CN103694236B - A kind of pyrimidine scaffold has the antitumoral compounds of activity of hedgehog path antagonist - Google Patents

Present invention is disclosed the new antitumoral compounds that a kind of pyrimidine scaffold has activity of hedgehog path antagonist, including the compound and its pharmaceutically acceptable salt, various isotopes, various isomers or various crystalline structures, with the structure shown in formula I：

A kind of pyrimidine scaffold has the antitumoral compounds of activity of hedgehog path antagonist

Technical field

There is the new of activity of hedgehog path antagonist the present invention relates to pharmaceutical technology field, more particularly to a kind of pyrimidine scaffold Type antitumoral compounds.

Background technology

Malignant tumour is one of main disease of harm human health, the annual malignant tumour new cases about 1090 in the whole world Ten thousand, and the patient about 6,700,000 [1] of the annual death because of malignant tumour, therefore, the preventing and treating of tumour is also the great class of the world of medicine Topic, the wherein research and development of antineoplastic are explored by years of researches and there occurs huge change；Commonly used with preclinical therapy Antineoplastic be mainly cytotoxic drug, this kind of antineoplastic has that poor selectivity, toxic and side effect are strong, be also easy to produce resistance The shortcomings of；Recently as the progress at full speed of life science, the tune of signal transduction, cell cycle in malignant cell The various basic processes such as control, the induction of Apoptosis, the interaction of angiogenesis and cell and extracellular matrix progressively by Illustrate, the key enzyme using some intracellular signal transduction pathway related to tumor cell differentiation propagation as drug screening target spot, In these specific target spots, be provided simultaneously with efficient, the pilot compound of low toxicity property has turned into current anti-swollen to selectively acting The important directions of tumor medicine research and development；Herceptin (trastuzumab), Imatinib (imatinib), Gefitinib And the successful listing of the targeted drug such as Erlotinib (erlotinib) is exactly typical example [2] (gefitinib).

The characteristics of transfer and regeneration are malignant tumours, is also the problem for treating malignant tumour, even the targeted drug of a new generation Transfer to tumour is little with regeneration curative effect.Based on this, the research of Hedgehog (Hh) signal path-hedgehog pathway in recent years receives science Boundary more and more payes attention to, be not only because Hh signal paths abnormal activation many tumours include basal-cell carcinoma, brain tumor, The generation evolution of breast cancer, prostate cancer and some alimentary system malignant tumours has all served very important [3-11], more important Be that Hh signal paths are embryonic development paths, to regulation and control tumor stem cell, so as to control metastases to be played an important role with regeneration.

Hedgehog signal paths are that a highly conserved cell asks signal transduction system, are sent out in fruit bat within 1980 It is existing, because the pathway gene mutation of fruit bat can cause larva body surface to reveal the furcella of many likeness in form hedgehogs, therefore it is named as hedgehog Path Hedgehog (Hh) [12].Hh signal paths are by Hh parts, two transmembrane protein acceptor patched membrane Receptor (PTCH) and smoothened transmembrane protein (SMO) and downstream transcription factor Gli albumen etc. Composition [13].PTCH and SMO are two kinds of transmembrane proteins being located on target cell membrane, and wherein PTCH is encoded by tumor suppressor gene PTCH 12 transmembrane proteins, be a kind of cell surface receptor, with isolate and transduction Hh double action；SMO be one 7 times across Memebrane protein, highly similar to g protein coupled receptor family in structure, the effect with transduction Hh signals.PTCH and SMO believes in Hh Play a part of acceptor in number transmittance process, wherein PTCH is the acceptor of Hh, when in the absence of Hh, PTCH prevents SMO indexings from arriving Cell membrane, so as to suppress the activity of SMO, and then suppresses the transcriptional expression of downstream gene；When Hh signals are present, Hh and PTCH is tied Close, induce multiple serine/threonine residues of SMO c-terminuses that phosphorylation occurs, cause SMO to assemble and activate in cell surface, swash SMO living and driving albumen sample molecule Costal2 (Cos2) and serine/threonine kinases fused (Fus), Suppressor Offused (Sufu) forms compound and is dissociateed from micro-pipe, and transcriptional activation is played in the form of total length, finally draws Play zinc finger sample transcription factor Gli activation, and the latter is into the transcription for causing target gene in nucleus.Therefore, in Hh signal paths In, Hh is the starting point of the signal path, and Gli is used as the terminal that transcription factor is the signal path, Hh and SMO as it is exciting because Son, PTCH regulates and controls the activity [12,14] of signal path as inhibiting factor.

