CN105801584A - Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof - Google Patents

Novel aromatic amide Raf kinase inhibitors and preparation method and application thereof Download PDF

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CN105801584A
CN105801584A CN201610158137.9A CN201610158137A CN105801584A CN 105801584 A CN105801584 A CN 105801584A CN 201610158137 A CN201610158137 A CN 201610158137A CN 105801584 A CN105801584 A CN 105801584A
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methyl
phenyl
trifluoromethyl
base
cyclopropane
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CN105801584B (en
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唐伟方
王路
陆涛
韩伟
唐三植
陈亚东
周湘
刘海春
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China Pharmaceutical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D473/00—Heterocyclic compounds containing purine ring systems

Abstract

The invention relates to novel aromatic amide compounds and a preparation method thereof, a medical composition containing the compounds and medical application of the compounds and the composition, and particularly application of the compounds and composition in serving as Raf kinase inhibitors. The novel compound composition can be used independently or used by combining at least one other drug for treating diseases such as cancers which are regulated by protein kinase. Please see the formula in the description.

Description

Novel aryl amide Raf kinase and its production and use
Invention field
The present invention relates to a class aryl amide noval chemical compound, their preparation method, the Pharmaceutical composition containing these compounds and their medical application, especially as the purposes of Raf kinase.This noval chemical compound compositions can be used alone or with for treating at least one other medicines coupling of disorders such as cancers regulated by protein kinase.
Background technology
Malignant tumor is commonly encountered diseases and the frequently-occurring disease of serious threat human life, and antitumor drug plays an important role in the clinical treatment of tumor.In recent years, along with the development of Protocols in Molecular Biology with Tumorigenesis is recognized further, for the research and development of targeted drug that improper signal conduction system in tumor cell is target, owing to its target spot is clear and definite, side effect is little, it is easily controlled and the feature such as orally available, achieves major progress.Signaling transduction networks plays an important role in the generation of tumor, development and Preventive with regulation and control, has become, for the targeted therapy of key molecule in tumor signal Signal Transduction Pathways, the effective means capturing malignant tumor.Such as tyrosine kinase receptor monoclonal antibody Trastuzumab, active tyrosine enzyme inhibitor Imatinib, epidermal growth factor receptor inhibitor Gefitinib, and Mutiple Targets new drug Sorafenib and Sunitinib etc. is successfully applied to clinic, the targeted therapy of tumor is advanced to a brand-new stage.
The phosphorylation of protein and dephosphorylation, as the signal transduction mechanism transmitting various information, play an important role in the biological action of cell.A series of protein kinase and phosphorylation thereof constitute the path of most feature in the biology that signal conducts.Ras/Raf/MAPK signal path is to study one of path the most active up to now, and Ras/Raf/MAPK path is the signal of interest pathway regulating Growth of Cells with propagation.The activation of this signal transduction pathway can cause a series of cascade reaction events in from cell surface to nucleus, ultimately results in the activation of specific gene and causes the different cell behaviors such as cell proliferation, apoptosis or differentiation.It turned out the change of the somatic mutation of this pathway members or expression relevant to the morbidity of kinds of tumors.Raf kinases is as one of the crucial effect protein in Ras downstream, it it is a kind of protein serine/threonine, it is first molecule of MAPK cascade reaction, Raf plays very important role in Ras/Raf/MAPK signal transduction pathway, it is activated by upstream Ras in the way of a kind of GTP relies on, the Raf of activation can activate the mapk kinase (MEK1/2) in downstream, and then activate MAPK (ERK1/2), constitute MAPK cascade reaction, MAPK can enter core and activate multiple nuclear factor and kinases after activating, and then affects genetic transcription, regulates cell function.Raf kinases includes hypotype 3 kinds main: A-Raf, B-Raf and C-Raf.Wherein, A-Raf and C-Raf is respectively necessary for the conservative serine of N end and tyrosine phosphorylation activates, but the N terminal filament propylhomoserin of B-Raf can continue phosphorylation, and therefore B-Raf relatively A-Raf, C-Raf is more easy to and is activated.In B-Raf, a part for valine 599 and valine 600 composition activation loop.Generally these amino acid residues are responsible for when B-Raf is not phosphorylated maintaining the nonactive conformation of B-Raf, but V599K or V600E sudden change makes these instability that interacts, and cause activation and cause the out of control of potential downstream signal and Growth of Cells.By sudden change, the Raf kinases of constitutive activation has the feature of oncogene, its expressed kinases does not rely on Ras in vivo and continues to stimulate ERK, and ultimately result in many physiological functions, such as the generation of cell proliferation, differentiation, angiogenesis, Apoptosis inhibitor and tumor.Modal B-Raf sudden change occurs closing on 600 residues of conservative DFG motif, and namely glutamic acid instead of valine (V600E).Have determined that at present B-Raf be activated after somatic mutation rate in melanoma up to 50-70%, ovarian cancer reaches 35%, thyroid carcinoma reaches 41%, colon cancer reaches 10%.B-RafV600ECatalysis specific activity wild type B-Raf (B-RafWT) activity is high 500 times, and B-RafV600EThe secretion stimulating VEGF (VEGFR) can be passed through thus promoting the generation of tumor peripheral vessels.Therefore, B-RafV600EBecome the ideal targets of developing anti-tumor medicaments.
Ras/Raf/MAPK signal path is the path of most feature in cytobiology, plays an important role in tumorigenesis, thus the antitumor research for targeted drug provides multiple potential target spot.Particularly noticeable currently for the research of Raf kinase whose targeted drug, include diarylurea derivative Sorafenib and Regorafenib and 7-azaindole derivatives Vemurafenib and pyrimidine derivatives Dabrafnib with its chemotherapy compound being target.
Summary of the invention
The present invention is by studying the crystal structure model of Raf protein kinase, Computer-Aided Drug Design means are utilized to build structure activity relationship model and the medicine virtual screening model of Raf inhibitor, designed and synthesized a series of brand new based on the isostructural aryl amide compound of purine and pyrimidine, preliminary pharmacological tests result shows: the compound of the present invention has good Raf kinase inhibiting activity, such that it is able to suppress the growth of malignant tumor.
Technical scheme is as follows:
The compound of formula (I) or its pharmaceutically acceptable salt:
Wherein Q be shown on 7H-pyrrolo-[2,3-d] pyrimidine-4-yl, 6-substituted pyrimidines-4-base, 2-substituted pyrimidines-4-base, 9H-purine-6-base and 2-substituted pyridines-4-base；
Wherein R1、R2Represent hydrogen, alkyl or R independently of one another1、R2Connect the carbocyclic ring of 3-6 the carbon atom formed；
R3Represent hydrogen, alkyl, halogen, cyano group, alkyl oxy, alkyl sulfenyl；
R4、R5It is each independently selected from hydrogen, halogen, cyano group, alkyl, aryl or Het1Substituent group, wherein said alkyl can be replaced by one or more halogens, cyano group further, described Het1Selected from pyrazolyl, furyl, thienyl, pyridine radicals, pyrazinyl, pyrimidine radicals；Or following aliphatic heterocycle: nafoxidine base, morpholinyl, morpholinyl alkyl, morpholinylalkoxy groups, morpholinyl alkylamino, piperazinyl, piperazinyl alkyl, piperazinyl alkoxy, piperazinyl alkylamino, piperidyl, piperidinylalkyl group, piperidyl alkoxyl, piperidyl alkylamino；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6SR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2With-O (CH2)1-6OR.Described R is selected from hydrogen or alkyl, described Het2Monocyclic heterocycles selected from piperidyl, pyrrole radicals, pyrazolyl, piperidyl, imidazole radicals, furyl, morpholinyl, thienyl, azoles base, isoxazole base, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl；Or selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl group, benzo isoxazole base, benzothiazolyl, benzisothiazole base, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [b] [1,4] bicyclic heterocycle of dioxane base or benzo [d] [1,3] dioxolanyl；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent groups, and each substituent group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl, or selected from C3-C8Aliphatic carbocyclic ring, or following aliphatic heterocycle: nafoxidine base, morpholinyl, alkoxyl morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L represents CONH, NHCO, NHCONH, NHSO independently of one another2Or SO2The connexons such as NH；
Abovementioned alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom；Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom；Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Alkoxyl is the saturated oxyl of straight or branched with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon oxygen base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon oxygen base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Alkylthio group is the straight or branched saturated hydrocarbons sulfenyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon sulfenyl of 3-6 carbon atom；Or for connecting the cyclic saturated hydrocarbon sulfenyl with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Armaticity carbocyclic ring is the carbocyclic ring selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is each optionally replaced by 1,2 or 3 substituent groups, and each substituent group is independently selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, sulfydryl, alkoxyl, alkylthio group, alkyl amino, alkoxyalkyl, aryl or Het, aryl alkyl or Het alkyl；
Halogen is selected from fluorine, chlorine, bromine or iodine.
The preferred version of the present invention is in that:
R1、R2Represent alkyl independently of one another；Or R1、R2Connect the carbocyclic ring of 3-6 the carbon atom formed；
R3Represent alkyl, halogen；
R4、R5Represent hydrogen, halogen, cyano group, alkyl, aryl or Het independently of one another1The aryl replaced, wherein said alkyl can be replaced by one or more halogens, cyano group further, Het1Selected from aliphatic heterocycle: morpholinyl, alkyl morpholine base, alkoxyl morpholinyl, piperazinyl, alkylpiperazinyl, alkoxyl piperazinyl, substituted piperazinyl, piperidyl, Alkylpiperidine base, alkoxypiperidin base；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2Or-O (CH2)1-6OR, R represent hydrogen, alkyl；Described Het2Aliphatic heterocycle selected from following: nafoxidine base, morpholinyl, alkoxyl morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L represents CONH, NHCO, NHCONH, NHSO independently of one another2Or SO2The connexons such as NH.
The present invention another preference is that:
R1、R2Preferred methyl, or R independently of one another1、R2Connect the carbocyclic ring of 3 yuan or five yuan formed；
R3It is preferably methyl or halogen；
R4、R5It is preferably hydrogen, halogen, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, morpholinyl, morpholine methyl, 2-(morpholine-1-base) ethyoxyl, 3-(morpholine-1-base) propoxyl group, piperidyl, piperidin-4-ylmethyl, 1-methyl piperidine-4-base oxygen base, 1-methyl piperidine-4-ylmethoxy, piperazinyl, 4-methyl piperazine base or 4-methyl piperazine methyl independently of one another；
R6It is preferably methylamino, methoxyethylamino, dimethylaminopropylamino, hydroxyethylamino, 2-(nafoxidine-1-base) ethylamino, 2-(nafoxidine-1-base) propylcarbamic, 2-(piperidin-1-yl) ethylamino, 1-methyl piperidine-4-base amino, 1-methyl piperidine-4-base methylamino, 2-(4-methylpiperazine-1-yl) ethylamino, 3-(morpholinyl-1-base) propylcarbamic, carbamoyl or methyl-carbamoyl；
L represents CONH, NHCO or NHCONH connexon independently of one another.
The preferred following structural compounds of compound of formula I:
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-1),
N-[3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (I-2),
N-[5-[4-chloro-3-(trifluoromethyl) phenyl urea groups]-2-aminomethyl phenyl]-1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1-cyclopropane carboxamide (I-3),
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-4),
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-5)
N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-6)
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-7)
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-8),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(6-methylaminopyrimidin-4-base) cyclopropane-1-formamido group] Benzoylamide (II-1),
N-[3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (II-2),
N-[5-[3-[4-chloro-3-(trifluoromethyl) phenyl] urea groups]-2-aminomethyl phenyl]-1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-Methanamide (II-3),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-4),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-hydroxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-5),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(methoxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-6),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[3-(dimethylaminopropylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-7),
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-[6-[1-(methyl piperidine-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-8),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(nafoxidine-1-base) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-9),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(piperidin-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-10),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(morpholinyl the third amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-11),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(1-methyl piperidine-4-base amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-12),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[(1-methyl piperidine base-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-13),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(4-methylpiperazine-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-14),
N-[4-[1-(methyl piperidine-4-base) oxygen base]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-15)
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-16)
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-17),
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-18),
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-19)
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-20),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(dimethylamino) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-21),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(morpholinyl) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-22),
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-23),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] Pentamethylene .-1-formamido group] Benzoylamide (II-24),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-1),
N-(3-isopropyl phenyl)-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-2),
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-3),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-(9H-purine-6-base) propionamido] Benzoylamide (III-4),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) Pentamethylene .-1-formamido group] Benzoylamide (III-5),
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-6),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-carbamyl) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-1),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-methyl-carbamoyl) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-2).
According to the present invention, pharmaceutically acceptable salt includes the acid-addition salts that compound of Formula I is formed with following acid: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid, benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.Additionally include the acid salt of inorganic base, as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The invention further relates to the compound shown in formula I or its pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The invention further relates to the compound shown in formula I or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it in preparation for preventing or treating the purposes in the medicine of the disease relevant with Raf kinase.
The invention further relates to the compound shown in formula I or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it purposes in the medicine of preparation treatment cancer class disease, wherein said cancer is selected from melanoma, hepatocarcinoma, renal carcinoma, acute leukemia, nonsmall-cell lung cancer, carcinoma of prostate, thyroid carcinoma, skin carcinoma, colorectal carcinoma, cancer of pancreas, ovarian cancer, breast carcinoma, myelodysplastic syndrome, the esophageal carcinoma, gastric cancer or mesothelioma etc..
The part of compounds preparation method of the present invention is as follows:
Method 1-1:
Method 1-2:
Method 1-3:
Method 1-4:
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, selects corresponding raw material according to the difference of the difference of substituent group and substituting group position.
