TW201237041A - Compounds and compositions as protein kinase inhibitors - Google Patents

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, AbI, Bcr-Abl, Aurora-A, AxI, BMX, CHK2, cSRc, Fes, FGFR1, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB Kinases.

Description

201237041 j , , ^-τρίΑ VI. Description of the Invention: [Technical Field] The present invention provides a novel class of compounds, and pharmaceutical compositions containing the same, and the above novel compounds and pharmaceutical compositions are treated and/or prevented by Use of a disease or discomfort caused by abnormal or uncontrolled kinase activity, particularly with Flt3, PDGFR, c-KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, Bcr-Ab, Aurora-A, Axl, BMX, CHK2 , cSRC, Fes, FGFIU, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rsld, SAPK2a, SAPK2ss, SAPK3, SAPK4, Syk,

Abnormally associated disease or discomfort of Tie2, TrkA and/or TrkB kinase. [Prior Art] To a large class of proteins, they play a central role in a variety of intracellular activities and in ensuring intracellular function control. Some of the classifications of non-complete protein kinases include: glutamate receptor kinases such as J-derived growth factor kinase (platelet derived (four) she adds klrse, /DGF_R), nerve growth factor, tr-acid egg, is Linhua's sacred nerves and neurotrophic factor-3 are ί路 ammonia 'enzyme'FGFR3; non-kinases like Ab and thefusion kinase BCR-Ab, Lck, c RAF to 'and coffee'; and serine-threonine Kinases such as b_RAF 'c RAF, sgk, MAp kinase (mokinetic protein kinase 2a, should initiate mediated W MKK64) and should be activated by % 3 _ activity abnormalities in many miscellaneous including benign and malignant L = 201237041 j / / jnun X and in immunity And was observed in the improper start of the nervous system. The novel compounds of the present invention inhibit one or more protein mutations and are therefore expected to be useful in the treatment of diseases associated with protein kinases. SUMMARY OF THE INVENTION The present invention provides a novel class of compounds, a drug group containing the compound, and the novel compounds and pharmaceutical compositions for treating and/or preventing diseases associated with sling or uncontrolled Unsuitable use. The present invention provides a compound represented by the structural formula ρπ or m,

Or a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, or a prodrug thereof, wherein X and Y are selected from N or CH, and at least one of them must be n, Wherein N may be suitably or not substituted by a hydrogen atom; R2 is selected from the group consisting of R7, 〇R7, 7'8, S(0)qR7, S02NR7R8, NR7S02R8, C(0)R7, c(0)0R7, C(0)NR7R8, NR7C(0)R8 or nr7c(o)or8, said q is independently selected from o, l or 2, said r7 and r8 being independently selected from: (a) Cu straight chain, branched chain Or a entangled smoky group, wherein the hydrocarbyl group is further substituted with from 5 to 8 members of 1 to 4 heteroprocyclic hydrocarbon groups selected from 0, N or S, and the hydrocarbyl group and the heterocyclic ring described herein The hydrocarbyl group may be 201237041 -> / / JHpil is substituted by one or a plurality of ii, and "optionally substituted by one halogen or a plurality of halogens" means that the halogen may be substituted or unsubstituted, and Including all substituted by dentate; (b) Cw linear, branched or cyclic hydrocarbon group ' and the hydrocarbyl group is further substituted with a guanamine or hydrazino group, and the hydrocarbyl group, the guanamine described herein Base and the sulfonate The guanamine group may also be optionally substituted by one halogen or a plurality of dentates; (C) a Ci_i 〇 straight bond, a bond or a ring-containing chain containing a plurality of singular bonds, and may optionally be a halogen or a plurality of halogen substitutions; (d) a Cuo direct bond, a bond or a ring-containing chain containing a plurality of bonds, and further containing 5 to 8 members of 1 to 4 hetero atoms selected from ruthenium, N or S a cyclic cycloalkyl group substituted 'and the chain and the heterocyclic ring hydrocarbon group described herein may also be optionally substituted by one or more halogens; (e) C^o is linear, branched or cyclic a chain of a hydrazone bond, and further substituted with a decylamino or sulfonylamino group, and wherein the chain, the guanamine group and the sulfonamide group are also selectively substituted by one halogen or a plurality of dentates Substituted; 'R! and R3 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl, arylalkenyl, alkynyl, ^yl , arylalkyl, arylalkynyl, aryloxyalkyl, alkoxycarbonylalkynyl, aryloxyalkynyl, arylsulfonylalkyl, arylsulfonylalkynyl, arylsulfonyl Alkenyl, carboxyl, carboxy olefin Base, carboxyalkyl, cycloalkyl, carboxyalkyl, cyano, cyano, cyano, cyanoalkynyl, cyclonicoxy oxyalkynyl, halogen, heterocyclic arylalkenyl, hetero Cycloaryl, heterocyclic aryl burning 201237041

a heterocyclic arylalkynyl group, a heterocyclic arylcarbonyl group, a heterocyclic arylcarbonylalkenyl group, a heterocyclic arylcarbonylalkyl group, a heterocyclic cycloalkyl group, a heterocyclic cycloalkylenyl group, a heterocyclic 2 alkylalkyl group, Heterocyclic hydrocarbyl alkynyl, heterocyclocycloalkyl hydrocarbylcarbonyl, heterocyclic methyl hydrocarbylcarbonyl, heterocyclocycloalkylcarbonylalkenyl, cycloalkylalkenyl, cycloalkyl=yl, (tetra)silyl, onionyl, halohydrocarbyl, heterocycle Silk, heterocyclic ring % sec, halocycloalkyl (10), deducted, via, hydroxyalkynyl, NRaRb, (NRaRb)alkenyl, (NRaRb)alkyl, (NRA), kiln ' _aRb) M-based, (NRaRb-aged, base-based alkyl group (RaRb) recorded alkynyl H, nitroalkenyl, nitroalkyl or nitro fast radical; and = site selected from hydrogen, occupation, burned oxygen Base, courtyard oxygen base, oxoalkyl, alkyl, aryl, alkylcarbonyl, hydrocarbyl sulphate, aryl, aryl oxygenated, aryloxyalkyl, aryl, aryl Carbonyl, arylsulfonylheteroaryl, dimethyl (tetra), quaternary, heterocyclic, hydrocarbyl, heterocyclo, hydrocarbyl, heterocyclic, hydrocarbyl, heterocyclic, heterocyclic, heterocyclic Base, transalkylene, silk Groups, cycloalkyl, cycloalkyl hydrocarbon group which ^ A ^, heteroaryl _ ^ MR · hydrocarbon group, the two aryl ^ soil NRcRd) fe group or (the NRA) several hydrocarbon group! a cyclonicanyl moiety of a hydrocarbyl group, a heterocyclic moiety, a cycloalkyl group, a heterocyclic aryl moiety of a cycloalkyl group, a heterocyclic aryl group and a heterocyclic ring and a heterocyclic ring: a ring; 201237041 J / / JHpil 1, 2, 3, 4 or 5 independently selected from alkenyl, decyloxy, alkoxycarbonyl, alkyl, alkynyl, hydrocarbylcarbonyl, aryl, arylhydrocarbyl, S, haloalkoxy, a group substituted with a hydrocarbyl group, a hydroxyl group, a nitro group, a NRcRd, a (NReRd) hydrocarbon group, a (NRcRd) hydrocarbylcarbonyl group, a (NRcRd)carbonyl group, a (NRcRd) thiodacyl group, a -fluorene- or a spiroheterocyclic hydrocarbon group, wherein The aryl moiety of the aryl and arylhydrocarbyl groups may in turn be further selected from 1, 2, 3, 4 or 5 independently selected from alkoxy, hydrocarbyl, cyano, pixel, dentate alkoxy, oxime hydrocarbyl, nitrate Substituted with a group of - or 〇-; and wherein Re and Rd are independently selected from the group consisting of argon, alkoxy, hydrocarbyl, aryl, carboxyhydrocarbyl, cycloalkyl, halohydrocarbyl, heterocyclic aryl, heterocycloalkyl, a heterocyclocycloalkyl hydrocarbon group, a hydroxyalkoxy hydrocarbon group, a hydroxyalkyl group or a (NReRf) hydrocarbon group; wherein the aryl group, heterocyclic aryl group and heterocyclic ring hydrocarbon group are optional Substituted 1, 2, 3, 4 or 5 independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, functional alkoxy, _hydrocarbyl, trans- or nitro-containing groups ;with