Transmembrane protein acceptor SMO as Hh signal paths key members, be the transcriber in Hh signal paths, it Extracellular Hh signals can be converted into intracellular Glil signals, so that the intragentic transcription of active cell core, believes Hh Number path has activation [15].Generation, the evolution of most tumour cells related to the activation of Hh cell pathways In there are the Functional mutations of SMO.Small molecule SMO protein antagonists are by resisting SMO and specific inhibition Hh signals are logical Road, and Hh signal paths are in inactivated state in Normal adult, so antagonist will not produce secondary work to other positions of body With this is the theoretical foundation of the magnetic target therapy feasibility of tumour.Therefore, SMO albumen has become current antineoplastic medicine and grinds One of target spot most attracted people's attention in hair, the synthesis for targetting the small molecular antagonists of SMO albumen also turns into major pharmacy in the world The research and development focus of company.

The small molecular antagonists (including following three compounds) of at least 5 targeting SMO albumen are carrying out clinic now The small molecule SMO antagonist GDC-0449 that test, Genentech companies of the U.S. and Curis companies research and develop jointly, in 2012 1 The moon is ratified the treatment [16] for late period basal-cell carcinoma patient by food and medicine Surveillance Authority of U.S. FDA.This proves small point Sub- SMO antagonists have good application value and market prospects as the research and development of anti-cancer agent.

Bibliography

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11.Thayer, S.P.；Pasca di Magliano, M.；Heiser, P.W.；Nielsen, C.M.；Roberts, D.J.；Lauwers, G.Y.；Qi, Y.P.；Gysin, S.；Fernandez-del Castillo, C.；Yajnik, V.； Antoniu, B.；McMahon, M.；Warshaw, A.L.；Hebrok, M.Hedgehog is an early and late Mediator of pancreatic cancer tumorigenesis.Nature2003,425,851856.

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16.Curis Pharmaceuticals press release∶

http∶//investors.curis.com/releasedetail.c fmReleaseID=643756

The content of the invention

In view of the defect that above-mentioned prior art is present, the purpose of the present invention is to propose to one kind blocking transmembrane protein acceptor SMO Pyrimidine scaffold new antitumoral compounds, hedgehog pathway Hedgehog can be blocked, so as to suppress cell abnormal growth, hinder Disconnected Nasopharyngeal neoplasms regeneration.

The purpose of the present invention is achieved by the following technical programs：

A kind of pyrimidine scaffold has a new antitumoral compounds of activity of hedgehog path antagonist, including the compound and its Pharmaceutically acceptable salt, various isotopes, various isomers or various crystalline structures, with the structure shown in formula I：

Wherein, X is five yuan or hexa-atomic aromatic rings, heteroaromatic, heterocycle, and the substitutive derivative n of the ring is 0,1, 2,3,4,5 or 6；R1, R2, R3, R4, R5, R6 are respectively and independently selected from：Hydrogen atom, halogen, alkane for halogen, cyano group, alkane for cyano group, Trifluoromethyl, alkyl, alkenyl, alkynyl, amino, O, hydroxyl, S, sulfydryl, alkoxy, aliphatic radical, amide groups, urea groups, oxo urea groups, Ghiourea group, sulfuryl, sulfoxide group, sulfophenyl, azido, for alkenyl, for alkynyl, for amino, for hydroxyl, alkane is for fat for alkane for alkane for alkane for alkane Base, for sulfuryl, for sulfoxide group, for sulfophenyl, alkane is for azido, cyclic alkyl, cyclic alkenyl radical, 3-12 heterocycles, fragrance for alkane for alkane for alkane Ring or 5-12 heteroaromatics or the substitution base containing heteroatom functional group.

