6NR6NR—C(O)CH2C(O)R6, —CO2R6, —C(O)R6, —C(O)N(R6)2, —OC(O)N(R6)2, —S(O)2R6, —SO2N(R6)2, —S(O)R6, —NR6SO2N(R6)2, —NR6SO2R6, —C(S)N(R6)2, —C(NH)N(R6)2, and —(CH2)yNHC(O)R6, wherein y is 1 to 4;
• or two adjacent RAr1 or RAr2 together are 1,2-methylenedioxy or 1,2-ethylenedioxy;
• each R5 is, independently, hydrogen or C1-4 aliphatic;
• each R7 is, independently, hydrogen or an optionally substituted C1-8 aliphatic, wherein each substituent of said optionally substituted aliphatic of R7 is, independently, —NH2, —NH(C1-4 aliphatic), —N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, —OH, —O(C1-4 aliphatic), —NO2, —CN, —CO2H, —OC2(C1-4 aliphatic), —C(O)NH2, —C(O)NH(C1-4 aliphatic), —C(O)N(C1-4 aliphatic)2, —O(halo(C1-4 aliphatic)), or halo(C1-4 aliphatic);
• or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• each R6 is, independently, hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, -Ph, or —O(Ph), wherein each substituent of said optionally substituted aliphatic of R6 is, independently, —NH2, —NH(C1-4 aliphatic), —N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, —OH, —O(C1-4 aliphatic), —NO2, —CN, —CO2H, —OC2(C1-4aliphatic), —C(O)NH2, —C(O)NH(C1-4 aliphatic), —C(O)N(C1-4aliphatic)2, —O(halo(C1-4 aliphatic)), or halo(C1-4 aliphatic);
• or two R6 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.