Re and Rf are independently selected from hydrogen or a hydrocarbyl group; R4 is selected from the group consisting of 1 to 3 independently selected from the group consisting of dentate, Ci/2 nicotine, chiral Ck alkoxy, (5:1 () heterocycle An anthrylaryl group substituted with a group of an aryl-c〇_4 hydrocarbon group or a C3.8 heterocyclic ring group-C〇_4 hydrocarbon group; a heterocyclic aryl substituent of the & and a heterocyclic cyclonicanyl group The substituent may be optionally substituted with a Q.6 smoki group or an oxide derivative; 尺 5 and Re are independently selected from hydrogen or a C!-6 hydrocarbon group; ^ Rs and R6' and together with a phenyl group attached to the heart Forming a C6_1 indenyl or C5_1()heteroaryl. 201237041 -» / / In some embodiments, x is N. In some embodiments, γ is N. In some embodiments of Formula I, χ is Ν, γ is CH. In some embodiments of Formula II, 'χ is N, γ is CH. In some embodiments of Formula III, χ is N when χ is N, or X is NH Y is N. In some embodiments, R2 is selected from the group consisting of R7, OR7, NR7R8, so2nr7r8^C(0)R7^C(〇)〇R7. C(〇)NR7Rs^NR C(〇)Rg or nr7c(o Or 8. In some embodiments 'at least one of R7 and R8 is independently selected : (a) a linear, branched or cyclic hydrocarbon group of Cl5, wherein the hydrocarbon group further has a heterocyclic ring containing ~3 selected heteroatoms selected from the group consisting of fluorene and N3ts, and the lysine group __cycloradyl may also be optionally substituted by a halogen or a plurality of halogens; (b) a linear, branched or cyclic hydrocarbon group of Cl.5, substituted one step with a guanamine or a silk, and this description (4) The amine group and the sulfonamide group may also be substituted with the hydrazine; & is selected by a dentate or a plurality of elements & straight, branched or cyclic chain-containing chains, and Optionally substituted by a halogen or a plurality of halogens. The bond is substituted with a cyclonicotinyl group and the chain described herein is substituted with the halogen or a plurality of halogens with the heteropoly 2, 2011,370, 141; (e) Cw straight a chain, a branched or a cyclic chain containing a plurality of ether linkages, and further substituted with a decylamino or sulfonylamino group, and wherein the chain, the guanamine group and the sulfonamide group are also Optionally substituted by one element or a plurality of halogens. In some embodiments, at least one of and R8 is independently selected from: (a) Ck is linear, branched or cyclic. a chain of ether linkages, and optionally substituted by one halogen or a plurality of ketones; (b) a linear, branched or cyclic chain containing a plurality of ether linkages, and further contained by 5 to 8 members ~ 2 heterocyclic ring hydrocarbon groups selected from hetero atoms of hydrazine, N or S are substituted ' and the chain and heterocyclic ring hydrocarbon groups described herein may also be optionally substituted by one # or more halogens; or (c) a Cw linear, branched or cyclic hydrocarbon group, and further substituted with a decylamino or sulfonylamino group and wherein the hydrocarbyl group, the sulfhydryl group and the hydrazine amino group are also selectively One halogen or multiple _ primes are substituted. In some embodiments, at least one of and r8 is independently selected from a Cm linear, branched or cyclic hydrocarbon group, and the hydrocarbon group is further contained by 5 to 8 members and 1 to 2 selected from 0, N4 s. The hetero atom of the heterocyclic ring hydrocarbon group is substituted, and the hydrocarbyl group and the heterocyclic ring hydrocarbon group described herein may also be optionally substituted by one dentin or a plurality of halogens. In some embodiments, at least one of R7 and Rs is independently selected from a C?.4 linear, branched or cyclic hydrocarbon group, and the hydrocarbon group is further further amidino or a hydrazino group. Substituting 'and the nicotine, the enriched amine group and the 201237041 ^ , ^-rpix described herein may also be optionally substituted by - or a plurality of halogens. In the two embodiments, at least one of 'R1 and R3' is independently selected from hydrogen, halogen or a hydrocarbon group. In the two-part scheme, at least one of the core and R3 is independently selected from hydrogen or a Cu hydrocarbon group. In the two embodiments, at least one of R1 and R3 is independently selected from hydrogen or halogen. In some embodiments, both Ri and R3 are hydrogen. In the two known schemes, 'R4 is selected from arbitrarily selected from 1 to 2 independently selected from dentate, halogenated Cl. 4 nicotinic, halogenated Cm alkoxy, C5.8 heteroaryl _C. a substituted aryl group of a cyclyl or C3.6 heterocyclic cyclonicanyl hydrocarbon group, the heterocyclic silyl (tetra)cyclocyclic hydrocarbon radical of the -R4 optionally being derived from a Ci-6 hydrocarbyl group or an N-oxide Substitute. And R. a c68 aryl group substituted with a group of a —Cg 4 hydrocarbon group; the heterocyclic aryl substituent and the heterocyclic cycloalkyl substituent of the R 4 are optionally substituted by a C 4 alkyl group or an N-oxide derivative. In the scheme, R4 is selected from the group consisting of aryl groups which may be substituted by 1 to 2 groups independently selected from the group consisting of the halo CM: or the dentate c] 4 alkoxy. 8 In some embodiments, R4 is selected Self-selectively substituted by 1 to 3 groups independently selected from the group consisting of a Cw hydrocarbyl group, a oxo group, a heterocyclic aryl group X (M hydrocarbyl group or a Cw heterocyclic cycloalkyl group _c 〇 4 hydrocarbyl group) C6, 11 201237041 aryl; or the heterocyclic aryl substituent of the R4 and the heterocyclic cycloalkyl substituent may be optionally substituted by a Cl. 6 hydrocarbon group or an N-oxide derivative. In the scheme, at least one of and R6 is independently selected from hydrogen or a hydrocarbyl group. In some embodiments, R5 and R6 are both hydrogen. In some embodiments, R1 and R6, and a phenyl group attached to the heart and r6 ring Forming a quinolyl or naphthyl group. In some embodiments, Ri, R3, Rs and R6 are independently selected from hydrogen, halogen or lower hydrocarbon; R4 is selected from 1-3 independently selected from _, A phenyl group substituted with a halogenated Q-6 hydrocarbyl group, a _ (6 alkoxy group, CVu) heterocyclic aryl group (: a fluorene 4 hydrocarbon group or a C3-8 heterocyclic aryl C 〇 4 fluorenyl group). And R. -C (M-hydrocarbyl or c3-8 heterocyclic aryl-c〇4 hydrocarbyl group-substituted stupid group. In other embodiments, ^ and r3 are independently selected from 1-3 independently selected from chlorine, a phenyl group substituted with a fluorine, trifluoromethyl, methoxy, trifluoromethoxy, ruthenium or pyridazinyl group, wherein the heart and the 3" The azine group substituents may be optionally substituted by decyl or ethyl. In some embodiments, the compounds of the invention are selected from at least one compound: 1·(4-(6-(Ν-(2_(呱啶_ι_) Ethyl)aminocarbonyl)_ιΗ_carbazole_4_yl)benzene ) -3- (3- (trifluoromethyl Yue yloxy) phenyl) urea; 121

201237041 -7 II l_(4_(6-(N-(2-(pyridazin-1-yl)ethyl)aminocarbonyl)-1Η-oxazol-4-yl)phenyl)-3-(3-( Trifluoromethoxy)phenyl)urea; 1 -(4-(6-(N-(2-(tetrakisyl-1-yl)ethyl))) Η-0 嗤4-yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)urea; l-(4-(6-(N-(2-(2-methoxy)ethoxy)) Aminocarbonyl)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; 1-(4-(6-(Ν-((2) -methoxyethoxy)indolyl)aminocarbonyl)-1Η-oxime.sodium-4-yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)urea; 1-(4 -(6-(Ν-(2-(acridin-1-yl)ethyl)aminosulfonyl)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) Phenyl)urea; 1-(4-(6-(N-(2-(pyridazin-1-yl)ethyl)aminosulfonyl)-1H-indazol-4-yl)phenyl) -3-(3-(Trifluorodecyloxy)phenyl)urea; l_(4-(6-(N-(2-(tetrahydroindol-1-yl)ethyl)aminosulfonyl)- 1Η-吲. sit-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; ^(4-(6-(1^-(2-(2-oxo) Ethyl ethoxy)ethyl)aminosulfonyl)-1Η-called oxime. -4-yl)phenyl)-3-(3-(trisethoxy)phenyl) gland; 1 _(4 -(6-(N-((2-methoxyethoxy)methyl)aminosulfonic acid)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoroantimony) Phenyl)urea; 1-(4-(6-(2-(acridin-1-yl)ethoxy)-1Η-oxazol-4-yl)phenyl)-3-(3-( Trifluoromethoxy)phenyl)urea; 1-(4-(6-(2-(pyridazin-1-yl)ethoxy)-1Η-oxazol-4-yl)phenyl)-3- (3-(Trifluorodecyloxy)phenyl)urea; 1-(4-(6-(2-(tetrahydroindol-1-yl)ethoxy)-1Η-oxazol-4-yl) Phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; 13 201237041 J / / JHpil l_(4_(6-(2-(2-decyloxyethoxy)ethoxy)) -1Η-吲 -4--4-yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)urea; 1-(4-(6-(2-(Acridine-1-yl))) Ethylamino)-1H-indazol-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; 1-(4-(6-(2-(pyridazine)- 1-yl)ethylamino)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; 1-(4-(6-(2- (tetrahydropyrrol-1-yl)ethylamino)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea; 1-(4-( 6-(2-(2-methoxyethoxy)ethylamino)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)urea 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(acridin-1-yl)ethyl)aminocarbonyl)-1Η- . More than [2,3-c]. Bis-1-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyridazine)-1) -yl)ethyl)aminocarbonyl)-1Η-indolo[2,3-c]acridin-1-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)benzene -3(4-(3-(N-(2-(tetrahydroindol-1-yl)ethyl)))###################################################### ° ratio -1 -yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(2-) Methoxyethoxy)ethyl)aminocarbonyl)-1Η-indolo[2,3-c]acridin-1-yl)phenyl)urea; 1-(4-chloro-3-(trifluoro) Mercapto)phenyl)-3-(4-(3-(N-((2-methoxyethoxy)))carbonyl)-1Η-.pyrho[2,3-c]吼Pyridin-1-yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(acridin-1-) Base) ethyl) gas sill yellow base) Η Π Π Π Π 并 [2,3-c] ° tba -1- yl) base, gland,

S 14 201237041 J / / 1_(4-gas-3-(dimurium)yl)_3-(4-(3-(N-(2-(()))))醯 )))-1Η-"Biluo[2,3_c]n ratio bite_1_yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3 -(4-(3-(>^-(2-(tetrahydro)-specific -1-yl)ethyl)amino group continued with a group)-1Η-° ratio σ[2,3-c]ni定-1_yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(Ν-(1-(2-曱)oxy) Ethyl ethoxy) fluorenyl) amino group ))) Η - «> piroxi[2,3_c]n ratio. -1-yl) stupid) urea; 1-(4-gas-3-( Trifluoromethyl)phenyl)-3-(4-(3-(4-(^^-1-^^)7yl)-1Η·pyrrolo[2,3-c]acridin-1-yl Phenyl)urea; 1-(4-ox-3-(tri-indolyl)phenyl)-3-(4-(3-(4-(^,-1-yl)butyl)-1Η- Pyrrolo[2,3_c]pyridin-1-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(tetra) Hydroquinone π each _1 _ yl) butyl)-1 Η-η ratio argonium [2,3-c] ° pyridine-1-yl) phenyl) urea; 1- (4- gas -3- (three Fluorinyl)phenyl)-3-(4-(3-(4-(2-methoxyethoxy)butyl)-1Η-indolo[2,3-c]° pyridine-1 -yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)benzene --3-(4-(3-(2-(2-methoxyethoxy)ethyl)-1Η-pyrrolo[2,3-c]pyridin-1-yl)phenyl)urea; -(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2_(σΧν)-1-yl)ethyl)aminocarbonyl)-1Η-pyrrole [3,2-c]pyridin-3-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2) -(σ; ί^σ桊-1-yl)ethyl)aminocarbonyl)-1Η-.pyrolo[3,2-c]°pyridin-3-yl)phenyl)urea; 1-(4 - gas-3-(tri-Itmethyl)phenyl)-3-(4-(1-(Ν-(2-(tetrahydroσ)-1-yl)ethyl)aminocarbonyl)-1Η-比比比和[3,2-c] oxaridin-3-yl)phenyl) 15 201237041 j / /^^pir urea; Μ4·gas-3-(trifluoromethyl)phenyl)-3-( 4-(l-(N-(2-(2-decyloxyethoxy)ethyl)aminocarbonyl)-1 Η-lado[3,2-c]acridin-3-yl)phenyl) Pulse, H4-gas-3-(trifluoromethyl)phenyl)_3·(4·(ι_(Ν-((2-methoxyethoxy)indolyl)aminocarbonylΗη·pyrrolo[3, 2-c] pyridine I yl) phenyl) urea; 1 (4 gas-3-(dimur methyl) phenyl)_3-(4-(l-(N-(2-(p 〇定定_ 1_yl)ethyl)aminosulfonyl)-1Η-pyrrolo[3,2_c]pyridine-3-yl)phenyl)urea; gas_3_(three Methyl)phenyl)-3-(4-(1-(Ν-(2-(pyridazine·i•yl)ethyl)aminosulfonyl)-1Η-η ratio Phenyl)urea; 1-(4-gas-3-((trifluoromethyl)phenyl)_3·(4_(1_(Ν_(2 1,4-pyridyl)ethyl)) lH-n ratio ρ and [3,2-c]n ratio biting-3-yl) stupid) gland. 1-(4-chloro-3·(difluoroindolyl)phenyl)_3_(4-( Iv_(ν_(2_(2.methoxyethoxy)ethyl)-denyl fluorenyl)_1Η_pyrrolocarbazide; 1-(4-chloro-3-(trifluoromethyl)phenyl)_3_(4_( 1·(Ν((2methoxyethyl)methyl)aminosulfonyl)·1Η_吼 并[3,2_c]n than pyridine-3-yl-f-phenyl) gland, 1-(4- Gas-3-(trifluoromethyl)phenyl)_3_(4 servant (3 guacamole) propoxy)-1 Η·° ratio η [3, 2 inch ratio α _3_ base) Phenyl)urea; 1-(4-gas_3_(trifluoromethyl)phenyl)-3-(4-(1_(3 十瓜瓜丙oxy)-1Η-°Bilo[3,2 -c]n ratio bite_3_yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)_3_(4 servant (3·(four gas materials·^ propoxyl) More than [3,2_decapyridinyl) phenyl) gland;