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that The compound and its pharmaceutically acceptable salt, various isotopes, various isomers or various crystalline structures, including formula II Or general formula III structure：

Wherein：A is that nitrogen-atoms or C-R7, n are 0,1,2,3,4,5 or 6；R1, R2, R3, R4, R5, R6, R7 are independently selected From：Hydrogen atom, halogen, alkane for halogen, cyano group, alkane for cyano group, trifluoromethyl, alkyl, alkenyl, alkynyl, amino, O, hydroxyl, S, Sulfydryl, alkoxy, aliphatic radical, amide groups, urea groups, oxo urea groups, ghiourea group, sulfuryl, sulfoxide group, sulfophenyl, azido, alkane is for alkene Base, for alkynyl, for amino, for hydroxyl, for aliphatic radical, for sulfuryl, for sulfoxide group, alkane is for sulfophenyl, and alkane generation is folded for alkane for alkane for alkane for alkane for alkane for alkane Nitrogen base, cyclic alkyl, cyclic alkenyl radical, 3-12 heterocycles, aromatic rings or 5-12 heteroaromatics or the substitution base containing heteroatom functional group.

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, preferably：

The alkyl is the 1-10 alkyl of the straight chain of the saturation of carbon atom composition, side chain, ring-type, double-ring or Spirocyclic Or substituted hydrocarbon radical；

The alkenyl is the straight chain containing at least one carbon-carbon double bond, side chain, ring-type, bicyclic that 1-10 carbon atom is constituted The alkyl or substituted hydrocarbon radical of shape or Spirocyclic；

The alkynyl is the straight chain containing at least one triple carbon-carbon bonds, side chain, ring-type, bicyclic that 1-10 carbon atom is constituted The alkyl or substituted hydrocarbon radical of shape or Spirocyclic；

The fragrant ring group for armaticity monocyclic, polycyclic or heterocyclic substituent and its substitutive derivative substitution base, with And with cyclic substituents derived from saturated rings；

The heterocyclic radical be the nonaromatic combination comprising an atom in nitrogen, oxygen and sulphur or multiple atom it is monocyclic, Bicyclic, three rings or spiral shell ring substituents, and their various oxidation state cyclic substituents；

The substitution base containing heteroatom functional group is halogeno-group containing F, Cl, Br or I or comprising in nitrogen, oxygen, sulphur and phosphorus One or more atoms substitution base, and their various oxidation state, and nitrogen quaternary ammonium salt.

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that The R1, R2, R3, R4, R5, R6, R7 are respectively and independently selected from：Hydrogen atom is by halogeno-group, cyano group, amino, hydroxyl, sulfydryl, alcoxyl Hydrogen atom, alkyl, alkenyl, alkynyl, fragrant ring group or heterocycle that base, ester group, sulfuryl, sulfoxide group, sulfophenyl or azido replace Base, and cyclic alkyl, cyclic alkenyl radical, 3-12 circle heterocycles base or 5-12 membered aromatic heterocycle bases；The hydrogen atom is taken by halogeno-group The alkyl in generation is preferably trifluoromethyl.

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that The structure of substituent X is any one in having structure, wherein pentacyclic structure is asked being asked respectively with the structure of hexatomic ring Bioequivalence body：

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that It includes following compounds, and its pharmaceutically acceptable salt, various isotopes, various isomers or various crystalline structures：

A kind of above-mentioned pyrimidine scaffold has in the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that Methylamino or substituted methylamine base in compound replace with any one in following amine and the like：

A kind of above-mentioned pyrimidine scaffold has the new antitumoral compounds of activity of hedgehog path antagonist, it is preferred that its Including following compound：

The present invention also provides a kind of antitumor medicine composition, comprising the above-mentioned pyrimidine scaffold with formula (I) structure It is new antitumoral compounds with activity of hedgehog path antagonist, its pharmaceutically acceptable salt, various isotopes, various different At least two compound groups in structure body or various crystalline structures into combination.