The RNH applied in method 1-1 to method 1-42Including bis-aryl amide aniline, double; two arylamine anilide, double; two aryl ureas aniline and Het1The bis-aryl amide aniline replaced.The synthetic method of these 4 kinds of amine is as follows:
Method 1-5: the synthetic method of bis-aryl amide amino benzenes compounds:
Method 1-6: the synthetic method of double; two arylamine anilide compounds:
Method 1-7: the synthetic method of double; two aryl ureas amino benzenes compounds:
Method 1-8:Het1The synthetic method of the bis-aryl amide aniline replaced:
In the present invention, aminated compounds can prepare by above-mentioned preparation method, selects corresponding raw material according to the difference of substituent group.
Partial pharmacologic test and result are presented herein below:
(1) part of compounds is to RafV600EThe research of kinase inhibiting activity
Material
Instrument: Bole's Westernblot electrophresis apparatus (BIO-RAD company of the U.S.)；Black wall black matrix 384 orifice plate (Corning company of the U.S.)；Plate shaker (light experimental apparatus factory of Jiangsu Province).
Reagent: B-Raf (truncated) (U.S. Sigma)；Lck(truncated)；MEK1unactive (U.S. Sigma)；AssayDilutionBuffer1 (U.S. Sigma)；Magnesium/ATPCocktail (U.S. Sigma)；Anti-phospho-MEK1 (Ser218/222)/MEK2 (U.S. Sigma)；Goatanti-rabbitHRPconjugatedlgG (U.S. Sigma)；DMSO (U.S. Sigma).
Method
Take EP pipe (50 μ L), add 20 μ LMagnesium/ATPCocktail；Add 1 μ LB-Raf；Add and treat sieve medicine 2 μ L (1.0 × 10-5mol/mL)；Add 0.84 μ LMEK1unactive, add 14.16 μ LAssayDilutionBuffer1；After micro centrifuge is centrifugal, 30 DEG C of 30min on shaking table；Add 40 μ Lsamplebuffer, boiling water boiling 5min；Every hole 10 μ L, SDS-PAGE electrophoresis, transferring film, tri-distilled water washes film twice；TBST containing 5% defatted milk powder closes, and greenhouse shaking table is shaken gently for 30min；Incubating primary antibodie Anti-phospho-MEK1 (Ser218/222)/MEK2,4 DEG C overnight；Three steamings are incubated Goatanti-rabbitHRPconjugatedlgG bis-and are resisted；Tri-distilled water washes film twice；Film 3-5min is washed with TBS-0.05%Tween-20；Tri-distilled water rinsing film 4-5 time；Westernblot chemiluminescence detection.
Part preferred compound suppresses RafV600EExperimental result:
Numbering IC50(nM) Numbering IC50(nM) Numbering IC50(nM) Numbering IC50(nM)
I-1 3.46 II-3 18.5 II-13 14.3 II-23 144
I-2 2.28 II-4 192.4 II-14 13.9 II-24 154
I-3 2.07 II-5 31.5 II-15 59.1 III-1 1.91
I-4 13.4 II-6 35.8 II-16 23.1 III-2 4.56
I-5 34.5 II-7 18.7 II-17 36.5 III-3 285
I-6 15.8 II-8 43.3 II-18 29.1 III-4 9.67
I-7 13.4 II-9 19.5 II-19 30.5 III-5 230
I-8 7.4 II-10 23.4 II-20 166 III-6 3.49
II-1 2.78 II-11 18.3 II-21 84 IV-1 > 0.3uM
II-2 4.31 II-12 21.4 II-22 73.8 IV-2 > 0.3uM
(2) part of compounds is to RafV600EThe research of the cancer cell suppression activity of kinases high expressed
Material:
Instrument: super-clean bench (upper marine clean cleaning equipment company limited produces)；Electronic balance (METTLERTOLEDOAL104 type)；Centrifuge (Anke/ flying pigeon TDL80-2B)；Inverted microscope (LeicaDMI3000B uses LASV3.7 software)；CO2Incubator (Thermo)；Microplate reader (TECANGENion).
Reagent: CellTiter-Glo (CTG) (Promega, production number: G7573)；Culture medium (DMEM, RPMI1640, EMEM, L-15 (100%air) and McCoy ' s5a): (Gibco product)；FBS-hyclone (Gibco produces, and lot number is C2027050)；Pancreatin (Amresco product)；PBS, PH7.2 (Gibco, production number: 10010-023)；DMSO (Sigma, production number D2650).
Cell strain: human renal carcinoma cell strain A498；Human colon cancer cell strain HT-29；Human colon cancer cell strain COLO-205；National People's Congress sclc cell line NCI-H460；Human melanoma cell strain A375；HepG2 cell lines；Lung cancer cell line EBC-1；Human thyroid squamous cell carcinoma strain SW579；Acute leukemia cells strain MV4-11.
Positive control drug: Vemurafenib, Dabrafenib, Sorafenibtosylate, LY3009120
Method: CellTiter-Glo method test cell maximum inhibition and cytoactive suppress IC50Value
Plating cells: collect and be in the cell of exponential phase of growth and carry out viable count with Vi-CellXR cell counter.By culture medium, cell suspension being adjusted suitable concentration, every hole adds 90 μ l cell suspension in 96-porocyte culture plate.The cell completed is placed in 37 DEG C, 5%CO2Incubator cultivate 24 hours.
Compound treatment: to being set as compound treatment plate, every strain cell per well adds the 10 × compound solution (final initial concentration 20 μMs or 10 μMs) of the 10 corresponding 3 times of gradient dilutions of μ l respectively, each 3 the multiple holes of each drug level.
Read T3: drug treating is after 72 hours, and every hole adds the 50 μ l CTG solution melting in advance and equilibrating to room temperature, mix 2 minutes with microwell plate oscillator, after room temperature is placed 10 minutes, read plate instrument with Envision2104 measure luminescence signal.
The computing formula of data analysis and experimental result: POC (percentofcontrol: with the percentage ratio compareed): the meansigma methods * 100% of the value in compound treatment hole/DMSO disposal hole, wherein the value in compound treatment hole is the T3luminescence value in drug treating hole, the meansigma methods of DMSO disposal hole is the meansigma methods of the T3luminescence value of 6 DMSO disposal hole on every block of plate, application GraphPadPrism5.0 software, uses nonlinear regression model (NLRM) draw S type dosage-POC curve and calculate IC50Value.
Result (the part of compounds test IC of cytoactive test50Value):
(ND represent do not test)
Pharmacology test result shows, external Raf kinases is all had inhibitory action in various degree by the compound of formula I and pharmaceutically acceptable salt thereof.Therefore, compound of Formula I and pharmaceutically acceptable salt thereof may be used for prevention or treat the clinical disease relevant with Raf kinase.The described disease relevant with Raf kinase can be melanoma, hepatocarcinoma, renal carcinoma, acute leukemia, nonsmall-cell lung cancer, carcinoma of prostate, thyroid carcinoma, skin carcinoma, colorectal carcinoma, cancer of pancreas, ovarian cancer, breast carcinoma, myelodysplastic syndrome, the esophageal carcinoma, gastric cancer or mesothelioma.
Detailed description of the invention
1H-NMR JEOLFX90Q type fourier transform NMR instrument, BRUKERACF-300 type nuclear magnetic resonance analyser and BRUKERAM-500 type nuclear magnetic resonance analyser complete (in TMS mark)；MS Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph measure.
Embodiment 1
The chloro-7-of 4-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine (I-a)
250mL eggplant-shape bottle adds the chloro-7H-pyrrolo-[2 of 4-, 3-d] pyrimidine (3.0g, 20mmo]) and triethylamine (6.1g, 60mmol), add 100mL anhydrous methylene chloride stirring and dissolving, add paratoluensulfonyl chloride (2.6g, 24mmol), 5h, TLC are stirred at room temperature and detect the disappearance of raw material point.Removing solvent under reduced pressure, column chromatographic isolation and purification obtains white solid I-a4.85g, yield 79.2%.ESI-MSm/z:308 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.37 (3H, s, CH3), 6.96 (1H, d, ArH, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, ArH, J=4.0Hz), 8.82 (1H, s, ArH).
Embodiment 2
2-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] diethyl malonate (I-b)
250mL eggplant-shape bottle adds diethyl malonate (5.3g, 33mmol), the anhydrous THF of 50mL dissolves, it is slowly added to sodium hydride (60%, 800mg, 33mmol) under ice bath and stirs 5min, by I-a (1.0g, being slowly added in reaction bulb after 3.3mmol) dissolving with the anhydrous THF of 20mL, backflow 2.5h, TLC detect raw material point and disappear.It is cooled to room temperature, pours in saturated ammonium chloride solution 100mL, extraction into ethyl acetate (50mL × 3), merge organic layer, saturated sodium-chloride washing (30mL × 3), anhydrous magnesium sulfate is dried overnight.Remove solvent, column chromatography purification under reduced pressure, obtain colorless oil I-b1.4g, yield 98.6%.ESI-MSm/z:432 [M+H]+。
Embodiment 3
2-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] ethyl acetate (I-c)
Being dissolved in dehydrated alcohol 50mL by I-b (850mg, 2mmol), add Sodium ethylate (13mg, 0.2mmol), backflow 2.5h, TLC detect raw material point and disappear.Being cooled to room temperature, dilute hydrochloric acid (1mol/L) regulates pH to neutral, removes solvent under reduced pressure, and column chromatographic isolation and purification obtains white solid I-c530mg, yield 77.0%.ESI-MSm/z:360 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.19 (3H, t, CH2CH 3, J=7.1Hz), 2.36 (3H, s, ArCH3), 4.08 (2H, q, CH 2CH3, J=7.1Hz), 4.34 (2H, s, CH2CO), 7.03 (1H, d, ArH, J=4.0Hz), 7.46 (1H, d, ArH, J=8.2Hz), 7.99 (1H, d, ArH, J=4.0Hz), 8.04 (2H, d, ArH, J=8.2Hz), 8.87 (1H, s, ArH).
Embodiment 4
1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-Ethyl formate (I-d)
I-c (1.0g2.7mmol) is dissolved in dry DMF 40mL, under ice bath, is slowly added to sodium hydroxide (334mg, 8.3mmol), dropping glycol dibromide (2.8g, 14mmol) after stirring 5min, it is warming up to and 5h, TLC detection raw material point disappearance is stirred at room temperature.Add water 100mL, regulate pH to neutral with dilute hydrochloric acid (1mol/L), extraction into ethyl acetate (50mL × 3), merge organic layer, saturated sodium-chloride washing (50mL × 3), anhydrous magnesium sulfate dries.Removing solvent under reduced pressure, column chromatographic isolation and purification obtains yellow-brown solid I-d350mg, yield 33, and 0%.ESI-MSm/z:386 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.04 (3H, t, CH2CH 3, J=7.0Hz), 1.51～1.54 (2H, m, CH2CH2), 1.57～1.62 (2H, m, CH2CH2), 2.36 (3H, s, ArCH3), 4.06 (2H, t, CH 2CH3), 6.84 (1H, d, ArH, J=4.0Hz), 7.47 (2H, d, ArH, J=8.1Hz), 7.98 (1H, d, ArH, J=4.0Hz), 8.06 (2H, d, ArH, J=8.1Hz), 8.86 (1H, s, ArH).
Embodiment 5
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-1)
100mL three-necked bottle adds I-d (100mg; 0.26mmol), N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,85mg; 0.26mmol); dry toluene 30mL dissolves, and nitrogen protection is slowly added to the toluene solution (2M of trimethyl aluminium under ice bath; 0.39mL; 0.78mmol), it is to slowly warm up to 80 DEG C of stirrings 5h, TLC and detects the disappearance of raw material point.Extracting reaction of going out, extraction into ethyl acetate (30mL × 3) with 1M dilute hydrochloric acid, saturated nacl aqueous solution washing (30mL × 3), anhydrous magnesium sulfate dries.Remove solvent under reduced pressure and obtain yellow solid I-e-193mg, yield 53.7%, directly cast single step reaction.
Embodiment 6
N-[4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (I-e-2)
With I-d (100mg, 0.26mmol), N-(4-methyl-3-aminophenyl)-4-chloro-3-(trifluoromethyl) Benzoylamide (VI-c, 85mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-287mg, yield 50.2%, directly casts single step reaction.
Embodiment 7
N-[5-[4-chloro-3-(trifluoromethyl) phenyl urea groups]-2-aminomethyl phenyl]-1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-Methanamide (I-e-3)
With I-d (100mg, 0.26mmol), N-(3-amino-4-aminomethyl phenyl)-N '-(the chloro-3-trifluoromethyl of 4-) urea (VII-b, 89mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-397mg, yield 54.7%, directly casts single step reaction.
Embodiment 8
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-4)
With I-d (100mg, 0.26mmol), N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-d-1,65mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-489.5mg, yield 47.9%, directly casts single step reaction.
Embodiment 9
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-5)
With I-d (100mg, 0.26mmol), N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-d-2,56mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-5106mg, yield 55.7%, directly casts single step reaction.
Embodiment 10
N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-6)
With I-d (100mg, 0.26mmol), N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-1,56mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-5113mg, yield 58.2%, directly casts single step reaction.
Embodiment 11
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-7)
With I-d (100mg, 0.26mmol), N-[4-[(1-methyl piperidine-4-base) methoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-2,56mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-7107.4mg, yield 54.3%, directly casts single step reaction.
Embodiment 12
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[7-(4-Methyl benzenesulfonyl base)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (I-e-8)
With I-d (100mg, 0.26mmol), N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB ((VIII-h-3,56mg, 0.26mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid I-e-8119.6mg, yield 59.2%, directly casts single step reaction.