16 S 201237041 1-(4-Gas-3-(difluoroindolyl)phenyl)_3_(4_(1_(2(2-methoxy)ethoxy)ethoxy[3,2· bite Urea; or 1-(4- gas-3-(dimethylmethyl) phenyloxyethoxy)ethyl each [3,2-(^ ratio bite_3_yl) Phenyl) urea. The purpose of X according to the present invention is to provide a pharmaceutical composition comprising: at least one compound of the formula I, II and III, or an N•oxide derivative thereof, or a single isomer or a mixture of isomers thereof Or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may also be combined with one or more other compounds. A further object of the present invention is to provide the use of the pharmaceutical composition for the preparation of a medicament for the treatment of a disease, which is useful for the treatment and/or prevention of and selected from the group consisting of Flt3, PDGFR, c_KIT, VEGFR1, VEGFR2, VEGFR3, c-RAF, Abl, Abl -T3151, FGFR1, FGFR3, Aurora-A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, JKK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rskl Diseases associated with kinase activity of SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB. A further object of the present invention is to provide a use of the structural formula I, II and III or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a kinase activity-related disease, in particular for the treatment and/or prevention thereof, selected from the group consisting of Flt3, PDGFR, c-KIT > VEGFR1 'VEGFR2 ' VEGFR3 ' c-RAF ' Abl ' Bcr-Ab Aurora- A, Axl, BMX, CHK2, cSRC, Fes, FGFIU, FGFR3, IKKa, IR, JNK2a2, Lck, Met Diseases associated with kinase activity of MKK6, 17 201237041 j/ /jnpir MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rsld, SAPK2a, SAPK2ss, SAPK3 SAPK4, Syk, Tie2, TrkA and/or TrkB. The present invention still further provides a preparation of the structural formula I, II and hydrazine, an N-oxide derivative thereof, a prodrug derivative thereof, a protective group-containing derivative thereof, a single isomer thereof and a mixture of isomers Or a pharmaceutically acceptable salt thereof. Definition of Terms The term "hydrocarbyl" as used herein refers to a saturated or unsaturated, branched or directly linked monovalent hydrocarbon group formed by the removal of one hydrogen atom from one carbon atom of the parent aliphatic hydrocarbon group. Included are the organic group terms alkyl, alkenyl and alkynyl. The term "lower hydrocarbon group" as used herein means a hydrocarbon group having 1 to 6 carbon atoms. As used herein, "alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon radical formed after the removal of one hydrogen atom from one carbon atom of the parent alkane. Typical alkyl groups include, but are not limited to, mercapto; ethyl; propyl, such as n-propyl, isopropyl, cycloprop-1-yl, etc.; butyl, such as n-butyl, isobutyl, 2-indenyl-propan-1-yl, 2-indenyl-propan-2-yl, cyclobut-1-yl, tert-butyl, and the like; and the like. In certain embodiments, the alkyl group contains from 1 to 20 carbon atoms. The term "lower alkyl," as used herein, refers to an alkyl group containing from 1 to 6 carbon atoms.

As used herein, "alkenyl" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical containing at least one C=C bond formed by the removal of one hydrogen atom from one carbon atom of the parent olefin. group. These groups of C=C 201237041

The I I bond may be either Z-constructed or E-configured (or both may be 仏<2 conformational). Typical dilute groups include, but are not limited to: ethyl hydrazino groups; propyl fluorenyl groups, such as propyl _1 _1 _ group, propyl _1 _ _2 yl group, prop-2-en-1-yl group (ene) Propyl), prop-2-en-2-yl, cyclopropen-1-yl, cycloprop-2-en-1yl, etc.; butenyl groups, such as butyl hydrazine _;μene 2_yl, 2-曱-prop-1-en-1-yl, butyl-2_thinyl, butyl-2_diluted _2-yl, butyl], 3-diene-1- , butyl-1,3-dien-2-yl, cyclobut-1-enyl, cyclobut-1-en-3-yl, cyclobutane-1,3-dien-1-yl, etc.; And similar hydrocarbon groups. In certain embodiments, the alkenyl group contains 2 to 20 carbon atoms. In another embodiment, the alkenyl group contains 2 to 6 carbon atoms, such as the term "lower alkenyl." As used herein, "alkynyl" refers to an unsaturated, branched or straight-chain hydrocarbyl group containing at least one CeC bond formed by the removal of one hydrogen atom from one carbon atom of the parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl' and the like. In certain embodiments, the alkynyl group contains 2 to 2 Å of stone anti-atoms. In another embodiment, the alkynyl group contains 2 to 6 carbon atoms, for example the term "lower alkynyl,". "Alkoxy" as used herein refers to a -〇R radical, wherein R represents a thiol or ring. Hydrocarbyl. Specific examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, etc. "Alkoxycarbonyl," refers to a _C. (0) a —OR atom wherein R is as defined above to represent a hydrocarbyl or a cyclic hydrocarbyl group. As used herein, "aryl" refers to a monocyclic or fused bicyclic aromatic oxime containing from 6 to 10 carbon atoms. For example, the phenyl group may be a phenyl group or a phenyl group, and 19 201237041 is preferably a stupid group. The term "arylene" as used herein refers to a heterocyclic aryl group, which refers to a divalent group on the 3-position of a radical = or more than one atom. mD a ^, group, fluorenyl, heptyl, fluorene: fluorenyldibenzopyranyl, benzo[1,3] biceps, taste: benzotetrazolyl, pyrazolyl, thiophene, etc. Wait. , —, —, —, — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — The hydrocarbon group (cyclofilament, ring = group), spiro compound group, and the center of the bridged ring compound. The cyclic hydrocarbon group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, an anthracene, a cyclohexenyl group, and the like. "Heterocyclic quinone," refers to a cyclic hydrocarbon e group as defined above, wherein none or more than one number of carbon atoms on the ring are selected from -Ο-, Ν=, - The group of NR·, _C(〇)...s_,· or _s(〇)2· is substituted with a protecting group wherein R is selected from nitrogen, Ci4 hydrocarbon group or nitrogen. For example, in the present application, _ (: 3·8 heterocyclic ring hydrocarbon filaments are described in the compound of the present invention, including morphine, tetrahydro η, specific groups, and tetrazine valence groups, 2_嗣, B.瓜 基 嗣 嗣 ° ° ° ° ° 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 The "dentate element" (or self-priming) herein is preferably gas or fluorine, but may also be desert or moth. The kinases listed in the "Kinase Catalog" herein include Abl (human),

S 20 201237041 «> / / ^~Γ|/λΑ.

Abl (T3 151), JAK2, JAK3, ALK, JNK 1 al, ALK4, KDR, Aurora-A, Lck, Blk, MAPia, Bmx, MAPUDK2, BRK, MEK1, CaMKII (rat), Met, CDKl/cyclinB, p70S6K7 CHK2, PAK2, CK1, PDGFRa, CK2, PDIU, c-kit, Pim-2, c-RAF, PKA(h), CSK, PKBa, cSrc, PKCa, DYRK2, Plk3, EGFR, ROCK-I, Fes, Ron , FGFR3, Ros, Flt3, SAPK2a, Fms, SGK, Fyn, SIK, GSK3/3, Syk, IGF-1R, Tie-2, IKWJ, TrKB, IR, WNK3, IRAK4, ZAP-70, ITK, AMPK (rat ), LIMK1, RsU, Ax, LKB1, SAPK2P, BrSK2, Lyn (h), SAPK3, BTK, MAPKAP-K3, SAPK4, CaMKIV, MARIU,

Snk, CDK2/cyclinAa MINK, SRPK1, CDK3/cyclinE, MKK4(m), TAK1, CDK51p25, MKK6〇i), TBK1, CDK61cyclinD3, MLCK, TrkA, CDK7icyclinWMATl, MRCKJ3, TSSKh CHK, es, CK1 d, MST2, ZIPK , c-Kit (D816V), MUSK, DAPK2, NEK2, DDR2, NEK6, DMPK, PAK4, DRAK1, PAR-lBa, EphA, PDGFRP, EphA2, Pim-Bu EphA5, PKBP, EphB2, PKCPI, EphB4, PKCG, FGFRI , PKCq, FGFR2, PKCB, FGFR4, PKD2, Fgr, PKG1P, FM, PRK2, Hck, PYK2, HIPK2, Ret, IKKa, RIPK2, IRR, ROCK-II (human), JNK2a2, Rse, JN, K3, Rskl ( h), PI3 Ky, PI3 KG and P13-KP. The compounds of the invention screen for kinases (wild type and/or mutant) in the kinase catalog and inhibit the activity of at least one of the kinases. As used herein, "treatment" refers to a method of reducing or ameliorating a disease and/or its symptoms 21 201237041. As used herein, "pharmaceutically acceptable," is generally used in the art, especially in humans. "Pharmaceutically acceptable salt," refers to a salt of a compound which is pharmaceutically acceptable. And possess the expected pharmacological activity of its parent compound. Some of the salts include: (1) acid addition salts, similar acids with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, Glycolic acid, pyruvic acid, lactic acid, malonic acid succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citrate, ^carboxylic acid, 3-(4-pyridyl)benzoic acid, cinnamon An acid, a salt of a citric acid or an oxime sulfonic acid; or (2) when an acidic proton in a parent compound is a metal ion such as a metal ion, a soil metal ion or a photographic ion, or an organic domain such as ethanolamine When chelated, such as diethanolamine, triethanolamine, N-methylamine, dicyclohexylamine, etc., it can form a salt. A further object of the invention relates to a pharmaceutical composition comprising: at least one of the above compounds and a pharmaceutically acceptable adjuvant. The term ''pharmaceutically acceptable excipient'' refers to any diluent, adjuvant, adjuvant or carrier with which at least one compound of the invention is administered. As used herein, "effective therapeutic amount refers to a compound used in A dose of a compound sufficient to treat a therapeutic effect of such a disease, discomfort or symptom when treating a clinical condition or at least one clinical condition of the disease or discomfort. The particular "effective therapeutic amount" can vary depending on the compound, the condition being treated, the discomfort and the disease or not, the severe shouting and/or recording, the age and/or weight of the silker'. Wherever possible, a suitable agent