The present invention also provides a kind of use in conjunction composition of antineoplastic, and the use in conjunction composition is above-mentioned phonetic Pyridine skeleton have the new antitumoral compounds and its pharmaceutical composition of activity of hedgehog path antagonist respectively with cis-platinum, Japanese yew One or more in alcohol, camptothecine, Herceptin, Gleevec, Imatinib, Gefitinib, Erlotinib, Lapatinib Combination carry out the composition that use in conjunction is obtained.

The present invention also provides new antitumoral compounds that above-mentioned pyrimidine scaffold has activity of hedgehog path antagonist, anti- The application of the pharmaceutical composition of tumour or the use in conjunction composition of antineoplastic in the medicine for preparing treatment tumour, it is described Tumour includes liver cancer, lung cancer, the carcinoma of the rectum, cervix cancer, cancer of pancreas, breast cancer, stomach cancer, carcinoma of mouth, the cancer of the esophagus, nasopharyngeal carcinoma, skin Cancer, osteocarcinoma, the combination of one or more in kidney and leukemia.

Prominent effect of the invention is：A kind of pyrimidine scaffold of the invention has the new anti-of activity of hedgehog path antagonist Neoplastic compound, by blocking transmembrane protein acceptor SMO, can block hedgehog pathway Hedgehog, so as to suppress cell exception Increase, blocking Nasopharyngeal neoplasms regeneration.

Below just in conjunction with the embodiments, specific embodiment of the invention is described in further detail, so that the technology of the present invention Scheme is more readily understood, grasps.

Specific embodiment

The method of the present invention is illustrated below by specific embodiment, but the invention is not limited in this.Following realities Experimental technique described in example is applied, unless otherwise specified, conventional method is；The reagent and material, unless otherwise specified, Obtain from commercial channels.It is pure or chemical pure that solvent for use and medicine are analysis；Solvent is using preceding by re-distillation；Nothing Aqueous solvent is processed according to standard method or literature method.Column chromatography silica gel (100-200 mesh) and tlc silica gel (GF254) it is Haiyang Chemical Plant, Qingdao and Yantai chemical plant product；If not otherwise specified, using petroleum ether (60-90 DEG C)/second Acetoacetic ester (v/v) is used as eluant, eluent；The ethanol solution of developer iodine or phosphomolybdic acid；All extractant unexplained references use nothing Water Na₂SO₄Dry.1H-NMR is recorded with Bruck-400 types NMR, and TMS is internal standard.LC-MS is public with U.S. Agilent Take charge of 1100 type HPLC- ESI- MSn combined instruments (LC-MSD Trap) to record, PDAD (DAD), Detection wavelength 214nm and 254nm, ion trap mass spectrometry (ESI sources).HPLC column be Agela Durashell C18 (4.6 × 50mm, 3.5μm)；Mobile phase is 0.1%NH₄HCO₃The aqueous solution: acetonitrile is (from 5: 95 to 95 in 5 minutes: 5)；Flow velocity is 1.8mL/min.

Embodiment 1

The present embodiment provides a kind of new antitumoral compounds A1, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 1-2：

By in the molten 40 milliliters of DMFs of 4- t-butoxycarbonylpiperidins ketone (10g, 50.2mmol), while stirring DMF dimethylacetal (6g, 50mmol) is added, is finished, 80 DEG C are reacted 12 hours.Room temperature is cooled to, is added To in ethyl acetate (150mL) and water (50mL), organic phase saturated aqueous common salt (50mL) is washed twice, anhydrous sodium sulfate drying mistake Filter, rotate an orange crude product (13g) directly casts single step reaction.