Embodiment 13
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-1)
50mL eggplant-shape bottle adds I-e-1 (93mg, 0.14mmol), ethanol 20mL dissolve, drip 1M sodium hydroxide solution 0.5mL, 1h, TLC are stirred at room temperature and detect the disappearance of raw material point.Remove under reduced pressure.Column chromatography (eluent: ethyl acetate: petroleum ether=1: 1) separates purification and obtains yellow solid I-153mg, yield 74.4%.ESI-MS:m/z:513 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.68～1.71 (2H, m, CH2), 1.90～1.98 (2H, m, CH2), 2.27 (3H, s, ArCH3), 6.58 (1H, d, ArH, J=1.7Hz), 7.37 (1H, d, ArH, J=8.0Hz), 7.57 (1H, t, J=2.8Hz), 7.71 (2H, d, ArH, J=8.5Hz), 8.08 (1H, s, ArH), 8.12 (1H, d, ArH, J=8.9Hz), 8.35 (1H, d, ArH, J=2.3Hz), 8.75 (1H, s, ArH), 10.10 (1H, s, CONH), 10.57 (1H, s, CONH), (12.18 1H, s, NH).
Embodiment 14
N-[3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (I-2)
With I-e-2 (87mg, 0.13mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 45mg, yield 67.3%.ESI-MSm/z:513 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61～1.63 (2H, m, CH2), 1.65～1.67 (2H, m, CH2), 2.10 (3H, s, ArCH3), 6.58 (1H, s, ArH), 7.18 (1H, d, ArH, J=8.2Hz), 7.51～7.56 (2H, m, ArH), 7.90～7.95 (2H, m, ArH), 8.26 (1H, d, ArH, J=8.3Hz), 8.38 (1H, s, ArH), 8.74 (1H, s, ArH), 10.05 (1H, s, CONH), 10.50 (1H, s, CONH), 12.19 (1H, s, NH).
Embodiment 15
N-[5-[4-chloro-3-(trifluoromethyl) phenyl urea groups]-2-aminomethyl phenyl]-1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1-cyclopropane carboxamide (I-3)
With I-e-3 (97mg, 0.14mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 53mg, yield 70.6%.ESI-MSm/z:529 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61～1.63 (2H, m, CH2), 1.69～1.71 (2H, m, CH2), 2.06 (3H, s, ArCH3), 7.07 (1H, d, ArH, J=8.2Hz), 7.20 (1H, d, ArH, J=7.8Hz), 7.56～7.69 (3H, m, ArH), 7.95 (1H, s, ArH), 8.11 (1H, s, ArH), 8.74 (1H, s, NHCONH), 8.84 (1H, s, ArH), 9.04 (1H, s, NHCONH), 10.00 (1H, s, CONH), 12.21 (1H, s, NH).
Embodiment 16
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-4)
With I-e-4 (86.3mg, 0.12mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 56.6mg, yield 83.5%.ESI-MSm/z:565 [M+H]+。1H-NMR [300MHz, DMSO-d6]: δ 1.62 (2H, m, CH2), 1.69 (2H, m, CH2), 2.20 (3H, s, ArCH3), 2.84 (4H, s, CH2NCH2), 3.70 (4H, s, CH2OCH2), 6.59 (1H, m, ArH), 7.36 (1H, d, ArH, J=7.7Hz), 7.58～7.61 (2H, m, ArH), 7.70～7.73 (1H, d, ArH, J=7.9Hz), 8.06 (1H, s, ArH), 8.15 (1H, s, ArH), 8.75 (1H, s, ArH), 10.08 (1H, s, CONH), 10.42 (1H, s, CONH), 12.20 (1H, s, NH).
Embodiment 17
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-5)
With I-e-5 (102.5mg, 0.14mmol) for raw material, the same I-e-1 of operational approach, obtain yellow solid 67.8mg, yield 83.9%.ESI-MSm/z:578 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61 (2H, m, CH2), 1.68 (2H, m, CH2), 2.37 (3H, s, NCH3), 2.56 (3H, s, ArCH3), 2.84～2.88 (4H, m, CH2NCH2), 3.68～3.71 (4H, m, CH2NCH2), 6.57 (1H, d, ArH, J=3.6Hz), 7.20 (1H, d, ArH, J=6.0Hz), 7.25 (1H, d, ArH, J=5.6Hz), 7.30 (1H, d, ArH, J=4.0Hz), 7.60 (2H, d, ArH, J=7.9Hz), 7.77 (1H, d, ArH, J=8.5Hz), 7.94 (1H, d, ArH, J=2.1Hz), 8.45 (1H, m, ArH), 8.77 (1H, s, ArH), 8.83 (1H, s, CONH), 9.68 (1H, s, CONH), 11.75 (1H, s, NH).
Embodiment 18
N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-6)
With I-e-6 (89.6mg, 0.12mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 59.9mg, yield 84.2%.ESI-MSm/z:593 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.59～1.61 (2H, m, CH2), 1.68～1.71 (5H, m, CH2), 1.91～1.93 (3H, m), 2.20 (4H, m), 2.22 (3H, s, ArCH3), 2.34 (2H, m, NCH2), 2.58 (2H, m, NCH2), 3.99～4.06 (1H, m, OCH), 6.59 (1H, d, ArH, J=2.0Hz), 7.30～7.36 (2H, m, ArH), 7.56～7.58 (1H, m, ArH), 7.69～7.72 (1H, m, ArH), 7.98 (1H, d, ArH, J=8.9Hz), 8.05～8.08 (2H, m, ArH), 8.75 (1H, s, ArH), (10.08 1H, s, CONH), (10.30 1H, s, CONH), (12.21 1H, s, NH).
Embodiment 19
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-7)
With I-e-7 (91.3mg, 0.12mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 61mg, yield 83.8%.ESI-MSm/z:607 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.39～1.43 (4H, m, CH 2CHCH 2), δ 1.61 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76～1.80 (1H, m, CH), 2.19 (3H, s, NCH3), 2.35 (3H, s, ArCH3), 2.50 (4H, m, CH2NCH2), 3.96～3.97 (2H, m, OCH2), 6.58 (1H, d, ArH, J=2.0Hz), 7.26 (1H, d, ArH, J=9.0Hz), 7.35 (1H, d, ArH, J=8.1Hz), 7.57 (1H, m, ArH), 7.71 (2H, m, ArH, J=8.0Hz), 8.00 (1H, d, ArH, J=8.7Hz), 8.05～8.08 (2H, m, ArH), 8.75 (1H, s, ArH), 10.00 (1H, s, CONH), 10.30 (1H, s, CONH), (12.21 1H, s, NH).
Embodiment 20
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-8)
With I-e-8 (93.2mg, 0.12mmol) for raw material, the same I-1 of operational approach, obtain yellow solid 62.5mg, yield 83.6%.ESI-MSm/z:623 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.62 (2H, m, CH2), 1.68 (2H, m, CH2), 1.85～1.90 (2H, m, OCH2CH 2CH2N), 2.27 (3H, s, ArCH3), 2.34 (4H, m, CH2NCH2), 2.43 (2H, t, CH2N), 3.55～3.58 (4H, m, CH2OCH2), 4.11～4.15 (2H, m, OCH 2CH2), 6.59 (1H, d, ArH, J=2.4Hz), 7.27 (1H, d, ArH, J=8.8Hz), 7.35 (1H, d, ArH, J=7.9Hz), 7.58 (1H, m, ArH), 7.69～7.72 (1H, d, ArH, J=7.7Hz), 7.99 (1H, d, ArH, J=9Hz), 8.05～8.08 (2H, m, ArH), 8.75 (1H, s, ArH), 10.00 (1H, s, CONH), 10.30 (1H, s, CONH), (12.21 1H, s, NH).
Embodiment 21
(6-chloropyrimide-4-base) diethyl malonate (II-a-1)
With 4,6-dichloro pyrimidine 5.0g (33mmol) for raw material, the same I-b of preparation method, give light yellow oil II-a-19.0g, yield 98.3%.Product, without purification, directly casts single step reaction.
Embodiment 22
(2-chloropyrimide-4-base) diethyl malonate (II-a-2)
With 2,4-dichloro pyrimidine 5.0g (33mmol) for raw material, the same I-b of preparation method, give light yellow oil II-a-28.8g, yield 95.6%.Product, without purification, directly casts single step reaction.
Embodiment 23
(6-chloropyrimide-4-base) ethyl acetate (II-b-1)
With II-a-19g (33mmol) for raw material, the same I-c of preparation method, obtain yellow oil II-b-15.7g, yield 86.6%.
Embodiment 24
(2-chloropyrimide-4-base) ethyl acetate (II-b-2)
With II-a-29.0g (33mmol) for raw material, the same I-c of preparation method, obtain yellow oil II-b-25.9g, yield 89.2%.
Embodiment 25
1-(6-chloropyrimide-4-base) cyclopropane-1-ethyl acetate (II-c-1)
With II-b-15.6g (28mmol) for raw material, the same I-d of preparation method, obtain yellow oil product I I-c-15.5g, yield 87.3%.
Embodiment 26
2-(6-chloropyrimide-4-base)-2 Methylpropionic acid ethyl ester (II-c-2)
With II-b-12.0g (10mmol) and iodomethane 5.7g (40mmol) for raw material, the same I-d of preparation method, obtain yellow oil II-c-22.1g, yield 90.7%.
Embodiment 27
(2-chloropyrimide-4-base) cyclopropane-1-ethyl acetate (II-c-3)
With II-b-25.6g (28mmol) for raw material, the same I-d of preparation method, obtain yellow oil product I I-c-35.5g, yield 87.3%.
Embodiment 28
1-(6-chloropyrimide-4-base) Pentamethylene .-1-ethyl acetate (II-c-4)
With II-b-12.0g (10mmol) and Isosorbide-5-Nitrae-dibromobutane 8.6g (40mmol) for raw material, the same I-d of preparation method, obtain yellow oil product I I-c-42.1g, yield 82.3%.
Embodiment 29
1-(6-methylaminopyrimidin-4-base) cyclopropane-1-ethyl acetate (II-d-1)
II-c-15.7g (28mmol) is dissolved in isopropanol by the eggplant-shape bottle of 250mL, under ice bath, drips 33% methylamine alcohol solution 24mL (170mmol).2h is stirred at room temperature, removes solvent under reduced pressure.Water 30mL washs, and ethyl acetate 50mL extracts, and saturated aqueous common salt 30mL washs, and anhydrous magnesium sulfate dries.Column chromatographic isolation and purification obtains white solid II-d-13.3g, yield 87.9%.MS (LR-ESI): m/z:222.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.18 (3H, t, OCH2CH 3, J=7.1Hz), 1.42-1.48 (4H, m, CH2), 2.81 (3Hd, NHCH3, J=4.2Hz), 4.01～4.16 (2H, m, OCH 2CH3), 6.72 (1H, s, ArH), 7.35 (1H, s, NH), 8.32 (1H, s, ArH).
Embodiment 30
2-methyl-2-[6-(methylamino) pyrimidine-4-yl] ethyl propionate (II-d-2)
II-c-22.0g (8.7mmol) and methylamine alcohol solution 6mL (43.5mmol) is raw material, and the same II-d-1 of preparation method obtains yellow solid II-d-111.8g, yield 93.5%.MS (LR-ESI): m/z:224.1 [M+H]+。
Embodiment 31
1-[6-(2-hydroxyethylamino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-3)
Being sequentially added into II-c-15.3g (24mmol), ethanolamine 1.74mL (29mmol), cesium carbonate 15.6g (48mmol), 2 dehydrated alcohol and dry DMF 60mL in 250mL eggplant-shape bottle, 60 DEG C are refluxed 3 hours.Add water 30mL in reactant liquor, with dichloromethane extraction (40mL × 3), merges organic layer, and saturated aqueous common salt 30mL washs, and anhydrous sodium sulfate dries.White solid II-d-35.5g, yield 87.3%, MS (LR-ESI): m/z:252 [M+H] is obtained through column chromatographic isolation and purification+。
Embodiment 32
1-[6-(2-methoxyethylamino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-4)
With II-c-15.5g (24mmol) and 2-methoxyethyl amine 1.8g (24mmol) for raw material, the same II-d-3 of preparation method, obtain white solid II-d-45.4g, yield 85.2%.MS (LR-ESI): m/z:266.3 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.11 (3H, t, OCH2CH 3, J=7.1Hz), 1.25～1.27 (4H, m, CH2CH2), 3.20 (3H, s, OCH3), 3.38～3.42 (4H, m, OCH2CH2NH), 4.00-4.072 (2H, m, OCH 2CH3), 6.68 (1H, m, NH), 7.45 (1H, s, ArH), 8.25 (1H, s, ArH).
