Inhibitors of c-Met and uses thereof

A compound having the formula:

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• W is —S—, —C(RC)═C(RC)—, or —C(R++)2S—;
• LA is a C1-2 alkylene, optionally substituted with 1-4 RLA, wherein one or both carbons of said alkylene are optionally replaced with —O—, —N(R++)—, —S—, —S(O)—, or —S(O)2—;
• and each RLA is, independently, selected from —OR++, —O(halo(C1-4 aliphatic)), —SR++, or C1-4aliphatic, each of which is optionally substituted with up to three substituents independently selected from halogen, —OH, —OR++, —SR++, —NO2, —CN, —N(R++)2;
• or two RLA together on the same carbon atom are ═O, ═S, ═NN(R++)2, ═NNHC(O)(R++), ═NNHC(O)OR++, ═NNHS(O)2(R++), or ═N(R++);
• or two RLA together on the same carbon atom form a C3-5 cycloalkyl, an ethylenedioxo, or an ethylenedithio;
• RA is selected from:
• each of RA2 and RA6 is, independently, selected from hydrogen, halogen, —CN, —C(O)OR++, —C(O)R++, —C(O)N(R++)2, —C(S)N(R++)2, —C(NH)N(R++)2, —OR++, —O(halo(C1-4 aliphatic)), —OC(O)N(R++)2, —SR++, —NO2, —N(R++)2, —N(R++)C(O)(R++), —N(R++)C(O)N(R++)2, —N(R++)C(O)OR++, —N(R++)N(R++)C(O)R++, —N(R)N(R++)C(O)N(R++)2, —N(R++)N(R++)C(O)OR, —N(R++)S(O)2N(R++)2, —N(R++)S(O)2R++, —S(O)2R++, —S(O)2N(R++)2, —S(O)R++, and C1-4 aliphatic optionally substituted with substituents independently selected from halogen, —OR++, —SR++, —NO2, —CN, —N(R++)2, or —N(R++)C(O)(R++);
• RA3 is RAr;
• or RA3, RA4 and the carbons to which they are bonded form a 6 membered aryl optionally substituted with up to 4 independent occurrences of RAr, or a 5-6 membered heterocyclyl or heteroaryl ring containing at least one O, N, or S, wherein said heterocyclyl or heteroaryl ring is optionally substituted with up to 3 independent occurrences of RAr;
• RA4 is —OH, —B(OR*)2, —SR*, —N(R*)2, —N(R*)C(O)R*, —N(R*)C(O)N(R*)2, —N(R*)C(O)OR*, —N(R*)N(R*)C(O)R*, —N(R*)N(R*)C(O)N(R*)2, —N(R*)N(R*)C(O)OR*, —N(R*)S(O)2N(R*)2, —N(R*)S(O)2R*, —C(O)OR*, —C(O)N(R*)2;
• RA5 is hydrogen or RAr;
• LB is a covalent bond between RB and the carbon to which LB is bonded or is a saturated or unsaturated C1-4 alkylene chain optionally substituted with up to 5 groups, independently selected from halogen, C1-4 aliphatic, halo(C1-4 aliphatic), —OR++, —O(halo(C1-4 aliphatic)), —NO2, —CN, —C(O)OR++, —C(O)N(R++)2, or —N(R++)2, wherein up to two saturated carbons of said alkylene chain are optionally replaced by —C(O)—, —C(O)N(R++)—, —C(O)N(R++)N(R++)—, —C(O)O—, —N(R++)—, —N(R++)C(O)—, —N(R++)C(O)O—, —N(R++)S(O)2—, —N(R++)C(O)N(R++)—, —N(R++)N(R++)—, —O—, —OC(O)—, —OC(O)N(R++)—, —S—, —S(O)—, —S(O)2—, or —S(O)2N(R++)—;
• RB is halogen, NH2, or a C1-8 aliphatic group, optionally substituted with R;
• a 6-10 membered aryl ring;
• a 3-7 membered carbocyclic 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 up to five independent occurrences of RAr;
• each RC is, independently, hydrogen or RAr;
• R is halogen, —R°, —OR°, —SR°, —OC(O)(C1-8 aliphatic), Ph optionally substituted with R°, —O(Ph) optionally substituted with R°, —CH2(Ph) optionally substituted with R°, —CH2CH2(Ph) optionally substituted with R°, —NO2, —CN, —N(R°)2, —NR° C(O)R°, —NR°C(O)N(R°)2, —NR°C(O)OR°, —NR°NR°C(O)R°, —NR°NR°C(O)N(R°)2, —NR°NR°C(O)OR°, —C(O)C(O)R°, —C(O)CH2C(O)R°, —C(O)OR°, —C(O)R°, —C(O)N(R°)2, —OC(O)N(R°)2, —S(O)2R°, —S(O)2N(R°)2, —S(O)R°, —NR°S(O)2N(R°)2, —NR°S(O)2R°, —C(═S)N(R°)2, —C(═NH)—N(R°)2, or —(CH2)yNHC(O)R°, wherein y is 1 to 4;
• or two R together on the same carbon atom are ═O, ═S, ═NNHR*, ═NN(R*)2, ═NNHC(O)R*, ═NNHC(O)O(C1-8 aliphatic), ═NNHS(O)2 (C1-8 aliphatic), or ═NR*;
• each RAr is, independently, selected from halogen, —R°, —OR°, —SR°, —OC(O)(C1-8 aliphatic), Ph optionally substituted with up to five independent occurrences of —R°, —CH2(Ph) optionally substituted with up to five independent occurrences of —R°, —(CH2)y(Ph) optionally substituted with up to five independent occurrences of —R°, —NO2, —CN, —N(R°)2, —NR°C(O)R°, —NR°C(O)N(R°)2, —NR°C(O)OR°, —NR°NR°C(O)R°, —NR°NR°C(O)N(R°)2, —NR°NR°C(O)OR°, —C(O)CH2C(O)R°, —C(O)OR°, —C(O)R°, —C(O)N(R°)2, —OC(O)N(R°)2, —S(O)2R°, —S(O)2N(R°)2, —S(O)R°, —NR°S(O)2N(R°)2, —NR°S(O)2R°, —C(S)N(R°)2, —C(NH)N(R°)2, and —(CH2)yNHC(O)R°, wherein y is 1 to 4;
• or two adjacent RAr groups taken together are 1,2-methylenedioxy or 1,2-ethylenedioxy;
• each R++ is, independently, hydrogen or C1-4 aliphatic;
• each R* is, independently, hydrogen or C1-8 aliphatic optionally substituted with up to five independent occurrences of —NH2, —NH(C1-4 aliphatic), —N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, —OH, —O(C1-4 aliphatic), —NO2, —CN, —C(O)OH, —C(O)O(C 1-4 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 R* 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;
• each R° 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 R° is, independently, —NH2, —NH(C1-4 aliphatic), —N(C1-4 aliphatic)2, halogen, C1-4 aliphatic, —OH, —O(C1-4 aliphatic), —NO2, —CN, —C(O)OH, —C(O)O(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 R° 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
• with the proviso that when LARA is —S—CH2-pyridyl, then LBRB is not —S—CH2-pyridyl.