2) synthesis of intermediate A 1-3：

Under normal temperature, the methyl thiourea of sulfuric acid half (6.98g, 25.1mmol) and caustic alcohol (3.28g, 40mmol) are dissolved in 40 milliliters In ethanol, after stirring half an hour, 10 milliliters of the ethanol solution of the intermediate A 1-2 (13g, 50.2mmol) of synthesis is walked in addition, returned Stream 12h, is cooled to room temperature, and vacuum distillation, concentrate is washed with water, ethyl acetate extraction, and organic phase is washed with saturated common salt, anhydrous After sodium sulphate dry filter, evaporated under reduced pressure, through column chromatography it is refined (mobile phase is ethyl acetate: dichloromethane=1: 25) an orange Color grease (7.38g, 52%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.24 (s, 1H), 4.50 (s, 2H), 3.69 (t, J=5.9Hz, 2H), 2.86 (t, J=5.8Hz, 2H), 2.52 (s, 3H), 1.47 (s, 9H).

3) synthesis of intermediate A 1-4：

After A1-3 (7.38g, 26.3mmol) is dissolved in 0 DEG C of 50 milliliters of dichloromethane, it is slowly added to ask while stirring Chloroperoxybenzoic acid (75%, 12.5g, 54.5mmol), stirring at normal temperature adds sodium acid carbonate (10mL) and thio sulphur after 12 hours The saturated aqueous solution (10mL) of sour sodium, stirring at normal temperature 2h, organic phase vacuum distillation concentration, through column chromatography, refined (mobile phase is stone Oily ether: ethyl acetate=3: 1) obtains a white solid (5.5g, 67%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)δ 8.63 (s, 1H), 4.70 (s, 2H), 3.79 (t, J=5.9Hz, 2H), 3.33 (s, 3H), 3.09 (t, J=5.8Hz, 2H), 1.49 (s, 9H).

4) synthesis of intermediate A 1-5：

A1-4 (1g, 3.19mmol) and methylamine alcohol solution (21%, 1mL) are dissolved in ethanol (10mL) successively under agitation, Backflow is heated to, after 12 hours, room temperature is cooled to, solvent is removed in decompression rotation, refined (mobile phase is oil to concentrate through column chromatography Ether: ethyl acetate=4: 1) obtains a white solid (700mg, 83%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)δ 8.03 (s, 1H), 4.41 (s, 2H), 3.67 (t, J=5.8Hz, 2H), 3.52 (s, 3H), 2.73 (t, J=5.7Hz, 2H), 1.56 (s, 9H).

5) synthesis of intermediate A 1-6：

After A1-5 (700mg, 2.65mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to (5 milliliters) and dichloro in saturated sodium bicarbonate aqueous solution In methane (20 milliliters), organic phase saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate drying filtering, be spin-dried for a white is solid Body (420mg, 96%).

6) synthesis of intermediate A 1-9：

By the chloro- 4- pyridine borates (7.56g, 40mmol) of 2,5- bis- and 3,5- dimethyl -2- bromopyridines (5.62g, 30mmol) be added in 60 milliliters of dioxane and 12 milliliters of mixed liquors of water, be subsequently adding Pd (dppf) C12 (1.35g, 1.7mmol) with three water potassium phosphates (16.2g, 60mmol), reaction system is exchanged three times with nitrogen, heated overnight at reflux.Reaction solution Room temperature is cooled to, 50 milliliters of water filtrations are added, filtrate is extracted three times with dichloromethane (50mL), and organic phase is dry with anhydrous sodium sulfate Dry filtering, filtrate was spin-dried for post (petroleum ether: ethyl acetate=10: product (3.1g, 41%) 1).Its chemical shift is as follows：¹H- NMR (400MHz, CDCl₃) δ 8.46 (s, 1H), 8.37 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 2.39 (s, 3H), 2.16 (s, 3H).