Embodiment 33
1-[6-(3-dimethylaminopropylamino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-5)
With II-c-15.5g (24mmol) and 3-dimethylaminopropylamine for raw material, the same II-d-3 of preparation method, obtain white solid II-d-55.9g, yield 84.6%.MS (LR-ESI): m/z:293.2 [M+H]+。
Embodiment 34
1-[6-[1-(methyl piperidine-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-6)
With II-c-12.0g (8.8mmol), 1-methyl-4-piperidines methylamine 5mL (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) is raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-62.3g, yield 82.3%.MS (LR-ESI): m/z:319 [M+H]+。
Embodiment 35
1-[6-[2-(nafoxidine-1-base) ethylamino] pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-7)
With II-c-12.0g (8.8mmol), 2-(nafoxidine-1-base) ethamine 4.0g (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) is raw material, the same II-d-3 of preparation method, obtain yellow solid II-d-72.24g, yield 83.6%.MS (LR-ESI): m/z:305 [M+H]+。
Embodiment 36
1-[6-[2-(piperidin-1-yl) ethylamino]-pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-8)
With II-c-12.0g (8.8mmol), 2-(piperidin-1-yl) ethamine 4.5g (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) is raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-82.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 37
1-[6-(morpholinyl the third amino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-9)
With II-c-42.0g (8.8mmol), morpholinyl propylamine 4.3mL (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) are raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-92.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 38
1-[6-(1-methyl piperidine-4-base amino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-10)
With II-c-12.0g (8.8mmol), 1-methyl piperidine-4-amine 4.4mL (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) is raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-102.1g, yield 80.2%.MS (LR-ESI): m/z:305 [M+H]+。
Embodiment 39
1-[6-[2-(4-methylpiperazine-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-11)
With II-c-12.0g (8.8mmol), 4-methyl isophthalic acid-piperazine ethanamine 5.3mL (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) is raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-112.2g, yield 81.6%.MS (LR-ESI): m/z:334 [M+H]+。
Embodiment 40
1-[(2-methylamino) pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-12)
II-c-35.7g (28mmol) is raw material, the same II-d-1 of preparation method, obtains yellow solid II-d-125.5g, yield 84.6%.MS (LR-ESI): m/z:222.1 [M+H]+。
Embodiment 41
1-[2-[3-(dimethylamino) the third amino] pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-13)
With II-c-32g (8.8mmol), N, N-dimethylaminopropylamine solution 5.6mL (44.1mmol) and diisopropylethylamine solution 7.3ml (44.1mmol) are raw material, the same II-d-3 of preparation method, obtain yellow solid II-d-132.1g, yield 86.4%.MS (LR-ESI): m/z:279.2 [M+H]+。
Embodiment 42
1-[2-[3-(morpholinyl) the third amino]-pyrimidine-4-yl] cyclopropane-1-ethyl acetate (II-d-14)
With II-c-32.0g (8.8mmol), morpholinyl propylamine 4.3mL (35.2mmol) and diisopropylethylamine solution 7.3mL (44.1mmol) are raw material, the same II-d-3 of preparation method, obtains yellow solid II-d-142.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 43
1-[(6-methylamino) pyrimidine-4-yl] Pentamethylene .-1-ethyl acetate (II-d-15)
II-c-42.0g (7.9mmol) and methylamine alcohol solution 6mL (39.3mmol) is raw material, and the same II-d-1 of preparation method obtains yellow solid II-d-151.71g, yield 87%.MS (LR-ESI): m/z:250 [M+H]+。
Embodiment 44
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(6-methylaminopyrimidin-4-base) cyclopropane-1-formamido group] Benzoylamide (II-1)
With II-d-10.11g (0.5mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,158mg, 0.48mmol) for raw material, the same I-e-1 of preparation method, obtain white solid II-10.2g, yield 82.7%.MS (LR-ESI): m/z:504 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.32 (2H, m, CH2), 1.58 (2H, m, CH2), 2.36 (3H, s, ArCH3), 2.81 (3H, s, NHCH3), 6.38 (1H, s, NH), 7.40～7.43 (2H, m, ArH), 7.68～7.73 (2H, m, ArH), 8.13 (1H, dd, ArH, J=2.2Hz, J=8.7Hz), 8.35～8.36 (2H, m, ArH), 8.47 (1H, s, ArH), 10.60 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 45
N-[3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (II-2)
With II-d-1 (22.1mg, 0.1mmol) with N-(4-methyl-3-aminophenyl)-4-chloro-3-(trifluoromethyl) Benzoylamide (VI-c33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-242.4mg, yield 84.2%.ESI-MSm/z:504 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.2 (2H, m, CH2), 1.3 (2H, m, CH2), 2.26 (3H, s, ArCH3), 2.81 (3H, s, NHCH3), 6.35 (1H, s, NH), 7.21 (1H, d, ArH, J=8.40Hz), 7.42 (1H, q, ArH, J=4.7Hz), 7.56 (1H, dd, ArH, J=1.95Hz, J=8.22Hz), 7.90 (1H, d, ArH, J=8.40Hz), 8.19 (1H, s, ArH), 8.27 (1H, dd, ArH, J=1.65Hz, J=8.4Hz), 8.40 (1H, d, ArH, J=1.5Hz), 8.46 (1H, s, ArH), 10.50 (1H, s, CONH), 11.50 (1H, s, CONH).
Embodiment 46
N-[5-[3-[4-chloro-3-(trifluoromethyl) phenyl] urea groups]-2-aminomethyl phenyl]-1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-Methanamide (II-3)
With II-d-1 (22.1mg, 0.1mmol), N-(3-amino-4-aminomethyl phenyl)-N '-(the chloro-3-trifluoromethyl of 4-) urea (VII-b34mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-345.6mg, yield 87.9%.ESI-MSm/z:519 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.3 (2H, m, CH2), 1.6 (2H, m, CH2), 2.2 (3H, s, ArCH3), 2.8 (3H, d, NHCH3, J=3.6Hz), 6.34 (1H, s, NH), 7.10～7.13 (1H, m, ArH), 7.20 (1H, dd, ArH, J=2Hz, J=8.2Hz), 7.41～7.43 (1H, m, ArH), 7.60 (2H, m, ArH), 7.95 (1H, s, ArH), 8.12 (1H, s, ArH), 8.45 (1H, s, ArH), 8.82 (1H, s, CONH), 9.01 (1H, s, CONH), (11.11 1H, s, CONH).
Embodiment 47
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-4)
With II-d-20.11g (0.5mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,165mg, 0.5mmol) for raw material, the same II-1 of operational approach, obtain white solid II-40.22g, yield 86.9%.ESI-MSm/z:506 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.53 (6H, s, 2 × CH3), 2.12 (3H, s, CH3, ArCH3), 2.82 (3H, d, NHCH3, J=4.4Hz), 6.52 (1H, m, NH), 7.17 (1H, d, ArH, J=8.2Hz), 7.43～7.44 (1H, m, ArH), 7.58 (1H, dd, ArH, J=1.8Hz, J=8.2Hz), 7.85 (1H, d, ArH, J=1.7Hz), 7.91 (1H, d, ArH, J=8.4Hz), 8.27 (1H, d, ArH, J=8.4Hz), 8.39 (1H, s, ArH), 8.47 (1H, s, ArH), 9.34 (1H, s, CONH), 10.48 (1H, s, CONH).
Embodiment 48
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-hydroxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-5)
With II-d-30.13g (0.5mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,165mg, 0.5mmol) for raw material, the same II-1 of preparation method, obtain white solid II-50.21g, yield 78.4%.MS (LR-ESI): m/z:534 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.31 (2H, m, CH2), 1.57 (2H, m, CH2), 2.30～2.36 (3H, m), 4.34 (4H, t, CH2, HOCH2CH2NH, J=5.0Hz), 4.76 (1H, s, OH), 6.45 (1H, s, NH), 7.39～7.47 (2H, m, ArH), 7.68～7.72 (2H, m, ArH), 8.11～8.14 (1H, m, ArH), 8.35 (2H, m, ArH), 8.44 (1H, s, ArH), 10.57 (1H, s, CONH), 11.26 (1H, s, CONH).
Embodiment 49
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(methoxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-6)
With II-d-40.13g (0.5mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,160mg, 0.5mmol) for raw material, the same II-1 of preparation method, obtain white solid II-60.21g, yield 78.4%.MS (LR-ESI): m/z:548 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.17～1.20 (2H, m, CH2), 1.31 (2H, m, CH2), 2.28 (3H, s, ArCH3), 3.26 (3H, s, OCH3), 3.45～3.46 (4H, m, OCH2CH2NH), 6.47 (1H, s, NH), 7.41 (1H, d, ArH, J=8.0Hz), 7.56 (1H, s, ArH), 7.68～7.73 (2H, m, ArH), 8.13 (1H, d, ArH, J=8.7Hz), 8.32～8.36 (2H, m, ArH), 8.46 (1H, s, ArH), 10.60 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 50
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[3-(dimethylaminopropylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-7)
With II-d-5 (29.2mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-747.5mg, yield 82.7%.ESI-MS:m/z:575 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2), 1.57 (2H, m, CH2), 1.88～1.93 (2H, m, NHCH2CH 2CH2N), 2.35 (3H, s, ArCH3), 2.73 (6H, s, 2 × NCH3), 3.06～3.11 (4H, m, NHCH 2CH2CH 2N), 6.52 (1H, s, NH), 7.41 (1H, d, ArH, J=8.0Hz), 7.70～7.73 (3H, m, ArH), 8.15～8.18 (1H, m, ArH), 8.34～8.47 (3H, m, ArH), 8.47 (1H, s, ArH), 10.70 (1H, s, CONH), 10.99 (1H, s, CONH).
Embodiment 51
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-[6-[1-(methyl piperidine-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-8)
With II-d-6 (0.32g, 1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-fluoro-3-AB (V-c-2,333mg, 1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-80.45g, yield 74.2%.ESI-MS:m/z:627 [M+Na]+。1H-NMR (300MHz, DMSO-d6): 1.34～1.48 (3H, m, CH2-cyclopropane, NHCH2CH), 1.61～1.65 (4H, m, CH2-cyclopropane, CH 2CH2), 1.75～1.82 (2H, t, CH2, J=11Hz), 2.12 (3H, s, NCH3), 2.71～2.74 (2H, m, CH2), 3.19～3.21 (2H, m, CH2), 3.44 (2H, m, NHCH2), 6.37 (1H, s, NH), 7.45～7.54 (2H, m, CH2, ArH), 7.71 (1H, d, ArH, J=8.8Hz), 7.77～7.82 (1H, m, ArH), 8.11 (1H, dd, ArH, J=2.2Hz, J=8.8Hz), 8.34 (1H, d, ArH, J=2.3Hz), 8.43 (1H, s, ArH), 8.63 (1H, dd, ArH, J=1.9Hz, J=7.3Hz), 10.67 (1H, s, CONH), 11.95 (1H, s, CONH).
Embodiment 52
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(nafoxidine-1-base) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-9)
With II-d-5 (0.3g, 1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,328mg, 1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-90.44g, yield 74.2%.1H-NMR (300MHz, DMSO-d6): 1.32 (2H, m, CH2-cyclopropane), 1.57 (2H, m, CH2-cyclopropane), 1.70 (4H, m, CH2CH 2CH 2CH2), 2.35 (3H, s, ArCH3), 2.63～2.73 (6H, m, NCH2), 3.42～3.44 (2H, m, NHCH2), 6.46 (1H, s, NH), 7.39～7.42 (2H, m, ArH), 7.68～7.73 (2H, m, ArH), 8.11～8.15 (1H, m, ArH), 8.34～8.36 (2H, m, ArH), 8.45 (1H, s, ArH), 10.59 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 53
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(piperidin-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-10)
With II-d-8 (31.8mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-1049.5mg, yield 82.5%.ESI-MSm/z:601 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2-cyclopropane), 1.41 (2H, m, CH2-cyclopropane), 1.58 (6H, m, CH2CH2CH2), 2.35 (4H, m, CH2NCH2), 2.54～2.73 (2H, m, NCH2), 3.34 (3H, s, ArCH3), 3.43～3.46 (2H, m, NHCH2), 6.47 (1H, s, NH), 7.41 (2H, d, ArH, J=8.1Hz), 7.69～7.73 (2H, m, ArH), 8.13 (1H, dd, ArH, J=2.2Hz, J=8.8Hz), 8.32 (1H, s, ArH), 8.36 (1H, d, ArH, J=2.2Hz), 8.50 (1H, s, ArH), 10.60 (1H, s, CONH), 11.10 (1H, s, CONH).
Embodiment 54
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(morpholinyl the third amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-11)
With II-d-9 (0.33g, 1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,328mg, 1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-80.44g, yield 70.8%.ESI-MSm/z:639 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.20 (2H, m, CH2-cyclopropane), 1.59 (2H, m, CH2-cyclopropane), 1.65～1.72 (2H, m, NHCH2CH 2CH2N), 1.92 (3H, s, ArCH3), 2.30～2.37 (8H, m, NHCH 2CH2CH 2N(CH 2)2), 3.55～3.58 (4H, m, CH2OCH2), 6.39 (1H, s, NH), 7.41 (1H, d, ArH, J=8Hz), 7.48 (1H, t, ArH, J=5.3Hz), 7.69～7.72 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2.2Hz, J=8.8Hz), 8.36～8.37 (2H, m, ArH), 8.45 (1H, s, ArH), 10.58 (1H, s, CONH), 11.26 (1H, s, CONH).
Embodiment 55
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(1-methyl piperidine-4-base amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-12)
With II-d-10 (30mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-1250mg, yield 84.6%.ESI-MS:m/z:587 [M+H]+, 609 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.32 (2H, m, CH2-cyclopropane), 1.40～1.51 (2H, m, CH2-cyclopropane), 1.59～1.60 (2H, m, CH 2CH), 1.82～1.86 (2H, m, CH 2CH), 1.95～2.02 (2H, m, NCH2), 2.15 (3H, s, ArCH3), 2.37 (3H, s, NCH3), 2.70～2.73 (2H, m, NCH2), 3.81 (1H, m, NHCH), 6.67 (1H, s, NH), 7.40～7.42 (2H, m, ArH), 7.69～7.72 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2.1Hz, J=8.8Hz), 8.37～8.53 (3H, m, ArH), 10.60 (1H, s, CONH), 11.27 (1H, s, CONH).
Embodiment 56
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[(1-methyl piperidine base-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-13)
With II-d-6 (0.32g, 1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-130.47g, yield 78.2%.ESI-MS:m/z:623 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.19～1.24 (2H, m, CH2-cyclopropane), 1.31 (2H, m, CH2-cyclopropane), 1.44～1.49 (1H, m, CH), 1.57～1.66 (4H, m, CH 2CHCH 2), 1.79～1.90 (2H, m, NCH2), 2.15 (3H, s, ArCH3), 2.36 (3H, s, NCH3), 2.74～2.77 (2H, m, NCH2), 3.21 (2H, m, NHCH2), 6.43 (1H, s, NH), 7.41 (1H, d, ArH, J=8.1Hz), 7.53 (1H, t, ArH, J=5.6Hz), 7.68～7.72 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2,2Hz, J=8.8Hz), 8.35～8.37 (3H, m, ArH), 10.60 (1H, s, CONH), 11.18 (1H, s, CONH).