The amount of 22 S 201237041 is determined by routine experimentation for those skilled in the art. It is obvious that, in the case of a digital claim that expresses a component, a reaction condition, etc., unless otherwise specified, unless there is a counterexample, the description of Kui and Quan J is "about". Corresponding to is a numerical parameter value in the book in its respective test measurement. The approximation of the variation of the bias value of the singer In this paper, when any variable is in the chemical enthalpy, its definition each time appears more than once with respect to the potting formula. The compound may contain one or two. The structures of the invention and the like may also be present in stereol Ltrrf bodies, optically active enantiomers or diastereoisomers, whether in partial or any chemical structure, all of the structurable structures of the compounds include Considering the stereoisomers, which are also =; the reflection vessel or the simple diastereomeric hybrid can be two ===: the domain and the stereoisomers _ = method into the step Compounds whose constituents are fluorescing or stereospecific 11 or 111 include, but are not limited to, their single exomers = isomers and mixtures thereof. In these two early enantiomers or diastereomers, such as optical 23 201237041 == can be prepared by chiral synthesis or hand-split method. Chiral demolition; 1ΪΓ is achieved by different methods, such as traditional assisted reagents, diterpenes, or chromatographic methods such as chiral high pressure liquid chromatography (HPLC). The compound of Μ or m may contain a double bond of z or singular (in cis or trans configuration). When the compound of the formula χ, π or m =, tautomers, these tautomers are also included in the dried body of the present invention. The compounds of the invention include, but are not limited to, compounds of the formula i, π or m and all forms which are pharmaceutically acceptable. Pharmaceutically acceptable forms of these compounds of the invention include pharmaceutically acceptable salts, solvates, crystalline forms thereof (including polymorphs or clathrates), integrators, non-covalent complexes thereof, pre-relations And it's a mixture. In certain embodiments, the compounds of the invention are pharmaceutically acceptable salts. As used herein, the term "compound," includes not only the compound itself, but also pharmaceutically acceptable salts, solvent compounds, chelates, non-covalent complexes, prodrugs, or mixtures of any of the foregoing. Steroidal drugs such as esters or lanthanide derivatives of structural formula I, η and m are also included within the scope of the above-mentioned chemicals. The term "prodrug" includes any which can be converted to a structural form when administered to a patient or Compounding a compound, for example, by metabolism of the prodrug. Examples of the prodrug include, but are not limited to, an acetyl derivative of a different functional group (eg, an alcohol or an amino group) on the structural formula, π, and m. , formamidine derivatives, benzamidine derivatives, and other similar derivatives. In various places in the specification of the present invention, the compounds of the present invention

24 S 201237041 J / / J*+pu Substituents are represented by various groups or ranges. It is specifically noted herein that the present invention encompasses each subcombination of the components encompassed by these groups and ranges. For example, the term "Cw alkyl" may specifically refer to the thiol, ethyl and c3 alkyl groups described (including n-propyl and isopropyl), respectively. In this article η-yuan, where! ! An integer is usually used to describe the number of ring atoms in a chemical structure and indicates that the number of ring atoms is η. For example, pyridine is an example of a 6-membered heterocyclic aryl ring, and thiophene is an example of a 5-membered heterocyclic aryl group. The present invention provides a class of compounds, compositions and methods of treatment for the treatment of kinases, particularly Flt3, PDGFR, c-KIT, VEGFIU, VEGFR2, VEGFR3, c-RAF, Abl, Bcr-Ab, Aurora·A, Axl, BMX , CHK2, cSRC, Fes, FGFIU, FGFR3, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2a, SAPK2ss, SAPK3, SAPK4, Syk,

Tie2, TrkA and/or TrkB kinase related diseases. For example, leukemia and other BCR-Abl-associated cell proliferative disorders can be treated by inhibiting wild-type and/or variant Bcr-Abl. Detailed embodiments of the invention can be seen as follows. When describing certain embodiments of the invention, it is to be understood that the embodiments of the invention are not limited to the scope of the embodiments described. On the contrary, the embodiments of the invention are intended to include alternatives, modifications, or equivalents, which are equivalent to the substance and scope of the embodiments of the invention as defined in the appended claims. Further preferred compounds of the invention are detailed in the following embodiments. 25 201237041 J//J4pil The above features and advantages of the present invention will be more apparent from the following description. In the following, the pharmaceutical composition and its administration are generally, the compound of the present invention will be administered in a therapeutically effective dose by a technically acceptable model, a second drug or in combination with one or more other therapeutic drugs. .疋蜀 1 Therapeutic doses are severely shouted by the disease, the money is expected. = The condition, the efficacy of the compound used and other factors. Total = dose approx. .03~2.5mg/kg body weight of the unified research and payment of 7 people full of results. Large mammals, such as humans, may be administered in a convenient dosage form such as a suitable oral unit dose containing about one formula. Route (4) 5 shirts recorded what routine administration = agent,: Ge, non-successful route, such as injection: = 1 inning.卩 administration such as the use of topical syrup, shovel ^ or sputum and two active ingredients of this = m type can be tablets or gelatin capsules containing with mannitol, singular i-cyanide i temple, (b) lubricant, such as矽

26 S 201237041 Glue, talc, octadecanoic acid or its magnesium or calcium salt and / or polyethyl 1, 篝. W agent, such as (four) Chi 'Ξ;: fruit: methyl cellulose nano, 姊华mi t (4) a secret agent, a domain powder, agar, a brown salt or an effervescent mixture ', etc.; and/or (e) an absorbent, a sulphur and a sweetener. The injectable dosage form may be an aqueous isotonic solution or a 'sludge through a fat emulsion sister' preparation or a gargle-containing adjuvant, such as a preservative, a stabilizer: = agent: ^ η solvent, a 5-week osmotic salt and/or Buffer, etc. In addition, to include other therapeutically valuable substances. Suitable transdermal dosage forms comprise a compound of the invention effective in the treatment of (iv) and an excipient. The drug, body, includes a readily absorbing pharmaceutically acceptable solvent to aid in the release of the active skin. For example, a transdermal device may formally comprise a tape forming a bottom layer 'a container containing a compound or supplemented with an excipient to selectively add a device that controls the rate of administration to the skin of the host'. The administration is carried out at a controlled and pre-set rate for a longer period of time - and means for attaching the device to the skin. A matrix percutaneous absorption dosage form can also be used. Suitable dosage forms for topical use, such as the skin and eyes, are preferably aqueous solutions, ointments, creams or granules well known in the art. This dosage form can contain a co-solvent, a stabilizer, a synergist, a buffer, and a preservative. The compounds of the invention may be administered in combination with one or more other therapeutic agents (drug combination) at a therapeutically effective dose. For example, a coordinated effect with other immunomodulatory or anti-inflammatory substances, such as: Cyclosporine, sputum, ascomycin or immunosuppressive analogues, such as ring 27 201237041 ^ / /J* Fpnmycin A (CsA), cyclosporin G, FK 5〇6, rapamycin or similar immunosuppressive compounds; corticosteroids; cyclopamine; azathioprine; ;buquina; leflunomide; imidazolidine; mycophenolic acid; mycophenolate mofetil; 1,5-deoxyspermectin; immunosuppressant antibody 'especially a single white blood cell receptor Antibodies such as MHc, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands; or, other immunomodulatory compounds such as CTLA41g. When the compound of the present invention is used in combination with other therapies, the dose of the combined administration of the compound will of course depend on the type of the combination to be used, the specific drug to be used in combination, and the physical condition of the subject. Ports - The present invention also provides a pharmaceutical composition, such as a kit, comprising: (a) a first agent, i.e., a morphological formula of a compound of the invention as shown herein, or a pharmaceutically acceptable salt thereof; and (8) At least the combination drug 2 can include its instructions for use. In this article, co-administration, (c〇-administrati〇n, combined administrate) or the like, means that the method of treatment here means selecting a therapeutic drug around a single patient, and is intended to include a treatment plan in which the above drug is necessary Administration via the same route of administration or at the same time. In the context of "pharmaceutical composition, it is meant that a combination of more than one of the products having a composition of yttrium and non-fixed ratios of glycerin" and "non-fixed ratio of glycerin" refers to structures such as structural formulas 11 and 111. The active ingredient of the compound ^ _ is used as a single-species or reagent at the same time = in the patient. The term "non-fixed composition" refers to a compound such as a structural formula, a compound of hydrazine, and an active ingredient of a combination drug as separate varieties.

S 28 201237041 or the reagents are each administered to the patient, and can be administered simultaneously, at the same time or with no specific time limit, and the effective drug level of the two chemicals can be achieved in the patient. The latter is also suitable for cocktail treatments, such as the use of three or more active ingredients. The invention also includes processes for the preparation of the compounds of the invention. In the reaction, the reactive groups in the final product, such as the amino group, the amino group, the imino group, the alcohol or the like, must be protected to avoid undesired reactions. Regular protection groups are used as standard. For example, see John Wiley and

Ns a Division, 1991, "Protective Groups in Organic Synthesis" (T W

Greene and P. G. M. Wuts, ed., Protective Groups in Organic Chemistry. Specific examples of the synthesis of the compounds of Structural Formulas I, II and III are described in detail in the following examples. Additional Process for the Preparation of Compounds of the Invention The compounds of the invention can be formulated into pharmaceutically acceptable acid addition salts by reaction of their free domains with a pharmaceutically acceptable inorganic or organic acid. The 'inventive compound can be formed into a salt by its free acid with a pharmaceutically acceptable organic domain or inorganic oxime. Similarly, these present inventions (4) can be prepared from starting materials or salts of intermediates. The free acid or free domain of the compounds of the invention may be prepared from the corresponding t-domain salts or acid addition salts, respectively. For example, a suitable domain of the acid addition rli' of the compounds of the invention (e.g., aqueous ammonia, sodium hydroxide, and the like) is converted to a '," The compound addition salt of the compound of the present invention can be converted to the corresponding free acid by reaction with a suitable acid (e.g., 29 201237041 salt S«L, exclusively). The non-oxide of the compound of the present invention can be N-oxidized and reduced by the compound of the present invention in an inert solvent C such as acetonitrile, ethanol or water-soluble dioxane or at a temperature of about 〇8 to 8 Torr. A reagent such as sulfur, sulfur disulfide, diphenylphosphonium dihydride, lithium borohydride, sodium tetrahydroborate, phosphorus trigas, tribromide or the like is prepared by reaction. Prodrug derivatives of the compounds of the invention can be prepared by methods known in the art to be known in the art (for further details see Bioorganic and Medicinal Chemistry Letters. 1994, '4:1985). For example, suitable prodrugs can be prepared by reacting a compound of the invention with a suitable ammoximation reagent such as decyloxyalkylcarbamate, p-nitrophenyl carbonate or the like. Protected derivatives of the compounds of the invention can be prepared by conventional techniques known in the art. For details on the application of protecting groups and deprotection, see J. H. Wiley and Sons, Inc., 1989, "T. W. Greene, Protecting group in Organic Chemistry" (third edition). The compounds of the present invention can be conveniently prepared or formed, e.g., solvates (e.g., hydrates), in accordance with the methods provided herein. The hydrate of the compound of the present invention can be conveniently prepared by recrystallization from a water/organic solvent mixture using an organic solvent such as dioxins, tetrahydrofuran or ethanol. The compounds of the present invention can be prepared as single optical isomers, and the racemic mixtures of these compounds are treated by optically active resolving agents to form their pair of diastereomers, resolved diastereomers and recovered optically pure enantiomeric systems. Got it.

