| 主权项 |
1. A method for treating or managing cancer in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an Axl inhibitor and a therapeutically effective amount of one or more chemotherapeutic agents, wherein the Axl inhibitor is a compound of formula (I): wherein: R1, R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R8, —C(O)N(R6)R7, and —C(═NR6)N(R6)R7; R2 and R3 are each independently a polycyclic heteroaryl containing more than 14 ring atoms optionally substituted by one or more substituents selected from the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —R9—OR8, —R9—O—R10—OR8, —R9—O—R10—O—R10—OR8, —R9—O—R10—CN, —R9—O—R10—C(O)OR, —R9—O—R10—C(O)N(R6)R7, —R9—O—R10—S(O)pR8 (where p is 0, 1 or 2), —R9—O—R10—N(R6)R7, —R9—O—R10—C(NR11)N(R11)H, —R9—OC(O)—R8, —R9—N(R6)R7, —R9—C(O)R8, —R9—C(O)OR8, —R9—C(O)N(R6)R7, —R9—N(R6)C(O)OR8, —R9—N(R6)C(O)R8, —R9—N(R6)S(O)tR8 (where t is 1 or 2), —R9—S(O)tOR8 (where t is 1 or 2), —R9—S(O)pR8 (where p is 0, 1 or 2), and —R9—S(O)tN(R6)R7 (where t is 1 or 2); or R2 is a polycyclic heteroaryl containing more than 14 ring atoms as described above and R3 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R13—OR12, —R13—OC(O)—R12, —R13—O—R14—N(R12)2, —R13—N(R12)—R14—N(R12)2, —R13—N(R12)—R14—N(R12)2, —R13—N(R12)2, —R13—C(O)R12, —R13—C(O)OR12, —R13—C(O)N(R12)2, —R13—C(O)N(R12)—R14—N(R12)R13, —R13—C(O)N(R12)—R14—OR12, —R13—N(R12)C(O)OR12, —R13—N(R12)C(O)R12, —R13—N(R12)S(O)tR12 (where t is 1 or 2), —R13—S(O)tOR12 (where t is 1 or 2), —R13—S(O)pR12 (where p is 0, 1 or 2), and —R13—S(O)tN(R12)2 (where t is 1 or 2); or R3 is a polycyclic heteroaryl containing more than 14 ring atoms as described above, and R2 is selected from the group consisting of aryl and heteroaryl, where the aryl and the heteroaryl are each independently optionally substituted by one or more substitutents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R13—OR12, —R13—OC(O)—R12, —R13—O—R14—N(R12)2, —R13—N(R12)—R14—N(R12)2, —R13—N(R12)—R14—N(R12)2, —R13—N(R12)2, —R13—C(O)R12, —R13—C(O)OR12, —R13—C(O)N(R12)2, —R13—C(O)N(R12)—R14—N(R12)R13, —R13—C(O)N(R12)—R14—OR12, —R13—N(R12)C(O)OR12, —R13—N(R12)C(O)R12, —R13—N(R12)S(O)tR12 (where t is 1 or 2), —R13—S(O)tOR12 (where t is 1 or 2), —R13—S(O)pR12 (where p is 0, 1 or 2), and —R13—S(O)tN(R12)2 (where t is 1 or 2); each R6 and R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R10—OR8, —R10—CN, —R10—NO2, —R10—N(R8)2, —R10—C(O)OR8 and —R10—C(O)N(R8)2, or any R6 and R7, together with the common nitrogen to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, and optionally substituted heteroarylalkynyl; each R9 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R10 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; each R11 is independently selected from the group consisting of hydrogen, alkyl, cyano, nitro and —OR8; each R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R10—OR8, —R10—CN, —R10—NO2, —R10—N(R8)2, —R10—C(O)OR8 and —R10—C(O)N(R8)2, or two R12's, together with the common nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; each R13 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; and each R14 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain and an optionally substituted straight or branched alkenylene chain; or a stereoisomer, tautomer, pharmaceutically acceptable salt or N-oxide thereof. |