Embodiment 57
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(4-methylpiperazine-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-14)
With II-d-11 (0.33g, 1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-140.45g, yield 73.1%.ESI-MS:m/z:638 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2-cyclopropane), 1.60 (2H, m, CH2-cyclopropane), 2.13 (3H, s, ArCH3), 2.31 (3H, s, NCH3), 2.37～2.58 (10H, m, NCH2), 3.40 (2H, m, NHCH2), 6.46 (1H, s, NH), 7.34 (1H, s, ArH), 7.41 (1H, d, ArH, J=8Hz), 7.70 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2Hz, J=8.8Hz), 8.37～8.46 (3H, m, ArH), 10.59 (1H, s, CONH), 11.31 (1H, s, CONH).
Embodiment 58
N-[4-[1-(methyl piperidine-4-base) oxygen base]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine 4-yl] cyclopropane-1-formamido group] Benzoylamide (II-15)
With II-d-1 (22.1mg, 0.1mmol) with N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-1,41mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-1550.8mg, yield 87.2%.ESI-MS:m/z:583 [M+H]+。1H-NMR (300MHz, DMSO-d6]): δ 1.64～1.82 (4H, m, CH2-cyclopropane), 1.95 (3H, s, ArCH3), 2.19 (4H, m, CH 2CHCH 2), 2.24～2.26 (2H, m, NCH2), 2.39 (3H, s, NCH3), 2.54-2.55 (2H, m, NCH2), 2.88 (3H, d, NHCH3null，J=3.3Hz)，4.58(1H，m，OCH)，6.42(1H，s，NH)，7.27-7.30(1H，m，ArH)，7.33-7.39(1H，m，ArH)，7.42-7.48(1H，m，ArH)，7.72(1H，dd，ArH，J=1.5Hz，J=7.9Hz)，7.90～8.07 (1H，m，ArH)，8.14～8.15 (1H，d，ArH，J=2.5Hz)，8.41(1H，s，pyrimidine-H)，8.50(1H，s，pyrimidine-H)，10.35(1H，s，CONH)，11.34(1H，s，CONH).
Embodiment 59
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-16)
With II-d-1 (22.1mg, 0.1mmol) and N-[4-[(1-methyl piperidine-4-base) methoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-c-2,42mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-1549.2mg, yield 82.5%.ESI-MS:m/z:597 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.33～1.40 (4H, m, CH2-cyclopropane), 1.58 (2H, m, CH2), 1.69～1.73 (3H, m, CH3), 1.87 (2H, t, CH2, J=10.9Hz), 2.16 (3H, s, ArCH3), 2.35 (3H, s, NCH3), 2.77～2.89 (5H, m, CH2NCH2, CH), 3.93～3.95 (2H, m, OCH2), 6.38 (1H, s, NH), 7.24 (1H, d, ArH, J=9.1Hz), 7.37～7.43 (2H, m, ArH), 7.68 (1H, d, ArH, J=7.8Hz), 8.0 (1H, d, ArH, J=9.0Hz), 8.08 (1H, d, ArH, J=2.2Hz), 8.33 (1H, s, ArH), 8.46 (1H, s, ArH), 10.28 (1H, s, CONH), 11.15 (1H, s, CONH).
Embodiment 60
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-17)
With II-d-1 (22.1mg, 0.1mmol) with N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-3,61.3mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-1749.8mg, yield 88.3%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6]): δ 1.34～1.46 (2H, m, CH2-cyclopropane), 1.61～1.69 (2H, m, CH2-cyclopropane), 1.84～1.92 (2H, m, CH2), 2.36～2.46 (2H, m, CH2), 2.12～2.26 (8H, m, CH2), 2.84～2.90 (3H, m, NHCH3), 3.45 (3H, s, ArCH3), 4.11～4.14 (2H, t, OCH2, J=6.0Hz), 6.40 (1H, s, NH), 7.26 (1H, d, ArH, J=9.1Hz), 7.38～7.45 (2H, m, ArH), 7.65～7.75 (1H, m, ArH), 8.00～8.04 (1H, m, ArH), 8.10～8.11 (1H, d, ArH, J=2.4Hz), 8.37 (1H, s, pyrimidine-H), 8.48 (1H, s, pyrimidine-H), (10.32 1H, s, CONH), (11.24 1H, s, CONH).
Embodiment 61
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-18)
With II-d-1 (22.1mg, 0.1mmol) with N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-i, 39.3mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-1847.9mg, yield 84.2%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.33 (2H, m, CH2-cyclopropane), 1.58 (2H, m, CH2-cyclopropane), 2.36～2.38 (7H, m, 2 × NCH2, ArCH3), 2.82 (3H, s, NHCH3), 3.58～3.59 (6H, m, CH2), 6.39 (1H, m, NH), 7.39～7.44 (2H, m, ArH), 7.68～7.74 (2H, m, ArH), 8.06 (1H, d, ArH, J=8.4Hz), 8.21 (1H, s, ArH), 8.34 (1H, s, ArH), 8.47 (1H, s, ArH), 10.47 (1H, s, CONH), 11.16 (1H, s, CONH).
Embodiment 62
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-19)
With II-d-2 (22mg, 0.1mmol) and N-[4-[(1-methyl piperidine-4-base) methoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-2,42.1mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-1951.7mg, yield 86.4%.ESI-MS:m/z:599 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.29～1.41 (2H, m, CH2), 1.55 (6H, s, 2 × CH3), 1.69～1.73 (3H, m, CH2, CH), 1.83～1.90 (2H, m, NCH2), 2.16 (3H, m, NCH3), 2.21 (3H, s, ArCH3), 2.77～2.83 (5H, m, NCH2, NHCH3), 3.94 (2H, d, OCH2, J=5.4Hz), 6.53 (1H, m, NH), 7.25 (1H, d, ArH, J=9.1Hz), 7.34～7.36 (1H, d, ArH, J=8.1Hz), 7.42 (1H, d, ArH, J=4.3Hz), 7.70 (1H, dd, ArH, J=1.6Hz, J=7.9Hz), 7.97～8.00 (2H, m, ArH), 8.07 (1H, d, ArH, J=2.4Hz), 8.47 (1H, s, ArH), 9.42 (1H, s, CONH), (10.29 1H, s, CONH).
Embodiment 63
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-20)
With II-d-12 (22mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-2044.1mg, yield 87.5%.ESI-MS:m/z:504 [M+H]+, 526 [M+Na]+。1H-NMR (300MHz, DMSO-d6]: 1.41 (2H, m, CH2), 1.56 (2H, m, CH2), 2.28 (3H, s, ArCH3), 2.79-2.82 (3H, m, NHCH3), 6.56 (1H, s, NH), 7.28 (1H, s, ArH), 7.40～7.43 (1H, d, ArH, J=7.9Hz), 7.71～7.76 (2H, m, ArH), 8.07 (1H, s, ArH), 8.11 (1H, d, ArH, J=2.0Hz), 8.23 (1H, d, pyrimidine-H, J=2.5Hz), 8.35 (1H, d, pyrimidine-H, J=2.3Hz), (10.60 1H, s, CONH), (10.74 1H, s, CONH).
Embodiment 64
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(dimethylamino) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-21)
With II-d-13 (29mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-2150.1mg, yield 87.2%.ESI-MS:m/z:575 [M+H]+, 597 [M+Na]+。1H-NMR (300MHz, DMSO-d6]: δ 1.39 (2H, s, CH2-cyclopropane), 1.53 (2H, s, CH2-cyclopropane), 1.62～1.72 (2H, m, NHCH2CH 2CH2), 2.17～2.19 (9H, m, ArCH3, N (CH3)2), 2.30～2.32 (2H, m, NCH2), 3.26～3.36 (2H, m, NHCH2), 6.52 (1H, m, NH), 7.22～7.28 (2H, m, ArH), 7.56～7.58 (1H, m, ArH), 7.90～7.93 (2H, m, ArH), 8.21～8.29 (2H, m, ArH), 8.40 (1H, s, ArH), 10.51 (1H, s, CONH), 10.70 (1H, s, CONH).
Embodiment 65
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(morpholinyl) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-22)
With II-d-14 (33.4mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-2250.3mg, yield 81.6%.ESI-MSm/z:617 [M+H]+, 639 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.40～1.41 (2H, m, CH2-cyclopropane), 1.57 (2H, m, CH2-cyclopropane), 1.63～1.72 (2H, m, NHCH2CH 2CH2), 2.29 (9H, m, 3 × NCH2, ArCH3), 3.27～3.34 (2H, m, NHCH2), 3.53 (4H, m, CH2OCH2), 6.53～6.55 (1H, m, NH), 7.31 (1H, s, ArH), 7.41 (1H, d, ArH, J=8Hz), 7.70～7.78 (2H, m, ArH), 8.12～8.16 (2H, m, ArH), 8.22 (1H, d, ArH, J=5Hz), 8.40 (1H, d, ArH, J=2.3Hz), 10.60 (1H, s, CONH), 10.80 (1H, s, CONH).
Embodiment 66
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-23)
With II-d-12 (22.1mg, 0.1mmol) with N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-6,32.8mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtain white solid II-2348.8mg, yield 86.5%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.41 (2H, m, CH2-cyclopropane), 1.56 (2H, m, CH2-cyclopropane), 1.86-1.90 (2H, m, NCH2CH 2CH2O), 2.28 (3H, s, ArCH3), 2.35～2.45 (6H, m, 3 × NCH2), 2.81 (3H, d, NHCH3, J=4.0Hz), 3.57 (4H, s, CH2OCH2), 4.11-4.13 (2H, m, OCH2), 6.55 (1H, m, NH), 7.26 (1H, s, ArH), 7.28 (1H, d, ArH, J=9.0Hz), 7.40 (1H, d, ArH, J=7.8Hz), 7.72 (1H, m, ArH), 7.98～8.08 (3H, m, ArH), 8.22～8.28 (1H, m, ArH), 10.30 (1H, s, CONH), 10.70 (1H, s, CONH).
Embodiment 67
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] Pentamethylene .-1-formamido group] Benzoylamide (II-24)
With II-d-15 (25mg, 0.1mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,33mg, 0.1mmol) for raw material, the same II-1 of preparation method, obtains white solid II-2444.8mg, yield 84.2%.ESI-MS:m/z:532 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.68 (4H, m, CH2-cyclopentane), 2.21 (3H, s, ArCH3), 2.34 (3H, s, NHCH3), 2.72 (4H, m, CH2-cyclopentane), 6.61 (1H, m, NH), 7.08～7.14 (1H, m, ArH), 7.41～7.47 (1H, m, ArH), 7.71～7.74 (1H, m, ArH), 7.78～7.86 (1H, m, ArH), 8.10 (1H, dd, ArH, J=2.3Hz, J=8.8Hz), 8.24～8.26 (2H, m, ArH), 8.32～8.33 (1H, d, ArH, J=2.3Hz), 9.45 (1H, s, CONH), (10.67 1H, s, CONH).
Embodiment 68
The chloro-9-of 6-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine (III-a)
Adding 6-chloropurine 1.0g (6.5mmol), 3,4-dihydros-2H-pyrans 1.8mL (19mmol), p-methyl benzenesulfonic acid 0.033g (0.2mmol) in 100mL eggplant-shape bottle, analytical pure ethyl acetate 20mL dissolves.Stirring 3h after being warming up to 75 DEG C, reactant liquor is cooled to room temperature, removes solvent under reduced pressure, column chromatographic isolation and purification obtains white solid III-a1.35g, yield 87.6%, ESI-MS:m/z:239 [M+H]+。
Embodiment 69
2-[9-[tetrahydrochysene-2H-pyrans-2-base]-9H-purine-6-base] diethyl malonate (III-b)
With III-a (20g, 83.6mmol) for raw material, the same I-b of preparation method, obtain white solid III-b17g, yield 56.2%, ESI-MS:m/z:363.1 [M+H]+。。
Embodiment 70
2-[9-[tetrahydrochysene-2H-pyrans-2-base]-9H-purine-6-base] ethyl acetate (III-c)
With III-b (9.0g, 25mmol) for raw material, the same I-c of preparation method, obtain faint yellow solid III-c6.7g, yield 92.4%.ESI-MS:m/z:291.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.18 (3H, t, CH2CH 3, J=7.1Hz), 1.58～1.65 (2H, m, pyran-H), 1.73～1.79 (1H, m, pyran-H), 1.98～2.03 (2H, m, pyran-H), 2.34～2.40 (1H, m, pyran-H), 3.68～3.77 (1H, m, pyran-H), 4.03 (1H, d, pyran-H, J=11.3Hz), 4.12 (2H, q, CH 2CH3, J=7.0Hz), 4.18 (2H, s, CH2CO), 5.80 (1H, dd, pyran-H, J=2.1Hz, J=10.9Hz), 8.78 (1H, s, purine-H), 8.88 (1H, s, purine-H).
Embodiment 71
1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] cyclopropane-1-ethyl acetate (III-d-1)
With III-c (6.7g, 23mmol) for raw material, the same I-d of preparation method, obtain Compound II per I-d-16.6g, yield 90.2%.ESI-MS:m/z:317.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.05 (3H, t, CH2CH 3, J=14.2Hz), 1.60～1.63 (6H, m, CH2-pyranandCH2CH2-cyclopropane), 1.72～1.78 (1H, m, pyran-H), 1.98～2.01 (2H, m, pyran-H), 2.33～2.37 (1H, m, pyran-H), 3.70～3.75 (1H, m, pyran-H), 4.01 (1H, d, pyran-H, J=5.8Hz), 4.07 (2H, q, CH 2CH3, J=7.1Hz), 5.77 (1H, dd, pyran-H), 8.73 (1H, s, purine-H), 8.83 (1H, s, purine-H).