S 30 201237041 -» / / When the enantiomeric resolution of the compounds of the invention may be carried out using their covalent diastereomeric derivatives, readily separable complexes (e.g., crystalline diastereomeric salts) are preferred. Diastereomers have significantly different physical properties (e.g., melting point, boiling point, solubility, activity, etc.) and can be readily resolved using these different characteristics. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based on solubility differences. The optically pure enantiomer, along with the resolving agent, can then be recovered by any practical method that does not result in racemization. A more detailed description of various techniques suitable for the resolution of stereoisomers from racemic mixtures of these compounds can be found in John Wiley And Sons, Inc., 1981, Enantiomers, Racemates and Resolutions (Jean Jacques, Andre Collet) And a book by Samuel H. Wilen. Briefly, compounds of structural formula I'II and in can be prepared by the following processes, including: (a) a reaction scheme widely employed by a pharmaceutical chemist or as disclosed in the examples described below; and (b) optionally Converting a compound of the invention to a pharmaceutically acceptable salt thereof; (c) optionally converting a salt form of a compound of the invention to its non-salt form; (d) optionally converting a non-oxidized form of a compound of the invention to its pharmaceutically acceptable form An acceptable N-oxide; (e) arbitrarily converting the [sf-oxide of the compound of the invention to its non-vaporized form; (0) optionally splitting the isomer mixture of the compound of the invention into its 31 201237041 J / / single isomer; pharmaceutical compound (4) recorded into a music precursor derivative of its j; or its non-long touch transformant can: =:::=::r, then These compounding methods are similarly prepared. The skilled person in the art as described in the following examples, the above-mentioned (four) process is only representative of the method for preparing the compound, and other known methods can also be used. I want to implement the method ^ the present invention further, However, it is not limited to, and is proved by the following examples illustrating the preparation of the compounds of the present invention, which are of the formulas I, II and III. Example 1 1 -(4_(6-(N- (2_(« Synthesis of guanidin-1 _yl)ethyl)aminoamino)_ 1 H_oxazolium hydrazide phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea

S 32 201237041 _? / / jnpn

Compound 1 18.1 g (0.1 mol) was dissolved in 100 ml of concentrated sulfuric acid, and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) 14.3 g (0.05 mol) was added in portions, and the reaction was stirred at room temperature. hour. The reaction solution was poured into 400 g of crushed ice and stirred for 20 minutes. The precipitated solid was filtered and dried to give 22.1 g of product 2 in a yield of 85%. At a temperature below -5 ° C, 7.2 g (0.06 mol) of thionyl chloride (Thiolyl chloride) was added dropwise to 50 ml of decyl alcohol, and 3-oxa-4-mercapto-5-succinyl benzoic acid (3- Bromo-4-methyl-5-nitrobenzoic acid 13.0 g 33 201237041 (0.05 mol), refluxed for 2 hours after stirring at room temperature. The methanol residue was distilled off under reduced pressure to give 11.2 g of product 3, yield 82%. ... Dissolve product 3 5.1g (〇.〇2m〇1) in 1〇〇mlTHF, add 1〇ml B@欠和5.6g 铁粉, stir and heat for ι〇小时. Cool to room temperature. The filtrate was evaporated to dryness under reduced pressure. The residue was added with water, extracted with ethyl acetate and dried over anhydrous Na? The obtained filtrate was dried to dryness. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The acetic acid was distilled off under reduced pressure, and water was added, and ethyl acetate was evaporated. The obtained ethyl acetate layer was concentrated under reduced pressure to remove solvent, and then purified by flash column chromatography to afford product 3, yield 61%. The product 4 3.1 g (〇.〇l2 mol) was dissolved in 50 ml of ethanol (EtOH), and a 0.43 g (0.018 mol) aqueous solution of iridium hydroxide (LiOH) was added thereto, and reacted to /m for 20 hours. The ethanol was evaporated under reduced pressure, and the residue was diluted with water and then adjusted to pH 4 with 1N hydrochloric acid (HC1). The precipitated solid precipitate was filtered to dry to give 2.32 g of product 5, yield 80%. The product 5 1.21g (0.005m〇l), carbonyl dimethine. Sit (CDI) 82.82g (0.005mol), 2-(piperidin-l-yl)ethanamine 0.83g (〇.〇〇5m〇l) and diisopropyl Ethylamine (DIPEA) 0.65 g (0.005 mol) was dissolved in 2 ml of DMF, and the reaction was stirred at room temperature for 2 hours. After distilling off the DMF under reduced pressure, the residue was purified by flash column chromatography to yield 1.05 g. In a nitrogen atmosphere, the product 6 0.35 lg, 4-aminophenylboronic acid 0.21 g, anhydrous sodium carbonate (sodium s 34 201237041 J / /JtUll carbonate) 〇.32g and tetrakisphenylphenylphosphonate ( Pd(pph3)4) 115 6 mg was dissolved in fME/H 2 〇 (4:1) 8 m, and reacted under a temperature machine for 16 hours. In the end, the reaction solution was cooled to room temperature, and then the organic phase was extracted with 25 ml of ethyl acetate, and the organic phase was washed with saturated brine, and then dried over anhydrous sodium sulfate (Na2SQ4). The liquid was evaporated to dryness and then purified by flash column chromatography to obtain 72 § compound 7 in a yield of 3 1 V 〇 ^ 7 7 , , , , , , , , , , , Phenyl formate (phenyI 3 flu〇r〇meth〇xy) fiber te) G.297g, in the temperature pit TM should be 1 hour, = two after evaporation and concentration of the spin-drying system reaction solution, the resulting residue added two: A After burning, the obtained filter cake was Compound 8, and the yield was 8〇/. LC-MS [M+H]+ m/z was 567.5. House sheep Example 2 1-(4-(6-(Ν-(2-(pyridazin-1-yl)ethyl) ammonia-based, glucosinyl)-1Η-carbazole-4-) base) Synthesis of -3-(3-(trifluoromethoxy)phenyl)urea

The LC-MS [M+H]+ m/z was 568.6 compound and the actual peach county was obtained. Title Example 3 35 201237041 1-(4-(6-(Ν-(2-(tetrahydrofuro-1) Synthesis of -ethyl)ethyl)aminocarbonyl)-1Η-indole-4-yl)phenyl)-3-(3-(trifluorodecyloxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 553.4. Example 4 i _(4-(6-(N-(2-(2-methoxyethoxy)ethyl)aminocarbonyl)-1Η-indolyl-4-yl)phenyl)-3-(3) -(trifluoromethoxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 558.3. Example 5 1-(4-(6-(Ν-((2-methoxyethoxy)indolyl)aminocarbonyl)-1Η-indol-4-yl)phenyl)-3-(3- Synthesis of (trifluorodecyloxy)phenyl)urea

S 36 201237041

The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 544.6. Example 6 1 _(4-(6-(N-(2-(2-(A))-yl)ethyl)sulfonyl)-1H-indazol-4-yl)phenyl)-3-( Synthesis of 3-(trifluoromethoxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 603.4. Example 7 1 _(4-(6-(N-(2-(2-(pyridazin-1-yl)ethyl)aminosulfonyl)-1H-indazol-4-yl)phenyl)-3-( Synthesis of 3-(trifluoromethoxy)phenyl) gland 37

20123' The title compound was obtained using a synthetic route similar to the one of the previous example, which had an LC-MS [M+H]+ m/z of 604.5. Example 8 1-(4-(6-(Ν-(2-(tetrahydropyrrol-1-yl)ethyl)aminosulfonyl)-1Η-indol-4-yl)phenyl)-3 Synthesis of -(3-(trifluoromethoxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 589.4. Example 9 1_(4-(6-(Ν-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)-1Η-oxazol-4-yl)phenyl)-3- Synthesis of (3-(trifluoromethoxy)phenyl)urea

S 38 201237041 _ / / /

1

H2n-r Et3N

CH2CI2 DBDMH h2so4

NaN02

Νθ2〇〇3 Pd(dppf)CI2 DME, H20

AcOH

The title compound was obtained using the above synthetic route with LC_MS [M+H]+ m/z of 594.4. Example 10 1-(4-(6-(Ν-((2-methoxyethoxy)indolyl)sulfonyl)-1Η-oxazol-4-yl)phenyl)-3-( Synthesis of 3-(trifluoromethoxy)phenyl)urea

39 201237041 -J / /-?TLIJ1 The title compound was obtained using a synthetic path similar to that of Example 9 to afford LC-MS [M+H]+ m/z of 580.3. Example 11 -Based) 1-(4-(6-(2-(2-)-yl)ethoxy)_1-yl)-3-(3-(trifluorodecyloxy)phenyl Urea synthesis

A synthetic route similar to the previous example was used with LC-MS [M+H]+ m/z of 540.4. 'To be titled Example 12 1-(4-(6-(2-(p-)-yl)ethoxy η jjn-yl)-3-(3-(trifluorodecyloxy)phenyl Urea synthesis &lt; base) stupid

Using a synthetic route similar to the previous embodiment, the LC-MS [M+H]+ m/z was 541.3. Titled Example 13 1 -(4-(6-(2-(tetrahydropyrrole-1-yl)ethoxy)-i Hnyl)-3-(3-(trifluorodecyloxy)phenyl Urea synthesis - base) stupid 201237041

The title compound was obtained by a synthetic route similar to that of the previous one, which had an LC-MS [M+H]+ m/z of 526. Example 14 1-(4-(6-(2-(2-methoxyethoxy)ethoxy)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoro) Synthesis of decyloxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had a LC-MS [M+H]+ m/z of 531.4. Example 15 1 -(4-(6-(2-(Acridine-1-yl)ethylamino)-1H-indazol-4-yl)phenyl)-3-(3-(trifluoroantimony) Synthesis of phenyl)urea Η μ

A titled 41 201237041 compound was obtained using a synthetic route similar to the one of the previous embodiment, which had an LC-MS [M+H]+ m/z of 539.5. Example 16 1 -(4-(6-(2-(pyridazin-1-yl)ethylamino)-1 Η-oxazol-4-yl)phenyl)-3-(3-(trifluoromethyl) Synthesis of oxy)phenyl)urea Η

The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 540.5. Example 17 1 -(4-(6-(2-(4-(4-(2-(4-(2-)-)-yl)-yl-yl) Synthesis of 3-(trifluoromethoxy)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 525.4. Example 18 1_(4-(6-(2-(2-methoxyethoxy)ethylamino)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoromethyl) Synthesis of oxy)phenyl)urea

S 42 201237041 j / /

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had a LC-MS [M+H]+ m/z of 530.5. Example 19 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(2-)-)-carbonyl) -1Η-ηpyrolo[2,3-c]acridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 585.9. Example 20 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyridazin-1-yl)ethyl)aminocarbonyl) Synthesis of -1Η-ηpyrolo[2,3-c]acridin-1-yl)phenyl)urea 43 201237041 j//jnpn

0

H was prepared using a synthetic route similar to that of the previous embodiment to give the title compound, which had an LC-MS [M+H]+ m/z of 587.0. Synthesis of H-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3 仏 (tetrahydroindenyl 1-yl)ethyl)aminocarbonyl)-1 Η-吼And [2,3-c&gt; than the bite seven base) benzoquinone gland ηνΛ.

Using a synthetic route complex similar to the previous example, LC-MS [M+H]+ m/z was 572.1. Example 22 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(Tetra(2α-oxy)ethyl)aminocarbonyl)-1Η-pyrrole And [2,3-clf —, —the synthesis of oxime 2] is better than the mouth + base) (10)

44 S 201237041

The title compound was obtained by a synthetic route similar to that of the previous ones, which had an LC-MS [M+H]+ m/z of 576. Example 23 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-((2-methoxy)ethoxy)indolyl)carbonyl) Synthesis of -1Η·-Bido-[2,3-c].pyridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones to give an LC-MS [M+H]+ m/z of 562.7. Example 24 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(acridin-1-yl)ethyl)aminosulfonium) Synthesis of -1Η-η-pyrolo[2,3-c]acridin-1-yl)phenyl)urea 45 201237041

The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 622.0. Example 25 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyridazin-1-yl)ethyl)aminosulfonium) Synthesis of 1-)-Η-[Bisolo[2,3-c]acridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 623.1. Example 26 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(tetrahydroindol-1-yl)ethyl)amino) Synthesis of sulfonyl)-1Η-ηpyrolo[2,3-c].pyridin-1-yl)phenyl)urea

S 46 201237041 ·»» i / -Γ μ;里i

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 608.0. Example 27 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(indolyl)-(1-(2-decyloxyethoxy)decyl)amino group Synthesis of sulfonyl)-1Η-pyrrolo[2,3-decidin-1-yl)phenyl)urea

The title compound was obtained by a synthetic route similar to that of the previous one, which had LC-MS [M+H]+ m/z of 598. Example 28 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(cyclohexyl-1-yl)butyl)-1Η-η ratio Synthesis of p-[2,3-c]acridin-1-yl)phenyl)urea

0 47 201237041 The title compound was obtained using a synthetic route similar to the one of the previous example, which had an LC-MS [M+H]+ m/z of 571.1. Example 29 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(indol-1-yl)butyl)-1 Η-吼 并Synthesis of [2,3-c]acridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 571.9. Example 30 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(tetrahydroindol-1-yl)butyl)-1Η-吼Synthesis of p-[2,3-c]acridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 557.1.

