N3-heteroarylsubstituted triazoles and N5-heteroarylsubstituted triazoles useful as Axl inhibitors

摘要

A compound of formula (Ia): ** Formula ** in which: R1, each of R4 and R5 is independently selected from the group consisting of hydrogen, -C (O) N (R6) R7, and -C ( = NR6) N (R6) R7; R2 is a heteroaryl selected from the group consisting of benzoxazolyl, pyridinyl, pyrimidinyl, 4,5-dihydro-1H-benzo [b] azepin-2 (3H) -onyl, 6,7,8,9-tetrahydro-5H- pyrido [3,2-d] azepinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydroquinolinyl, 1H-pyrrolo [2,3-b] -pyridinyl, benzo [b] thiophenyl, 7 ', 8'-dihydro-5'H-spiro [1,3] dioxolane-2,6'-quinoline] -3'-yl, 4b, 5,6,7,7a, 8- hexahydropentalene [2,1-b] pyridinyl, and 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridinyl, each optionally substituted with 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 heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkylkenyl, optionally substituted heteroarylalkyl-R-9-optionally substituted-heteroaryl-alkyl-9 -R10-OR8, -R9-O-R10-O-R10-OR8, -R9-O-R10-CN, -R9-O-R10-C (O) OR8, -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-C (O) R8, -R9-C (O) OR8, -R9-C (O) N (R6) R7 , -R9- C (O) -R10-N (R6) R7, -R9-N (R6) R7, -R9-N (R6) -R10-N (R6) R7, -R9-N (R6) C (O) OR8, -R9-N (R6) C (O) -R10-N (R6) R7, -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); and R3 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, cycloalkylalkyl optionally substituted, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R13-OR12, -R13-OC (O) -R12, -R13-O-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- 30 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, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, alkyl, optionally substituted optionally substituted, -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 optionally substituted N-heterocyclyl; each R8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted heteroaryl, and heteroaryl substituted; each R9 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; each R10 is independently an optionally substituted straight or branched alkylene chain; each R13 is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and each R14 is independently an optionally substituted straight or branched alkylene chain; as an isolated stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof; where "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having three to fifteen carbon atoms; "Heterocyclyl" refers to a stable 3-18 membered non-aromatic ring radical comprising from one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the radical Heterocyclyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include spirocyclic, fused, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated; "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, from one to thirteen carbon atoms, from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and to minus one aromatic ring, the heteroaryl radical may be attached to the precursor molecule via an aromatic ring of the heteroaryl radical; the heteroaryl radical can be a monocyclic, bicyclic, or tricyclic ring system, which can include spiralic ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can optionally be quaternized;