Embodiment 72
2-methyl-2-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] ethyl propionate (III-d-2)
With III-c (3.0g, 10.3mmol) and iodomethane (5.87g, 41.3mmol) for raw material, the same I-d of preparation method, obtain Compound II per I-d-23.1g, yield 94.3%.ESI-MS:m/z:319.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.05 (3H, t, CH2CH 3, J=7Hz), 1.60～1.64 (2H, m, pyran-H), 1.68 (6H, s, 2 × CH3), 1.98～2.01 (4H, m, pyran-H), 3.72～3.73 (1H, m, pyran-H), 3.99～4.04 (1H, m, pyran-H), 4.06～4.10 (2H, q, CH 2CH3, J=7.0Hz), 5.82 (1H, s, pyran-H), 8.5 (1H, s, pyrine-H), 8.82 (1H, s, pyrine-H).
Embodiment 73
1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] Pentamethylene .-1-ethyl acetate (III-d-3)
With III-c (5.0g, 17.2mmol) and Isosorbide-5-Nitrae-dibromobutane (14.9g, 68.8mmol) for raw material, the same I-d of preparation method, obtain Compound II per I-d-35.35g, yield 90.2%.ESI-MS:m/z:345 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.12 (3H, t, CH2CH 3, J=10.0Hz), 1.59～1.75 (7H, m, pyran-Handcyclopentane-H), 1.97～2.01 (6H, m, pyran-Handcyclopentane-H), 2.3～2.42 (1H, m, pyran-H), 3.68～3.74 (1H, m, pyran-H), 3.95～4.12 (1H, d, pyran-H), 4.09 (2H, q, CH 2CH3, J=10.0Hz), 5.79～5.81 (1H, d, pyran-H), 8.77 (1H, s, pyrine-H), 8.82 (1H, s, pyrine-H).
Embodiment 74
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] cyclopropane-1-formamido group] Benzoylamide (III-e-1)
With III-d-1 (0.2g, 0.63mmol) and V-c-1 (0.23g, 0.69mmol) for raw material, the same I-e-1 of preparation method, obtain light yellow solid III-e-10.32g, productivity 83.6%.ESI-MS:m/z:599 [M+H]+。
Embodiment 75
N-(3-isopropyl phenyl)-4-methyl-3-[1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] cyclopropane-1-formamido group] Benzoylamide (III-e-2)
With III-d-1 (0.2g, 0.63mmol) and N-(3-isopropyl phenyl)-4-methyl-3-AB (V-c-3,0.19g, 0.69mmol) for raw material, the same I-e-1 of preparation method, obtains light yellow solid III-e-20.29g, productivity 85.2%.ESI-MS:m/z:539.3 [M+H]+。
Embodiment 76
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] cyclopropanecarbonyl amino] Benzoylamide (III-e-3)
With III-d-1 (0.2g, 0.63mmol) and V-c-2 (0.23g, 0.69mmol) for raw material, the same I-e-1 of preparation method, obtain light yellow solid III-e-30.31g, productivity 8.4%.ESI-MS:m/z:603 [M+H]+。
Embodiment 77
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] propionamido] Benzoylamide (III-e-4)
With III-d-2 (0.2g, 0.69mmol) and V-c-1 (0.25g, 0.76mmol) for raw material, the same I-e-1 of preparation method, obtain light yellow solid III-e-40.35g, productivity 83.7%.ESI-MSm/z:601 [M+H]+。
Embodiment 78
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] Pentamethylene .-1-formamido group] Benzoylamide (III-e-5)
With III-d-3 (0.2g, 0.58mmol) and V-c-1 (0.21g, 0.64mmol) for raw material, the same I-e-1 of preparation method, obtain light yellow solid III-e-50.32g, productivity 87.4%.ESI-MS:m/z:627.2 [M+H]+。
Embodiment 79
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[9-(tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base] cyclopropane-1-formamido group] Benzoylamide (III-e-6)
With III-d-1 (0.18g, 0.58mmol) and VIII-i (0.25g, 0.64mmol) for raw material, the same I-e-1 of preparation method, obtain light yellow solid III-e-60.34g, productivity 87.4%.ESI-MS:m/z:664 [M+H]+。
Embodiment 80
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-1)
Adding III-e-10.30g in 50ml eggplant-shape bottle, with methanol for solvent, dropping concentrated hydrochloric acid, to dissolving, filters after stirring 2h, obtains white solid III-10.24g, productivity 94.2%.ESI-MS:m/z:515.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.86～1.87 (2H, m, CH2-cyclopropane), 2.12～2.17 (2H, m, CH2-cyclopropane), 2.41 (3H, s, ArCH3), 6.96 (1H, s, ArH), 7.22 (1H, t, ArH, J=8.2Hz), 7.34～7.41 (2H, m, ArH), 7.55～7.63 (2H, m, ArH), 8.61 (1H, s, purine-H), 8.93 (1H, s, purine-H), (10.13 1H, s, NHCO), 11.15 (1H, s, NHCO), 13.51 (1H, s, purine-NH).
Embodiment 81
N-(3-isopropyl phenyl)-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-2)
With III-e-20.30g for raw material, the same III-1 of preparation method, obtain white solid III-20.24g, productivity 93.6%.ESI-MS:m/z:477.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.21 (6H, d, CH (CH 3)2, J=6.9Hz), 1.82 (2H, m, CH2-cyclopropane), 2.12 (2H, m, CH2-cyclopropane), 2.42 (3H, s, ArCH3), 2.82～2.91 (1H, m, CH(CH3)2), 6.97 (1H, d, ArH, J=6.8Hz), 7.27 (1H, t, ArH, J=8.1Hz), 7.37 (1H, d, ArH, J=8.0Hz), 7.63～7.69 (3H, m, ArH), 8.28 (1H, s, ArH), 8.55 (1H, s, purine-H), 8.91 (1H, s, purine-H), 10.10 (1H, s, NHCO), 11.37 (1H, s, NHCO), 13.68 (1H, s, purine-NH).
Embodiment 82
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-3)
With III-e-30.30g for raw material, the same III-1 of preparation method, obtain white solid III-30.26g, productivity 94.3%.ESI-MS:m/z:519.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.87 (2H, m, CH2-cyclopropane), 2.35 (2H, m, CH2-cyclopropane), 7.41～7.48 (3H, m, ArH), 7.88 (1H, d, ArH, J=7.4Hz), 7.91～7.94 (1H, m, ArH), 8.13 (1H, s, ArH), 8.58 (1H, s, purine-H), 8.97 (1H, s, purine-H), (10.23 1H, s, NHCO), 11.52 (1H, s, NHCO), 13.83 (1H, s, purine-NH).
Embodiment 83
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-(9H-purine-6-base) propionamido] Benzoylamide (III-4)
With III-e-40.30g for raw material, the same III-1 of preparation method, obtain white solid III-40.24g, productivity 93.7%.ESI-MS:m/z:517.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.86 (6H, s, 2 × CH3), 2.17 (3H, s, ArCH3), 7.37 (1H, d, ArH, J=8.0Hz), 7.72 (1H, d, ArH, J=8.8Hz), 7.79 (1H, d, ArH, J=8.0Hz), 7.87 (1H, s, ArH), 8.16 (1H, dd, ArH, J=2.0Hz, J=8.0Hz), 8.40 (1H, d, ArH, J=2.0Hz), 8.74 (1H, s, NHCO), 8.97 (1H, s, purine-H), 9.15 (1H, s, purine-H), (10.67 1H, s, NHCO).
Embodiment 84
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) Pentamethylene .-1-formamido group] Benzoylamide (III-5)
With III-e-50.30g for raw material, the same III-1 of preparation method, obtain white solid III-50.24g, productivity 91.6%.ESI-MSm/z:543.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.73～1.77 (4H, m, cyclopentane-H), 2.09 (3H, s, ArCH3), 2.51-2.68 (4H, m, cyclopentane-H), 7.34 (1H, d, ArH, J=8.0Hz), 7.70～7.77 (2H, m, ArH), 7.86 (1H, s, ArH), 8.14 (1H, d, ArH, J=8.0Hz), 8.38 (1H, s, ArH), 8.75 (1H, s, NHCO), 8.97 (1H, s, purine-H), 9.10 (1H, s, purine-H), (10.67 1H, s, NHCO), (13.23 1H, s, purine-NH).
Embodiment 85
J-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-6)
With III-e-60.30g for raw material, the same III-1 of preparation method, obtain white solid III-60.24g, productivity 91.6%.ESI-MS:m/z:580 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.82～1.84 (2H, m, CH2-cyclopropane), 2.11 (2H, m, CH2-cyclopropane), 2.38 (7H, s, CH2NCH2, ArCH3), 3.58～3.60 (6H, m, ArCH2N, CH2OCH2), 7.39 (1H, d, ArH, J=7.95Hz), 7.69～7.74 (2H, m, ArH), 8.06 (1H, d, ArH, J=8.34Hz), 8.20 (1H, s, ArH), 8.32 (1H, s, ArH), 8.56 (1H, s, purine-H), 8.91 (1H, s, purine-H), 10.47 (1H, s, NHCO), 11.38 (1H, s, NHCO), 13.65 (1H, s, purine-NH).
Embodiment 86
2-(2-bromopyridine-4-base) ethyl acetate (IV-a)
250mL eggplant-shape bottle adds the bromo-4-picoline (3.44g of 2-, 20mmol) with lithium diisopropylamine 2M/L tetrahydrofuran solution (20mL, 40mmol), add anhydrous tetrahydro furan 100mL to dissolve, diethyl carbonate (2.84g is added after stirring 2h, 24mmol), 10h, TLC are stirred at room temperature and detect the disappearance of raw material point.Reactant liquor being poured into saturated ammonium chloride solution 50mL, extraction into ethyl acetate (200mL × 3), merges organic layer, saturated nacl aqueous solution washing (100mL × 3), anhydrous magnesium sulfate is dried overnight.Decompression removes excess of solvent, column chromatography purification, obtains white solid IV-a3,4g, yield 70.1%.ESI-MS:m/z:266 [M+Na]+。
Embodiment 87
1-(2-bromopyridine-4-base) cyclopropane-1-ethyl acetate (IV-b)
250mL eggplant-shape bottle adds IV-a (3.40g, 14mmol), dissolve with dry DMF 50mL, under ice bath, be slowly added to sodium hydroxide (1.68g, 42mmol), stirring 30min, glycol dibromide (3.20g, 16.8mmol) is slowly added in reaction bulb, normal-temperature reaction 1h, TLC detect raw material point and disappear.Reactant liquor being poured into saturated ammonium chloride solution 100mL, extraction into ethyl acetate (200mL × 3), merges organic layer, saturated nacl aqueous solution washing (50mL × 3), anhydrous magnesium sulfate is dried overnight.Decompression removes excess of solvent, column chromatography purification, obtains clear oil thing IV-b2.5g, yield 65%.ESI-MS:m/z:292 [M+Na]+。
Embodiment 88
1-(2-cyanopyridine-4-base) cyclopropane-1-ethyl acetate (IV-c)
100mL two neck bottle adds IV-b (2.5g, 9mmol), zinc cyanide (1.6g, 9mmol) and tetra-triphenylphosphine palladium (0.52g; 0.45mmol), dry DMF 40mL dissolves, nitrogen protection; 90 DEG C are heated to reflux 2h, TLC and detect the disappearance of raw material point.It is poured into 50mL water dilute reaction solution.Gained liquid being poured into saturated ammonium chloride solution 100mL, extraction into ethyl acetate (200mL × 3), merges organic layer, saturated nacl aqueous solution washing (50mL × 3), anhydrous magnesium sulfate is dried overnight.Decompression removes excess of solvent, and column chromatography purification obtains IV-c1.7g, yield 88%.ESI-MS:m/z:239 [M+Na]+。
Embodiment 89
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-cyano group) pyridin-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-d-1)
250mL three-necked bottle adds IV-c (1.7g; 7.86mmol), VII-b-2 (3.23g, 9.4mmol); dissolve with 80mL dry toluene; nitrogen protection, is slowly added to toluene solution (2M, the 11.8mL of trimethyl aluminium under ice bath; 23.6mmol); remove ice bath, be to slowly warm up to 80 DEG C of stirrings 5h, TLC and detect the disappearance of raw material point.Extracting reaction of going out, extraction into ethyl acetate (200mL × 3) with 1M dilute hydrochloric acid, saturated sodium bicarbonate solution washing (100mL × 3), anhydrous magnesium sulfate dries.Decompression removes excess of solvent, obtains yellow solid IV-d-12.42g, yield 60%, ESI-MSm/z:536 [M+Na]+。
Embodiment 90
1-[2-(carbamoyl) pyrimidine-4 base] cyclopropyl-1-ethyl acetate (IV-d-2)
IV-c (1.7g, 7.9mmol) is dissolved in dry DMF 40mL, under ice bath, is slowly added to ammonia (1.38g, 39.5mmol), stirring 30min after dropping hydrogen peroxide (30%, 2.3g, 20mmol), 2h, TLC are stirred at room temperature and detect the disappearance of raw material point.By reacting liquid filtering, obtain solid, shaped crude product, column chromatographic isolation and purification, obtain solid IV-d-21.6g, yield 85%.ESI-MS:m/z:235 [M+H]+。
Embodiment 91
1-[2-(methylamino Methanamide) pyridin-4-yl] cyclopropane-1-ethyl acetate (IV-e)
It is dissolved in dry DMF 20ml with IV-d-2 (1.6g, 6.8mmol) for raw material, adds NaH (60%, 7.5mmol), add iodomethane (0.97g, 6.8mmol) after stirring 30min when ice bath, add shrend after reaction 30min and go out reaction.Washing (50mL × 2), ethyl acetate extracts (100mL × 2).Column chromatographic isolation and purification obtains IV-e1.57g, yield 93%, ESI-MS:m/z:249 [M+H]+。
Embodiment 92
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-carbamyl) pyridin-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-1)
With IV-d-1 (2.42,4.7mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,1.55g, 4.7mmol) for raw material, the same II-1 of preparation method, obtains IV-12.0g, yield 82%.ESI-MS:m/z:532 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.24～1.26 (2H, m, CH2), 1.51～1.56 (2H, m, CH2), 2.17 (3H, s, ArCH3), 7.42 (1H, d, ArH, J=7.8Hz), 7.55 (1H, dd, ArH, J=1.7Hz, J=5.0Hz), 7.59～7.62 (1H, m, ArH), 7.68 (1H, s, NH 2), 7.71～7.73 (1H, m, ArH), 7.97 (1H, d, ArH, J=1.0Hz), 8.13 (1H, s, NH 2), 8.37 (1H, d, ArH, J=1.7Hz), 8.56 (1H, d, ArH, J=5.0Hz), 8.64 (1H, d, ArH, J=7.8Hz), 8.82～8.85 (1H, m, ArH), 9.08 (1H, s, CONH), (10.54 1H, s, CONH).