S 48

201237041 / I Example 31 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(2-methoxyethoxy)butyl)- Synthesis of 1Η-吼 并[2,3-decapyridin-1-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 561.9. Example 32 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-(2-decyloxyethoxy)ethyl)-1Η-η Synthesis of benolo[2,3-c]acridin-1-yl)phenyl)urea

The title compound was obtained by a synthetic route similar to the previous two examples, which had LC-MS [M+H]+ m/z of 533·8. Example 33 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(1-(indol-(2-(foxidin-1-yl)ethyl)aminocarbonyl)) Synthesis of -1Η-.Bisto[3,2-c].pyridin-3-yl)phenyl)urea 49 201237041

1

NIS

Β〇〇2〇

The title compound 7' was obtained as LC-MS [M+H]+ m/z. Example 34 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(1-(indol-(2-(pyridazin-1-yl)ethyl)aminocarbonyl) Synthesis of -1Η-pyrrolo[3,2-c]pyridin-3-yl)phenyl)urea

The title compound was obtained using a synthetic path similar to that of Example 33, which had an LC-MS [M+H]+ m/z of 586.9. Example 35 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(indol-(2-(tetrahydroindol-1-yl)ethyl)amino) Synthesis of carbonyl)-1Η-.pyrolo[3,2-c]acridin-3-yl)phenyl)urea 0 α〆

The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 571.8. Example 36 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(1-(fluorenyl)ethoxy)ethyl)amino Synthesis of carbonyl)-1Η-indolo[3,2-φ-pyridin-3-yl)phenyl)urea 51

201237041 The title compound was obtained using a synthetic route analogous to the previous ones to afford LC-MS [M+H]+ m/z 576.7. ', Example 37 1-(4·Chloro-3-(trifluoromethyl)phenyl)-3_(4-(l-(N-((2-methoxy)ethoxy)methyl)amino) Synthesis of -1H-pyrrolo[3,2-c]pyridyl) phenylene

The title compound was obtained using a synthetic path similar to the one of the previous ones to give an LC-MS [M+H]+ m/z of 562.8. Example 38 ^(4-Gas_3_(Trifluoromethyl)phenyl)_3_(4_(1_(Team (2 saguaro)) Ethyl) Amino-Amino-Alkyl [3,2-c]° ratio. Synthesis of _3_base)

52 S 201237041 The title compound was obtained using a synthetic route similar to the one of the previous ones with LC-MS [M+H]+ m/z of 622.0. Example 39 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(1-(indol-(2-(foxazin-1-yl)ethyl)aminosulfonium) -1Η-ηpyrolo[3,2-c]acridin-3-yl)phenyl)urea

Synthesis of Pnh The title compound was obtained using a synthetic path similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 623.1. Example 40 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2-(吼)-1-yl)ethyl)aminosulfonium) Synthesis of )-Η-吼吼[3,2-c]acridin-3-yl)phenyl)urea

53 201237041 The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 607.9. Example 41 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-(2-(2-)oxyethoxy)ethyl)amino continued醯))-1Η-πΛ和[3,2-c]e ratio. 3)))

The title compound was obtained using a Synthetic Path # similar to the one of the above-mentioned, which had a LC-MS [M+H]+ m/z of 612.9. Example 42 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-((methyl)methyl)aminosulfonyl)-1Η-pyrrole And [3,2-small bite, synthesis of 3 broad milk, stupid base) urea

Using a synthetic path similar to the previous embodiment to make 3^ days

54 S 201237041 Compound with LC-MS [M+H]+ m/z 599.0. Example 43 H4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(3-(foxidin-1-yl)propoxy)-1 H-atb) Synthesis of 3,2-c] ° ratio σ-3-yl) base) gland

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had a LC-MS [M+H]+ m/z of 572.8. Example 44 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(3-(foxazin-1-yl)propoxy)-1Η-吼) Synthesis of [3,2-c]Acridine-3-yl)phenyl)urea

55 201237041 The title compound was obtained using a synthetic route similar to the one of the previous example, which had an LC-MS [M+H]+ m/z of 574.0. Example 45 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(3-(tetrahydroindol-1-yl)propoxy)-1Η- »Synthesis of berbolo[3,2-c]acridin-3-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 558.9. Example 46 1-(4-Gas-3-(trifluoromethyl)phenyl)-3-(4-(1-(2-(2-decyloxyethoxy)ethoxy)-1Η- Synthesis of fluorenyl[3,2-c]acridin-3-yl)phenyl)urea

The title compound was obtained using a synthetic route similar to the one of the previous ones, which had an LC-MS [M+H]+ m/z of 549.8. Example 47

S 56 201237041 J / / jnuil fluoro-3-(.yl)ethyl)-1Η-pyrrolo[3,2-c]pyridine-3-yl)phenyl)urea

A synthetic route similar to the previous embodiment was used, which had an LC-MS [M+H]+ m/z of 533.8.知知化 Effect test

Upstate KinaseprofiierTM #射酶膜膜试验 The compounds of the invention are directed against each of the kinase activities of the kinase catalog. These compounds were repeated twice under the conditions of a final concentration of 〇 5 μΜ as in the general procedure. Note that the different kinases in the kinase catalog use different kinase buffers and substrates. Kinase buffer (2.5 吣, containing 10x MnCb, if required), activated kinase (3) 〇〇1〇〇1 mono 2; 2.5 μΙ〇, special or P〇iy (Glu4_Tyr) peptides (5 5〇〇_戈0.01 mg/mL of kinase buffer and kinase buffer (5 μm; 5 μιη) were mixed in an eppendorf tube placed in ice/cold. A Mg/ATP compound (lOpL; 67.5 mM MgCl2 or 33.75 mM MgCl2, 450 μM or 225 μM ATP and 1 Ci/pL [-32P] (3000 Ci/mmol)) was added and the reaction was incubated at 30 ° C for 10 minutes. Pipette the reaction solution 2 (PL to 2 cm x 2 cm (phosphorescent cellulose for positively charged peptide substrates) or Whatman No. 1 (for poly(Glu4_Tye) peptide substrates) on squared paper. 201237041 mnpii plaid paper is washed 4 times with 0.75% phosphoric acid for 5 minutes each time, then washed once with acetone for 1 time for 5 minutes. Move the checkered paper into the test bottle and add 5mL of scintillation cocktail to the bottom of the peptide. The 32P (cpm) of the substance is counted in a Beckman scintillation counter. The inhibition rate of each reaction is calculated. The unsalted form of the compound of the formula I, II and III or a pharmaceutically acceptable salt thereof exhibits valuable value. Pharmacological properties, such as those in the in vitro assays described herein. For example, at concentrations of 〇·2 μΜ, compounds of the formula Ι, π, and III, for Flt3, pDGFR, pDGFR, c KIT, VEGFIU, VEGFR2, VEGFR3, c-RAF, Abb AM-T315I, FGFR1 and FGFR3 kinases exhibit inhibition rates above 25 〇/〇, more preferably above 50%. It will be appreciated that the specific embodiments and embodiments described herein are illustrative of the purpose of the invention. And to the ability The general practitioner S provides &amp;amp; includes the breadth of the dependent claims of the present invention. The documents, patents, and patent applications of the Japanese version of the text are provided for the purpose of disclosure. Certain embodiments of the present invention have been made. Example compound in the inhibition of enzyme test

S 58 201237041 ^ιι Table 1 ___—*--&quot;Γ* - Example 3 Example 4 j inhibition rate at a concentration of 0.2 μΜ (%) j Example i Example 6 Example 9 Fltl(h) 17 22 26 60 55 Flt3(h) 67 67 62 53 36 Flt4(h) 92 92 95 95 ___ KDR(h) 88 84 94 87 JiJ PDGFRa(h) 52 53 44 29 18 PDGFRP(h) 48 49 29 28 11 Ret (h) 39 27 44 76 64 Tie2 (h) 11 19 11 75 10 Although the invention has been disclosed above by way of example, it is not intended to limit the invention, and any one of ordinary skill in the art In the spirit and scope of the invention, 'when there may be some changes and refinements, this is the right that is defined by the scope of the patent application. M. 〇 [Main component symbol description] 59

Claims (1)