Embodiment 93
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-methyl-carbamoyl) pyridin-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-2)
With IV-e (1.57g, 6.3mmol) and N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1,2.06g, 6.3mmol) for raw material, the same II-1 of preparation method, obtains IV-22g, yield 60%.ESI-MS:m/z:546 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.26～1.28 (2H, m, CH2), 1.52～1.58 (2H, m, CH2), 2.18 (3H, s, ArCH3), 2.82～2.83 (3H, d, NHCH 3), 7.39 (1H, d, ArH, J=8.0Hz), 7.61～7.62 (1H, m, ArH), 7.71 (1H, d, ArH, J=8.9Hz), 7.76～7.79 (1H, m, ArH), 7.82 (1H, s, ArH), 8.07 (1H, s, NH), 8.13 (1H, dd, ArH, J=2.1Hz, J=8.9Hz), 8.35 (1H, d, ArH, J=2.1Hz), 8.61 (1H, d, NH, J=4.8Hz), 8.81～8.83 (1H, m, ArH), 9.04 (1H, s, CONH), 10.58 (1H, s, CONH).
Embodiment 94
4-methyl-3-nitro Benzenecarbonyl chloride. (V-a-1)
100mL eggplant-shape bottle adds 4-methyl-3-nitro benzoic acid (1.81g, 10.0mmol) and 50mL thionyl chloride, after back flow reaction 3h, decompression is distilled off unnecessary thionyl chloride, obtain yellow oil V-a-11.90g, productivity 95.0%, direct plunge into next step.
Embodiment 95
The fluoro-3-nitrobenzoyl chloride (V-a-2) of 4-
With the fluoro-3-nitrobenzoic acid (1.85g, 10.0mmol) of 4-for raw material, the same V-a-1 of preparation method, obtain yellow oil V-a-21.93g, productivity 89.6%.
Embodiment 96
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (V-b-1)
100mL eggplant-shape bottle adds 4-chloro-3-(trifluoromethyl) aniline (0.78g, 4mmol) and anhydrous triethylamine (2.67g, 26.7mmol), anhydrous CH2Cl220mL dissolves, and stirs in ice bath.V-a-1 (1.90g, 9.5mmol) is used anhydrous CH2Cl250mL dissolves, and instills wherein, stirs 3h under room temperature, detects raw material through TLC and disappears.Remove excess of solvent, column chromatographic isolation and purification (eluant is ethyl acetate: petroleum ether=50: 1) under reduced pressure, obtain off-white color solid V-b-11.10g, yield 76.9%.Mp:174～175 DEG C.ESI-MS:m/z:359.0 [M+H]+。1H-NMR (300MHz, CDCl3): δ 2.48 (3H, s, ArCH3), 7.52 (1H, d, ArH, J=8.7Hz), 7.69 (1H, dd, ArH, J=2.4Hz, J=9.0Hz), 8.00 (1H, d, ArH, J=8.7Hz), 8.24～8.30 (2H, m, ArH), 8.64 (1H, d, ArH, J=8.1Hz), 10.83 (1H, s, NHCO).
Embodiment 97
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-nitrobenzamide (V-b-2) of-4-
With the chloro-3-5-trifluoromethylaniline (0.44g, 4mmol) of V-a-2 (1.93g, 9.0mmol) and 4-for raw material, the same V-b-1 of preparation method, obtain white solid V-b-21.19g, yield 81.2%.Mp:181～182 DEG C.ESI-MS:m/z:363.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 7.68～7.75 (2H, m, ArH), 7.92 (1H, d, ArH, J=2.1Hz), 8.08 (1H, d, ArH, J=8.1Hz), 8.51～8.56 (2H, m, ArH), 10.82 (1H, s, NHCO).
Embodiment 98
N-(3-isopropyl phenyl)-4-methyl-3-nitro Benzoylamide (V-b-3)
With V-a-1 (1.90g, 9.5mmol) and 3-isopropyl aniline (0.54g, 4mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid V-b-30.893g, yield 74.8%.Mp:102～104 DEG C.ESI-MS:m/z:299.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.22 (6H, d, CH (CH3)2, J=6.9Hz), 2.48 (3H, s, ArCH3), 2.82～2.93 (1H, m, CH (CH3)2), 7.03 (1H, d, ArH, J=7.5Hz), 7.29 (1H, t, ArH, J=8.4Hz), 7.62 (2H, d, ArH, J=1.8Hz), 7.98 (1H, d, ArH, J=8.4Hz), 8.27 (1H, dd, ArH, J=2.1Hz, J=8.4Hz), 8.64 (1H, d, ArH, J=2.1Hz), 10.49 (1H, s, NHCO).
Embodiment 99
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (V-c-1)
100mL eggplant-shape bottle adds V-b-1 (0.97g, 3mmol), iron powder (0.54g, 9.6mmol), NH4Cl (0.39g, 7.2mmol) and 75% ethanol 50mL, is warming up to backflow 0.5h.Reactant liquor is cooled to room temperature, and sucking filtration removes iron powder, removes excess of solvent, column chromatographic isolation and purification under reduced pressure, obtains white solid V-c-10.654g, yield 66.3%.Mp:154～156 DEG C.ESI-MS:m/z:329.0 [M+H]+。1H-NMR (300MHz, CDCl3): δ 2.24 (3H, s, ArCH3), 3.80 (2H, s, ArNH2), 7.13～7.18 (2H, m, ArH), 7.21 (1H, s, ArH), 7.48 (1H, d, ArH, J=8.7Hz), 7.88 (1H, d, ArH, J=8.7Hz), 7.94 (1H, s, ArH), 7.95 (1H, s, CONH).
Embodiment 100
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-AB of-4-(V-c-2)
With V-b-2 (1.09g, 3mmol) for raw material, the same V-c-1 of preparation method, obtain off-white color solid V-c-20.722g, yield 72.3%.Mp:174～175 DEG C.ESI-MS:m/z:333.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 5.43 (2H, s, ArNH2), 7.15 (2H, d, ArH, J=8.7Hz), 7.35 (1H, d, ArH, J=8.1Hz), 8.51～8.56 (2H, m, ArH), 10.82 (1H, s, NHCO).
Embodiment 101
N-(3-isopropyl phenyl)-4-methyl-3-AB (V-c-3)
With V-b-3 (0.84g, 3mmol) for raw material, the same V-c-1 of preparation method, obtain off-white color solid V-c-20.534g, yield 66.2%.Mp:152～154 DEG C.ESI-MSm/z:269.1 [M+H]+。1H-NMR (300MHz, CDCl3): δ 1.26 (6H, d, (CH3)2CH, J=6.9Hz), 2.20 (3H, s, ArCH3), 2.90～2.93 (1H, m, (CH3)2CH), 3.77 (2H, s, ArNH2), 7.00 (1H, d, ArH, J=7.8Hz), 7.09～7.15 (2H, m, ArH), 7.22-7.29 (2H, m, ArH), 7.46 (1H, d, ArH, J=8.1Hz), 7.50 (1H, s, ArH), 7.82 (1H, s, CONH).
Embodiment 102
The chloro-3-trifluoromethyl benzoyl chloride (VI-a) of 4-
With the chloro-3-(Trifluoromethyl)benzoic acid. of 4-for raw material, the same V-a-1 of preparation method, obtain yellow oil VI-a, productivity 92.8%.
Embodiment 103
N-(4-methyl-3-nitro phenyl)-[the chloro-3-of 4-(trifluoromethyl)] Benzoylamide (VI-b)
With VI-a-1 and 4-methyl-3-nitro aniline (O.61g, 4mmol) for raw material, the same V-b-1 of preparation method, obtain white solid VI-b-11.07g, yield 82.6%.Mp:165～167 DEG C.ESI-MS:m/z:324.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.45 (3H, s, ArCH3), 7.51 (1H, d, ArH, J=7.8Hz), 7.76 (1H, t, ArH, J=7.9Hz), 8.01 (1H, d, ArH, J=8.5Hz), 8.05 (1H, d, ArH, J=8.4Hz), 8.21 (1H, s, ArH), 8.29 (1H, dd, ArH, J=2.1Hz, J=8.4Hz), 8.67 (1H, d, ArH, J=2.1Hz), 10.80 (1H, s, NHCO).
Embodiment 104
N-(3-amino-4-aminomethyl phenyl)-4-chloro-3-(trifluoromethyl) Benzoylamide (VI-c)
With VI-b for raw material, the same V-c-1 of preparation method, obtain off-white color solid VI-c0.736g, yield 83.4%.Mp:157～159 DEG C.ESI-MS:m/z:294.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.03 (3H, s, ArCH3), 4.87 (2H, s, ArNH2), 6.80～6.89 (2H, m, ArH), 7.11 (1H, d, ArH, J=2.1Hz), 7.76 (1H, t, ArH, J=7.8Hz), 7.94 (1H, d, ArH, J=7.8Hz), 8.21～8.25 (2H, m, ArH), (10.13 1H, s, CONH).
Embodiment 105
N-[4-chloro-3-(trifluoromethyl) phenyl]-N '-(4-methyl-3-nitro phenyl) urea (VII-a)
100mL eggplant-shape bottle adds the chloro-3-5-trifluoromethylaniline (2g, 10.2mmol) of 4-and CDI (1.76g, 10.9mmol), anhydrous methylene chloride 30mL dissolve.Stir 16h under room temperature, add 4-methyl-3-nitro aniline (1.55g, 10.2mmol), stir 18h.TLC detects reaction raw materials and disappears, and sucking filtration uses a small amount of washed with dichloromethane, dries to obtain light yellow solid VII-a3.35g, yield 95.6%.Mp:219～220 DEG C.ESI-MS:m/z:373.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.46 (3H, s, ArCH3), 7.42 (1H, d, ArH, J=8.4Hz), 7.58～7.69 (3H, m, ArH), 8.10～8.11 (1H, m, ArH), 8.28 (1H, d, ArH, J=7.6Hz), 9.26 (1H, s, NHCONH), 9.31 (1H, s, NHCONH)。
Embodiment 106
N-[4-chloro-3-(trifluoromethyl) phenyl]-N '-(4-methyl-3-aminophenyl) urea (VII-b)
100mL eggplant-shape bottle adds VI-a-2 (1.12g, 3mmol), the same V-c-1 of preparation method, obtains white solid VII-b0.720g, yield 69.8%.Mp:199～201 DEG C.ESI-MS:m/z:344.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.98 (3H, s, ArCH3), 4.76 (2H, s, ArNH2), 6.55 (1H, d, ArH, J=8.1Hz), 6.78 (1H, d, ArH, J=8.4Hz), 6.87 (1H, d, ArH, J=2.1Hz), 7.54～7.63 (2H, m, ArH), 8.18 (1H, d, ArH, J=2.1Hz), 9.18 (1H, s, NHCONH), 9.82 (1H, s, NHCONH)。
Embodiment 107
4-[4-nitro-2-(trifluoromethyl) phenyl] morpholine (VIII-a-1)
With 4-fluoro-3-trifluoromethyl nitrobenzene 0.42g (2mmol) and morpholine 0.9mL (10mmol) for raw material, dimethyl sulfoxide 5mL dissolves, and 100 DEG C are heated 5 hours.Cooling, removes solvent under reduced pressure, give light yellow oil VIII-a-1, not purified direct throwing next step.
Embodiment 108
1-methyl-4-[4-nitro-2-(trifluoromethyl) phenyl] piperazine (VIII-a-2)
With 4-fluoro-3-trifluoromethyl nitrobenzene 0.42g (2mmol) and N methyl piperazine 1.1mL (10mmol) for raw material, preparation method same VIII-a-1, give light yellow oil VIII-a-20.45g, not purified direct throwing next step.
Embodiment 109
4-[4-amino-2-(trifluoromethyl) phenyl] morpholine (VIII-b-1)
With VIII-a-12.8g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-b-12.3g, yield 92.4%.
Embodiment 110
1-methyl-4-[4-amino-2-(trifluoromethyl) phenyl] piperazine (VIII-b-2)
With VIII-a-22.9g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-b-22.3g, yield 87.8%.
Embodiment 111
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-c-1)
With VIII-b-12.5g (10mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-c-13.8g, yield 91.8%.
Embodiment 112
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-c-2)
With VIII-b-22.6g (10mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-c-23.9g, yield 93.5%.
Embodiment 113
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-d-1)
With VIII-c-14.1g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-d-13.2g, yield 84.8%, ESI-MS:m/z:380 [M+H]+。
Embodiment 114
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-d-2)
With VIII-c-24.2g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-d-23.3g, yield 83.5%, ESI-MS:m/z:393 [M+H]+。
Embodiment 115
1-methyl-4-[4-nitro-2-(trifluoromethyl) phenoxy group] piperidines (VIII-e-1)
1-methyl-4-piperidine alcohols 1.15g (10mmol) is dissolved in DMF10mL, adds sodium hydrogen 0.48g (12mmol), after 0.5h, add 4-fluoro-3-trifluoromethyl nitrobenzene 0.42g (2mmol), 100 DEG C of heating 5h.Being cooled to room temperature, wash (50mL × 2), ethyl acetate extracts (100mL × 2), removes solvent under reduced pressure, give light yellow oil VIII-e-1, not purified direct throwing next step.
Embodiment 116
1-methyl-4-[4-nitro-2-(trifluoromethyl) Phenoxymethyl] piperidines (VIII-e-2)
With 1-methyl-4-piperidine carbinols 1.29g (10mmol) for raw material, preparation method same VIII-e-1, give light yellow oil VIII-e-2, not purified direct throwing next step.
Embodiment 117
4-[3-[4-nitro-2-(trifluoromethyl) phenoxy group] propyl group] morpholine (VIII-e-3)
With 3-(4-morpholinyl)-1-propanol 1.45g (10mmol) for raw material, preparation method same VIII-e-1, give light yellow oil VIII-e-3, not purified direct throwing next step.
Embodiment 118
1-methyl-4-[4-amino-2-(trifluoromethyl) phenoxy group] piperidines (VIII-f-1)
With VIII-e-12.8g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-f-12.45g, yield 89.4%.
Embodiment 119
1-methyl-4-[4-amino-2-(trifluoromethyl) Phenoxymethyl] piperidines (VIII-f-2)
With VIII-e-23.18g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-f-22.49g, yield 86.4%.
Embodiment 120
4-[3-[4-amino-2-(trifluoromethyl) phenoxy group] propyl group] morpholine (VIII-f-3)
With VIII-e-32.9g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-f-32.6g, yield 85.2%.
Embodiment 121
N-[4-[1-(methyl piperidine-4-base) oxygen base]-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-g-1)
With VIII-f-12.74g (10mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-g-13.74g, yield 85.6%.
Embodiment 122
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-g-2)
With VIII-f-22.88g (10mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-g-13.95g, yield 87.6%.
Embodiment 123
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-g-3)
With VIII-f-33.04g (10mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-g-34.08g, yield 87.2%.
Embodiment 124
N-[4-[1-(methyl piperidine-4-base) oxygen base]-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-1)
With VIII-g-14.37g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-h-13.52g, yield 86.4%, ESI-MS:m/z:408 [M+H]+。
Embodiment 125
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-2)
With VIII-g-24.51g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-h-23.61g, yield 85.7%, ESI-MSm/z:422 [M+H]+。
Embodiment 126
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-h-3)
With VIII-g-34.67g (10mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-h-33.81g, yield 87.2%, ESI-MS:m/z:438 [M+H]+。
Embodiment 127
1-bromomethyl-4-nitro-2-(trifluoromethyl) benzene (VIII-i)
1-methyl-4-nitro-2-(trifluoromethyl) benzene 2.05g (10mmol) and N-bromosuccinimide 2.14g (12mmol) is dissolved in 1,2-dichloroethanes 30mL, back flow reaction 5h.Being cooled to room temperature, remove solvent under reduced pressure, wash (100mL × 2), ethyl acetate extracts (200mL × 2).Remove solvent, column chromatographic isolation and purification under reduced pressure, obtain light yellow solid VIII-i2.45g, yield 86.4%, ESI-MS:m/z:284 [M+H]+。
Embodiment 128
4-[4-nitro-2-(trifluoromethyl) benzyl] morpholine (VIII-g)
Being dissolved in THF20mL by VIII-i1.14g (4mmol) and morpholine 0.5mL (6mmol), with triethylamine 0.9mL (6mmol) for acid binding agent, reflux 2h.Being cooled to room temperature, remove solvent under reduced pressure, wash (100mL × 2), ethyl acetate extracts (200mL × 2), removes solvent under reduced pressure, give light yellow oil VIII-j, not purified direct throwing next step.
Embodiment 129
4-(morpholine-4-ylmethyl)-3-(trifluoromethyl) aniline (VIII-k)
With VIII-g1.16g (4mmol) for raw material, the same V-c-1 of preparation method, obtain yellow solid VIII-k0.96g, yield 92.3%, ESI-MS:m/z:261 [M+H]+。
Embodiment 130
N-[4-(morpholine-4-ylmethyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-nitro Benzoylamide (VIII-1)
With VIII-k1g (4mmol) for raw material, the same V-b-1 of preparation method, obtain light yellow solid VIII-l1.43g, yield 84.3%.
Embodiment 131
N-[4-(morpholine-4-ylmethyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-AB (VIII-m)
With VIII-l1.7g (4mmol) for raw material, the same V-c-1 of preparation method, obtain light yellow solid VIII-m1.36g, yield 86.4%, ESI-MS:m/z:394 [M+H]+。

Claims (8)

1. the compound of formula (I) or its pharmaceutically acceptable salt:
Wherein Q is selected from 7H-pyrrolo-[2, the 3-d] pyrimidine-4-yl shown on being, 6-substituted pyrimidines-4-base, 2-substituted pyrimidines-4-base, 9H-purine-6-base and 2-substituted pyridines-4-base；
Wherein R1、R2Represent hydrogen, alkyl or R independently of one another1、R2Connect the carbocyclic ring of 3-6 the carbon atom formed；
R3Represent hydrogen, alkyl, halogen, cyano group, alkyl oxy, alkyl sulfenyl；
R4、R5It is each independently selected from hydrogen, halogen, cyano group, alkyl, aryl or Het1Substituent group, wherein said alkyl can be replaced by one or more halogens, cyano group further, described Het1Selected from pyrazolyl, furyl, thienyl, pyridine radicals, pyrazinyl, pyrimidine radicals；Or following aliphatic heterocycle: nafoxidine base, morpholinyl, morpholinyl alkyl, morpholinylalkoxy groups, morpholinyl alkylamino, piperazinyl, piperazinyl alkyl, piperazinyl alkoxy, piperazinyl alkylamino, piperidyl, piperidinylalkyl group, piperidyl alkoxyl, piperidyl alkylamino；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6SR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2With-O (CH2)1-6OR.Described R is selected from hydrogen or alkyl, described Het2Monocyclic heterocycles selected from piperidyl, pyrrole radicals, pyrazolyl, piperidyl, imidazole radicals, furyl, morpholinyl, thienyl, azoles base, isoxazole base, thiazolyl, isothiazolyl, pyridine radicals, pyrimidine radicals, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl；Or selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl group, benzo isoxazole base, benzothiazolyl, benzisothiazole base, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [b] [1,4] bicyclic heterocycle of dioxane base or benzo [d] [1,3] dioxolanyl；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent groups, and each substituent group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl, or selected from C3-C8Aliphatic carbocyclic ring, or following aliphatic heterocycle: nafoxidine base, morpholinyl, alkoxyl morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L represents CONH, NHCO, NHCONH, NHSO independently of one another2Or SO2The connexons such as NH；
Abovementioned alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom；Or for having the cyclic saturated hydrocarbon base of 3-6 carbon atom；Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Alkoxyl is the saturated oxyl of straight or branched with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon oxygen base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon oxygen base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Alkylthio group is the straight or branched saturated hydrocarbons sulfenyl with 1-6 carbon atom, or for having the cyclic saturated hydrocarbon sulfenyl of 3-6 carbon atom；Or for connecting the cyclic saturated hydrocarbon sulfenyl with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom；
Armaticity carbocyclic ring is the carbocyclic ring selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is each optionally replaced by 1,2 or 3 substituent groups, and each substituent group is independently selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, sulfydryl, alkoxyl, alkylthio group, alkyl amino, alkoxyalkyl, aryl or Het, aryl alkyl or Het alkyl；
Halogen is selected from fluorine, chlorine, bromine or iodine.
2. formula according to claim 1 (I) compound or its pharmaceutically acceptable salt, wherein R1、R2Represent alkyl independently of one another；Or R1、R2Connect the carbocyclic ring of 3-6 the carbon atom formed；
R3Represent alkyl, halogen；
R4、R5Represent hydrogen, halogen, cyano group, alkyl, aryl or Het independently of one another1The aryl replaced, wherein said alkyl can be replaced by one or more halogens, cyano group further, Het1Selected from aliphatic heterocycle: morpholinyl, alkyl morpholine base, alkoxyl morpholinyl, piperazinyl, alkylpiperazinyl, alkoxyl piperazinyl, substituted piperazinyl, piperidyl, Alkylpiperidine base, alkoxypiperidin base；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2Or-O (CH2)1-6OR, R represent hydrogen, alkyl；Described Het2Aliphatic heterocycle selected from following: nafoxidine base, morpholinyl, alkoxyl morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L represents CONH, NHCO, NHCONH, NHSO independently of one another2Or SO2The connexons such as NH.
3. formula according to claim 1 (I) compound or its pharmaceutically acceptable salt, wherein R1、R2Preferred methyl, or R independently of one another1、R2Connect the carbocyclic ring of 3 yuan or five yuan formed；
R3It is preferably methyl or halogen；
R4、R5It is preferably hydrogen, halogen, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, morpholinyl, morpholine methyl, 2-(morpholine-1-base) ethyoxyl, 3-(morpholine-1-base) propoxyl group, piperidyl, piperidin-4-ylmethyl, 1-methyl piperidine-4-base oxygen base, 1-methyl piperidine-4-ylmethoxy, piperazinyl, 4-methyl piperazine base or 4-methyl piperazine methyl independently of one another；
R6It is preferably methylamino, methoxyethylamino, dimethylaminopropylamino, hydroxyethylamino, 2-(nafoxidine-1-base) ethylamino, 2-(nafoxidine-1-base) propylcarbamic, 2-(piperidin-1-yl) ethylamino, 1-methyl piperidine-4-base amino, 1-methyl piperidine-4-base methylamino, 2-(4-methylpiperazine-1-yl) ethylamino, 3-(morpholinyl-1-base) propylcarbamic, carbamoyl or methyl-carbamoyl；
L represents CONH, NHCO or NHCONH connexon independently of one another.
4. formula according to claim 1 (I) compound or its pharmaceutically acceptable salt, is wherein following arbitrary compound or its pharmaceutically acceptable salt:
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-1),
N-[3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (I-2),
N-[5-[4-chloro-3-(trifluoromethyl) phenyl urea groups]-2-aminomethyl phenyl]-1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1-cyclopropane carboxamide (I-3),
N-[4-morpholinyl-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-4),
N-[4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-5)
N-[4-(1-methyl piperidine-4-base oxygen base)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-6)
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-7)
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl) cyclopropane-1-formamido group] Benzoylamide (I-8),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(6-methylaminopyrimidin-4-base) cyclopropane-1-formamido group] Benzoylamide (II-1),
N-[3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group]-4-aminomethyl phenyl]-4-chloro-3-(trifluoromethyl) Benzoylamide (II-2),
N-[5-[3-[4-chloro-3-(trifluoromethyl) phenyl] urea groups]-2-aminomethyl phenyl]-1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-Methanamide (II-3),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-4),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-hydroxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-5),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(methoxyethylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-6),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[3-(dimethylaminopropylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-7),
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-[6-[1-(methyl piperidine-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-8),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(nafoxidine-1-base) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-9),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(piperidin-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-10),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(morpholinyl the third amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-11),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(1-methyl piperidine-4-base amino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-12),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[(1-methyl piperidine base-4-base) methylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-13),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-[2-(4-methylpiperazine-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-14),
N-[4-[1-(methyl piperidine-4-base) oxygen base]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-15)
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-16)
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-17),
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-18),
N-[4-[(1-methyl piperidine-4-base) methoxyl group]-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-[6-(methylamino) pyrimidine-4-yl] propionamido] Benzoylamide (II-19)
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-20),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(dimethylamino) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-21),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-[3-(morpholinyl) the third amino] pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-22),
N-[4-(morpholinyl propoxyl group)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[2-(methylamino) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (II-23),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(methylamino) pyrimidine-4-yl] Pentamethylene .-1-formamido group] Benzoylamide (II-24),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-1),
N-(3-isopropyl phenyl)-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-2),
N-[4-chloro-3-(trifluoromethyl) phenyl] the fluoro-3-of-4-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-3),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[2-methyl-2-(9H-purine-6-base) propionamido] Benzoylamide (III-4),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) Pentamethylene .-1-formamido group] Benzoylamide (III-5),
N-[4-(morpholinyl methyl)-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-(9H-purine-6-base) cyclopropane-1-formamido group] Benzoylamide (III-6),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-carbamyl) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-1),
N-[4-chloro-3-(trifluoromethyl) phenyl]-4-methyl-3-[1-[6-(2-methyl-carbamoyl) pyrimidine-4-yl] cyclopropane-1-formamido group] Benzoylamide (IV-2).
5. formula according to claim 1 (I) compound or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt includes the acid-addition salts that formula (I) compound is formed with following acid: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, maleic acid, benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.Additionally include the acid salt of inorganic base, as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
6., according to a kind of pharmaceutical composition, wherein contain formula (I) compound of claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
7. the compound of formula according to claim 1 (I) or its pharmaceutically acceptable salt in preparation for preventing or treating the purposes in the medicine of the disease relevant with Raf kinase.
8. purposes according to claim 7, wherein relevant with Raf kinase disease is melanoma, hepatocarcinoma, renal carcinoma, acute leukemia, nonsmall-cell lung cancer, carcinoma of prostate, thyroid carcinoma, skin carcinoma, colorectal carcinoma, cancer of pancreas, ovarian cancer, breast carcinoma, myelodysplastic syndrome, the esophageal carcinoma, gastric cancer or mesothelioma etc..
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