201237041 VII. Patent application scope: 1. A compound 'is represented by structural formula I, II or III. Wherein X and Y are independently selected from N or CH, and at least one of X and Y is N, wherein said N may be suitably or not substituted by a hydrogen atom; R2 is selected from the group consisting of r7, 0R7, NR7R8, S ( 0) qR7, s〇2NR7R8, nr7so2r8, c(o)r7, C(0)0R7, c(o)nr7r8, NR7C(0)R8 or NR7C(0)OR8, wherein 'the q is independently selected from 〇 , 1 or 2, the 117 and 118 are independently selected from: (a) a Cw linear, branched or cyclic hydrocarbon group, the hydrocarbon group further being 5 to 8 members containing 1 to 4 selected from the group consisting of ruthenium and N4s. a heteroatom heterocyclic cycloalkyl group substituted, and the hydrocarbyl group and the heterocyclic ring hydrocarbyl group may be optionally substituted by one halogen or a plurality of halogens; one step is substituted with a guanamine or sulfonylamino group, (b) Cm a linear, branched or cyclic hydrocarbon group, and the hydrocarbon group and the sulfonamide group are optionally linearly, branched or branched by a (c) CM and the hydrocarbon group, the hydrazine Amine-based halogen or a plurality of halogens; optionally may be a dentate or a plurality of halogen (d) Cho straight bonds, a bond or a ge. A straight-chain branch or a ring-shaped bond containing a plurality of key words, and a halogen or a plurality of _ primes; ίο linear, branched or looped with a plurality of __, and 201237041 further by 5~8 The element contains 1 to 4 substituents selected from the group consisting of an anthracene, an N-ring cyclic hydrocarbon group and the chain is substituted with the impurity == one ii or a plurality of halogens; a linear, branched or cyclic substituted multi-step substituted with amidino or sulfonylamino group ', and = two R1... is selected from the group consisting of nitrogen, alkyl, base: = base, and base-based Base 'aryl aryl group:; group: skeletal alkyl group, aryl alkynyl group, aryl oxyalkyl group, alkane = hydrazine alkyl group, aromatic aryl group: aryl group, fluorenyl group, alkyl group , cycloalkyl, alkyne = its alkenyl group, cyanowyl group, cyano group, cycloalkyl group, oxygen group, halogen group, aryl group, heterocyclic aryl group, heterocyclic aryl group, heterocyclic ring Silk, heterocyclic silk county, miscellaneous silk-based dilute group, ^cycloaryl m Newtyl, heterocyclic cycloalkyl group, transcyclic hydrocarbyl group, heterocyclic mono-alkyl group, hetero- Wei hydrocarbon group, heterocyclic ring Keith, heterocyclic ring=hydrocarbyl group, cyclohydrocarbyl group, heterocyclic ring hydrocarbon group, cyclonicolyl group, cycloalkyl block group, methylenyl group, formamyl group, _hydrocarbyl group, Heterocyclic aryl, heterocyclocycloalkylcarbonyl hydrocarbyl, heterocyclocycloalkyloxyalkenyl, hydroxyalkenyl, hydroxyalkyl, hydroxyalkynyl, NRaRb, (NRaRb)alkenyl, (NRaRb) leunt, (NRaRb) alkyne (NRaRb)carbonyl, (NRaRb)carbonylalkenyl, (NRaRb a carbonylalkyl group, (NRaRb)carbonylalkynyl, nitro, nitroalkenyl, nitroalkyl or nitroalkynyl; and Ra and Rb are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkenyl, alkoxy Alkyl group, 61 201237041 alkane minus base form New Zealand, ruthenium, fluorenyl hydrocarbyl group, hydrocarbyl aryl group, aryl (4) 乂 I I, aryl aryl aryl, aryl alkoxy carbonyl Ια方'&quot; occupation, aryl, aryl, heterocyclic aryl, heterocyclic «, cyclohydrocarbyl, translating, cycline, heterocyclic cyclopentanylcarbonyl, heterocyclic ring &lt;τ&lt; It sells its &quot;its (4)~: kewei hydrocarbyl sulfonyl, hydroxy hydrazine, hydroxy group, county hydrocarbon, ring, cycloalkyl, dimethyl ketone te, heterocyclic aryl, heterocyclic aryl Hydrocarbyl group, (ΝκΛ)nicotinyl group: soil, (NRCR minus group, (NRcRd) hydrocarbon group or (10) upper heteroalky group; the same - the aryl 'aryl aerobic carrier, aryl alkoxy a heterocyclic aryl group, a heterocyclic aryl group, a heterocyclic green hydrocarbon group and a heterocyclic aryl group, a heterocyclic aryl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl group, a heterocyclic aryl group Part, rotating wire, and heterocyclic ring The heterocyclic cycloalkyl moiety of the hydrocarbyl hydrocarbyl group and the heterocyclocycloalkyl hydrocarbyl group may be further selected from the group consisting of 2, 3, 4 or 1 side selected from the group, the silk group, the alkoxy group, and the f group. , alkynyl, hydrocarbylcarbonyl, aryl, arylhydrocarbyl, halogen, haloalkoxy, halohydrocarbyl, hydroxy, nitro, NRcRd, (NRcRd) hydrocarbyl, (NReRd) hydrocarbylcarbonyl, (NReRd)carbonyl, (NReRd a group substituted with a carbonyl hydrocarbyl group, a _〇_f spiroheterocycloalkyl group, wherein the aryl moiety of the aryl and aryl hydrocarbyl groups may, in turn, be further selectively 1, 2, 3, 4 or 5 independently selected from a group substituted with an alkoxy group, a hydrocarbyl group, a cyano group, a functional group, a haloalkoxy group, a functional hydrocarbyl group, a nitro group or a hydrazine group; and wherein Rc and Rd are independently selected from hydrogen, alkoxy group, hydrocarbyl group, aryl group , a carboxyhydrocarbyl group, a cycloalkyl group, a hydrocarbyl group, a heterocyclic aryl group, a heterocyclic cycloalkyl group, a heterocyclocycloalkyl hydrocarbon group, a hydroxyalkoxy hydrocarbon group, a hydroxyhydrocarbyl group or a (NReRf) 62 1 201237041 -J / / JTUll hydrocarbon group; , aryl and heterocyclocyclobutanyl can be optionally selected from 2, 3, 4 or 5 independently selected from alkenyl, decyloxy, fenyl, and aryl. Substituted with a halogen, i-substituted lactide, S-sodium, hetero or nitro group; and Re and Rf are independently selected from hydrogen or a thio group; R4 is selected from 1 to 3 independently selected from _ a C6_1G aryl group substituted with a group of a Ci6 nicotinic group, a halogenated Cm alkoxy group, a Cmo heterocyclic aryl-Cw hydrocarbon group or a Gy heterocyclic cycloalkyl-Qm hydrocarbon group; the heterocyclic aryl group of the &amp; The substituent and the heterocyclic cycloalkyl substituent may be optionally substituted by a Cl6 nicotinic or N-oxide derivative; the smectites I and R6 are independently selected from hydrogen or a Cl. 6 hydrocarbyl group; or &amp; and R6, and The phenyl group attached to the ruthenium and the heart forms an "aryl or C5i., group; '' or a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a covalent complex or a prodrug thereof . , Qiu 2. For the compound described in claim 1, the bean N. ',|八疋 3. For example, the compound described in claim 1 of the patent scope, N. '1 疋 4. The structure of the compound: the compound described in item 1, wherein the compound is represented by 'where X is Ν and γ is CH. The compound of the invention is as described in claim 1, and the compound is as described in the first paragraph of the patent. Configuration 11 represents where X is Ν and γ is CH. ° If the compound described in the scope of the patent application, the compound 63 201237041 J / / Jtpu is represented by the structural formula III, wherein it is again Y * NH, or, when x is NH, Y is N. 7. The compound of any one of claims 1, 4, 5 or 5, wherein R2 is selected from the group consisting of R?, 〇R7, nr7r8, so2NR7R8, c(o)r7, C(0)0R7 , c (〇) NR R8, N nr7c (o) or 8. The compound of claim 7, wherein at least one of r7 and R8 is independently selected from the group consisting of: (a) a C!-5 linear, branched or cyclic hydrocarbon group, and the hydrocarbon group Further, the step is substituted by a heterocyclic ring hydrocarbon group having 5 to 8 members of a hetero atom selected from the group consisting of 〇 and Ν0, and the hydrocarbon group and the heterocyclic ring hydrocarbon group may be selectively substituted by one dentate or Substituting a plurality of dentates; (b) a Cw linear, branched or cyclic hydrocarbon group, and the hydrocarbon group is further substituted with a decylamino or sulfonylamino group, and the hydrocarbon group, the guanamine group and the The 35 amino group may be optionally substituted by one dentin or a plurality of dentates; (c) a Cw linear, branched or cyclic chain containing a plurality of ether linkages, and optionally a _ Or a plurality of dentates are substituted; (d) Ci_g is a direct bond, a bond, or a bond containing a plurality of 趟 bonds, and the step is 5 to 8 yuan! ~3 heterocyclic anthracenyl groups selected from hetero atoms of hydrazine, N and s, and the chain and the heterocyclic ring hydrocarbon group may be optionally substituted by one halogen or a plurality of dentates; (e) Q· a linear, branched or cyclic chain containing a plurality of ether linkages, and further substituted with a decylamino or sulfonylamino group, and said chain, said guanamine oxime sulfonamide It may be optionally substituted by one or more than one element. A compound according to claim 7 wherein at least one of r and R8 is independently selected from the group consisting of: 7 (a) Cw linear, branched or cyclic a chain of a plurality of ether linkages, and may be optionally substituted by one or a plurality of auxins; (b) a C, 6 linear, branched or cyclic chain containing a plurality of ether linkages, and The step is substituted with 5 to 8 members containing 2 heterocyclic ring hydrocarbon groups selected from the group consisting of a hetero atom, and the chain and the heterocyclic ring hydrocarbon group may optionally have one halogen or a plurality of halogens. Substituting; (〇Cm linear, branched or cyclic chain containing a plurality of ether linkages, and further stepped by an amine group or a two amine filament, and the chain, the saponin The amine group may be optionally substituted with -(tetra) or a plurality of ketones, 10. The compound of claim 9, wherein Ri, I, I and I are independently selected from hydrogen, halogen or lower hydrocarbon group. , & is a benzene substituted with 3 groups selected from the group consisting of a group selected from a group consisting of a group selected from a group consisting of a group selected from a group consisting of a halogen group, a halogenated Ci6 alkoxy group, a Cw heterocyclic aryl-Qm hydrocarbon group or a Cw heterocyclic cycloalkyl group _Cq* hydrocarbon group. If you apply for a patent The compound according to Item 9, wherein Ri, R3, R5 and R6 are all hydrogen, and R4 is optionally substituted by 丨~3 groups independently selected from halogen, halogenated Cm hydrocarbon group, orthoCi-6 alkoxy group. U. The compound of claim 7, wherein at least one of R7 Shoukou r8 is independently selected from the group consisting of Ci4 linear, branched or looped tobacco. 5 to 8 yuan contains U heterocyclic ring filaments selected from hydrazine or N, a hetero atom, and the hydrocarbon group can be optionally substituted by one halogen or a plurality of halogens.", Yi II 65 201237041 J ff ^-ruii 13. The compound according to claim 12, wherein the 1-3, Rs and Re are independently selected from the group consisting of hydrogen, a physin or a lower sulphur group, and the chemistry is: a phenyl group substituted with a Ci6 hydrocarbon group, a Ci6 alkoxy group, a 5-10% by mole, an aryl group C (M hydrocarbon group &amp;&amp;&amp; heterocyclic group. R I4 · as described in claim 12 A compound wherein 1 a, R 1 and Re are all hydrogen, and hydrazine is a phenyl group optionally substituted with 3 groups independently selected from the group consisting of hydrazine, 4th generation Cm hydrocarbon group and _ generation cN6 alkoxy group. The compound of claim 7, wherein at least one of &amp; 8 is independently selected from the group consisting of Cm linear, branched or cyclic hydrocarbons, the further further being ugly amine or hydrazino And the compound of claim 15, wherein 1 R3 R5 and uldent 6 are independently selected from hydrogen, a functional group or a lower hydrocarbon group, and K is a fluorene-based, chiral Ci-6 hydrocarbon-based shop. Dependent base, take ^ ^ base -c. • 4 hydrocarbyl or C 3 .8 heterocyclocycloalkyl-c. The group of the invention is the compound of claim 15, wherein _ s = 1 and R 6 are both nitrogen ' R 4 is optionally 1 to 3 independently selected from ... tooth C - a phenyl group substituted with a group of alkoxy groups. And D apply for a compound of the scope of claim 1 and at least one of the intermediate soil RI is independently selected from the group consisting of hydrogen, quinone or nicotinic//19. Wherein at least one of Ri 66 1 201237041 and R3 is independently selected from hydrogen, a tropin or a CK6 hydrocarbon group. The compound of claim 1, wherein at least one of R1 and R3 is independently selected from hydrogen or halogen. 21. The compound of claim 1, wherein r] and R3 are both gases. θ 22. The compound according to claim 1, wherein the compound is independently selected from the group consisting of halogen, halogenated CM hydrocarbon, haloalkoxy, C5.8 heterocyclic aryl-CG_4. a C6_ioaryl group substituted with a hydrocarbyl group or a C3·6 heterocyclocycloalkyl-Qm hydrocarbyl group; the heterocyclic aryl substituent or heterocyclocycloalkyl substituent of R4 may be optionally substituted by ci·4 alkyl or N - Oxide derivative substitution. 23. The compound of claim 3, wherein the hydrazine is optionally 1 to 3 independently selected from the group consisting of halogen, halogenated Cm hydrocarbon, halogenated Cl alkoxy, (5-8 heterocyclic aryl) _C (A8 aryl substituted with a group of a M hydrocarbyl group or a C3.6 heterocyclic cycloalkyl hydrocarbyl group; the heterocyclic aryl substituent of R4 may be optionally a CM hydrocarbyl group or a group Substituting an oxide derivative. 24. The compound of claim 1, wherein the center is selected from the group consisting of 1-2 groups independently selected from the group consisting of halogen, halogenated rcm hydrocarbon, and halogen Ci-4 alkoxy. Substituted c6_8 aryl. 25. The compound of claim 1, wherein i is optionally 1 to 3 independently selected from the group consisting of halogen, halogenated Cm hydrocarbon, dentate Cy alkoxy, C5_1Q a heteroaryl group substituted with a aryl group of a cycloaryl-cm hydrocarbyl group or a CM heterocyclic cyclohydrocarbyl group; a heterocyclic aryl substituent of the R4 or a heterocyclic group of the cyclinyl group optionally substituted by C16 Substituting a hydrocarbyl group or an N-oxide derivative. The compound of claim 1, wherein at least one of R5 and Re is independently The compound of claim 1, wherein &amp; and R6 are both nitrogen. 28. The compound of claim 1, wherein r5 and R6' And a quinolyl or a naphthol group formed by the phenyl group attached to the ruthenium 5 and R6. 29. The compound of claim 1, wherein the compound is selected from the group consisting of: "-(4-(6·( Ν-(2 hexadecidinyl)ethyl)amino]yl)_1Η_α azole _4_yl)phenyl)-3-(3-(trifluoromethoxy)phenyl)urea; ·0Κ6-(Ν- (2 10 guarazine _! base) ethyl) aminocarbonyl) _ i H_ oxazolidine phenyl)-3-(3-(trifluoromethoxy)phenyl)urea; 1-(4 -(6.(2-(tetrahydro-(indolyl)ethyl)aminocarbonyl)-Chloropurinyl)phenyl)_3_(3_(trifluoromethoxy)phenyl)urea; K4-( 6-(N-(2_(2-methoxyethoxy)ethyl)aminocarbonyl)_ιη· 十坐-4-yl) stupid)·3_(3_(trifluoromethoxy)phenyl)urea Η4-(6-(Ν-((2-methoxyethoxy)methyl)aminocarbonyl)·ιη吲 sialyl)phenyl)-3-(3.(trifluoromethoxy)benzene Urea; 1 (4 (6-N-(2 saponin) ethyl) sulfamoyl)_1H Azole-4-yl)phenyl)-3_(3-(trifluoromethoxy)phenyl) gland; 4^4:(6 (N-(2, sulphide)ethyl)amino) _1H-° azole (group)) benzyl 3-(3-(trifluoromethoxy)phenyl) gland; £ 68 201237041 1·(4-(6-(Ν-(2_〇 《 ”咯 丨 基 基 ) 乙基 乙基 乙基 基 基 基 基 基 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- -(Ν-(2-(2-methoxyethoxy)ethyl)aminosulfonyl)-1Η-oxazol-4-yl)phenyl)-3-(3-(trifluoromethoxy) Phenyl)urea; 1·(4-(6-(Ν-((2-methoxyethoxy)indolyl)aminosulfonyl)_1H_ 吲 __4_yl)phenyl)-3_( 3-(4-(6-(2-(acridin-1-yl)ethoxy)_1H-indazole ice-based)phenyl)-3-() 3-(4-(6-(2-(pyridazin-1-yl)ethoxy)_1H-indazole-4-yl)phenyl)_3 -(3_(trifluoromethoxy)phenyl)urea; 1-(4-(6-(2-(tetrahydro)&quot; 比比_ι_基)ethoxy)_阳_吲0坐·4 _)phenyl)-3-(3-(trimethylmethoxy)phenyl)urea; 1-(4-(6-(2-(2-methoxy)ethoxy)ethoxy)_ιη -吲峻-4-yl) Stupid) Winter (3-(Trifluoro) Oxy)phenyl)urea; 1-(4-(6-(2-(acridin-1-yl)ethylamino)_iH-indazol-4-yl)phenyl)-3-0-(three Fluoromethoxy)phenyl)urea; 1 -(4-(6-(2-(pyridazin-1-yl)ethylamino) i H_carbazole _4_yl)phenyl)·3_(3_ (_Ξ^methoxy)phenyl)urea; 1-(4-(6-(2-(tetrahydroindol-1-yl)ethylamino)_1Η-indazol-4-yl)phenyl) 3-(4-trifluoromethoxy)phenyl]urea; 1-(4-(6-(2-(2-oximeoxyethoxy)ethylamino)-ΐΗ-α弓卜坐-4- Base) _3_(3_(trifluorodecyloxy)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)_3-(4-(3-(Ν-( 2-(Acridine-1-yl)ethyl)aminocarbonyl)-1Η-pyrrolo[2,3-c]pyridin-1-yl)phenyl)urea; 69 201237041 j I / jnpn 1-(4- Gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(pyridazin-1-yl)ethyl))yl)-carbyl)_ 洛和[2 ,3-c]B is more than -1 -yl), the base, gland, 1-(4-a-3-(trifluoromethyl)phenyl)-3-(4-(3-(Ν-( 2-(tetrahydrogen. Pilo-1-yl)ethyl)aminocarbonyl)-1Η-«bido[2,3-c]acridin-1-yl)phenyl)urea; 1-(4- gas-3-(three Fluorinyl)phenyl)-3-(4-(3-(N-(2-(2-decyloxyethoxy)ethyl)aminocarbonyl)-1Η-indolo[2,3-c Acridine-1-yl)phenyl) gland, 1-(4-a-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-((2-yloxy)oxy) Ethoxy)indolyl)aminocarbonyl)-1Η-«bido[2,3-decidin-1-yl)phenyl)urea; 1-(4-murine-3-(dione) Phenyl)-3-(4-(3-(Ν-(2-(σ&gt;/^σ定-1-yl)ethyl)aminosulfonyl)-1Η-η ratio 咯[2,3- c; h:pyridin-1-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(呱)) Pyridazin-1-yl)ethyl)aminosulfonyl)-1Η-ηpyrolo[2,3-c]acridin-1-yl)phenyl)urea; 1-(4-chloro-3-( Trifluoromethyl)phenyl)-3-(4-(3-(N-(2-(tetrahydroindol-1-yl)ethyl)))))) 2,3-c]β ratio β-l-yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3-(4-(3-(Ν- (1-(2-decyloxyethoxy)methyl)aminosulfonyl)-1Η-«bido[2,3-c]acridin-1-yl)phenyl)urea; 1-( 4-gas-3-(trifluoromethyl) 3-(4-(3-(4-(acridin-1-yl)butylpyrolo[2,3-c]acridin-1-yl)phenyl)urea; 1-(4 -Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(pyridazin-1-yl)butyl)-1Η-.pyrho[2,3-c Bis-1-yl)phenyl)urea; 201237041 / / 1-(4-A-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-(tetrahydro))吼 -1- 1-yl) butyl)-1 Η-吼 吼[2,3-c].pyridyl-bu)phenyl)urea; 1-(4- gas-3-(trifluoromethyl) Phenyl)-3-(4-(3-(4-(2-decyloxyethoxy)butyl)-lH"pyrho[2,3-c].pyridin-1-yl)benzene Urea; 1-(4-carb-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-(2-decyloxyethoxy)ethyl)-1Η-吼[6,3-c:h-pyridin-1-yl)phenyl)urea; 1-(4-a-3-(trifluoromethyl)phenyl)-3-(4-(1- (Ν-(2-(Acridine-1-yl)ethyl)aminocarbonyl)-1Η-indolo[3,2-c]acridin-3-yl)phenyl)urea; 1-(4- Gas-3-(trifluoromethyl)phenyl)-3-(4-(indole(Ν-(2-(azizin-1-yl)ethyl)aminocarbonyl)-1Η-吼)[3, 2-c]a-pyridin-3-yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2- (tetrahydrofuran-1-yl)ethyl)aminocarbonyl)-1Η-吼 并 [3 , 2-c] acridine-3-yl)phenyl)urea; 1-(4- gas-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2- (2-methoxyethoxy)ethyl)aminocarbonyl)-1Η-ηpyr-[3,2-c]acridin-3-yl)phenyl)urea; 1-(4-chloro-3) -(trifluoromethyl)phenyl)-3-(4-(1-(indolyl-((2-decyloxyethoxy)indolyl)aminocarbonyl)-1Η-indolo[3,2- c] acridine-3-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2-(呱)) -1-yl) Ethyl)aminosulfonyl)-1Η-. More than [3,2-c]. Bispin-3-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(Ν-(2-(呱. Qin-) 1-yl)ethyl)aminosulfonyl)-1Η-ηpyr-[3,2-c]acridin-3-yl)phenyl)urea; 1-(4- gas-3-(trifluoro) Methyl)phenyl)-3-(4-(indolyl-(2-(acridin-1-yl)ethyl)aminosulfonyl)-1Η-indolo[3,2-c]吼Pyridin-3-yl)phenyl)urea; 71 201237041 j / / j-rpn 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(l-(N-( 2-(2-decyloxyethoxy)ethyl)aminosulfonyl)-1Η-indolo[3,2-decaderidin-3-yl)phenyl)urea; 1-(4-chloro -3-(Trifluoromethyl)phenyl)-3-(4-(1-(indolyl-((2-methoxyethoxy)indolyl)aminosulfonyl)-1Η-吼-[ 3,2-c]Acridine-3-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(3-) fox Pyridin-1-yl)propoxy)-1Η-indolo[3,2-c]acridin-3-yl)phenyl)urea; 1-(4-chloro-3-(trifluoromethyl) Phenyl)-3-(4-(1-(3-(foxazolyl-1-yl)propoxy)-1Η-η-pyrolo[3,2-c]acridin-3-yl)phenyl Urea; 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(3-(tetradecyl)pyran-1-yl)propoxy)-1Η -η is a specific ratio of [3,2-c]acridin-3-yl)phenyl)urea; 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(1-(2-(2-methoxyethoxy)ethoxy)-1Η-. [3,2-c] acridine-3-yl)phenyl)urea; or 1-(4-a-3-(trifluoromethyl)phenyl)-3-(4-(1-(2-) (2-Methoxyethoxy)ethyl)-1Η-indolo[3,2-c]acridin-3-yl)phenyl)urea. 30. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Excipients. 31. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient And at least one other compound. 32. Use of a pharmaceutical group S 72 201237041 J / / J*TU11 as described in claim 30 or 31 for the preparation of a therapeutic and/or prophylactic agent selected from the group consisting of Flt3, PDGFR, c-KIT A drug for a disease associated with kinase activity of RET, Tie2, VEGFR1, VEGFR2, VEGFR3, c-RAF, AW, Abl_T315I, FGFR1 and/or FGFR3. 33. Use of a pharmaceutical composition according to claim 30 or 31 for the preparation of a treatment and/or prevention selected from the group consisting of Aurora-A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR Drugs related to kinase activity of JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rsld, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or TrkB . The use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the preparation of a therapeutic and/or prophylactic agent selected from the group consisting of Flt3, PDGFR, c-KIT , RET, Tie2, VEGFIU, VEGFR2, VEGFR3, c-RAF, Ab Abl-T315I 'FGFR1 and/or FGFR3 are related to the kinase activity of the disease. The use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the preparation of a treatment and/or prevention selected from the group consisting of Aurora-A, Axl, BMX, CHK2, cSRC, Fes, IKKa, IR, JNK2a2, Lck, Met, MKK6, MST2, p70S6K, PKD2, PKA, SAPK2a, ROCK-II, Ros, Rsld, SAPK2ss, SAPK3, SAPK4, Syk, Tie2, TrkA and/or A drug for the disease-associated disease of TrkB. 73 201237041 IV. Designation of the representative representative: (1) The designated representative of the case: None. (2) A brief description of the component symbols of this representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Structural formula III