7) synthesis of product A1：

A1-6 (100mg, 0.610mmol), cesium fluoride (50mg, 0.329mmol) and A1-9 (50mg, 0.198mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, Solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (45mg, 60%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.43 (s, 1H), 6.65 (s, 1H), 4.54 (s, 2H), 3.90 (s, 2H), 3.00 (d, J=5.0Hz, 3H), 2.88 (s, 2H), 2.37 (s, 3H), 2.17 (s, 3H)；ESI-MS(m/z)：380.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 2

The present embodiment provides a kind of new antitumoral compounds A2, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 2-1：

A1-4 (1g, 3.19mmol) and ethylamine solution (71%, 1mL) are dissolved in ethanol (10mL) successively under agitation, Backflow is heated to, after 12 hours, room temperature is cooled to, solvent is removed in decompression rotation, refined (mobile phase is petroleum ether to concentrate through column chromatography : ethyl acetate=4: 1) obtain a white solid (400mg, 45%).

2) synthesis of intermediate A 2-2：

After A2-1 (400mg, 1.44mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, concentrate to be added to saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane In alkane (20mL), organic phase saturated aqueous common salt (10mL) is washed, anhydrous sodium sulfate drying filtering after a white solid (250mg, 97%).

3) synthesis of product A2：

A2-2 (100mg, 0.562mmol), cesium fluoride (50mg, 0.329mmol) and A1-9 (50mg, 0.198mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, Solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (25mg, 32%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.34 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.41 (s, 1H), 6.63 (s, 1H), 4.52 (s, 2H), 3.89 (t, J=5.6Hz, 2H), 3.47-3.37 (m, 2H), 2.85 (t, J=5.8Hz, 2H), 2.36 (s, 3H), 2.16 (s, 3H), 1.21 (t, J=7.2Hz, 3H)；ESI-MS(m/z)∶394.9[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 3

The present embodiment provides a kind of new antitumoral compounds A3, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 3-1：

A1-4 (1g, 3.19mmol) and cyclopropylamine (300mg, 5.26mmol) are dissolved in ethanol (10mL) successively under agitation In, backflow is heated to, after 12 hours, it is cooled to room temperature, solvent is removed in decompression rotation, and through column chromatography, refined (mobile phase is stone to concentrate Oily ether: ethyl acetate=4: 1) obtains a white solid (460mg, 50%).

2) synthesis of intermediate A 3-2：

After A3-1 (460mg, 1.58mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, concentrate to be added to saturated sodium bicarbonate aqueous solution and wash (5mL) and dichloro In methane (20mL), organic phase saturated aqueous common salt (10mL) is washed, and a white solid is obtained after anhydrous sodium sulfate drying filtering (270mg, 90%).

3) product A3 synthesis：

A3-2 (100mg, 0.345mmol), cesium fluoride (50mg, 0.329mmol) and A1-9 (50mg, 0.198mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, Solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (30mg, 40%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.39 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.42 (s, 1H), 6.65 (s, 1H), 4.55 (s, 2H), 3.90 (t, J=5.6Hz, 2H), 2.88 (t, J=5.8Hz, 2H), 2.77 (m, 1H), 2.42 (s, 3H), 2.21 (s, 3H), 1.29 (s, 1H), 0.87-079 (m, 2H), 0.62-0.55 (m, 2H)；ESI-MS(m/z)∶406.9[M+ 1]⁺。

The solid spectrum analysis of gained are

Embodiment 4

The present embodiment provides a kind of new antitumoral compounds A4, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 4-1：

A1-4 (1g, 3.19mmol) and nafoxidine (300mg, 4.22mmol) are dissolved in ethanol (10mL) successively under agitation In, backflow is heated to, after 12 hours, it is cooled to room temperature, solvent is removed in decompression rotation, and through column chromatography, refined (mobile phase is stone to concentrate Oily ether: ethyl acetate=4: 1) obtains a white solid (600mg, 62%).

2) synthesis of intermediate A 4-2：

After A4-1 (600mg, 1.97mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to saturated sodium bicarbonate aqueous solution and wash (5mL) and dichloromethane In alkane (20mL), organic phase saturated aqueous common salt (10mL) is washed, and with anhydrous sodium sulfate drying, a white solid is obtained after filtering and concentrating (360mg, 89%).

3) synthesis of product A4：

A4-2 (100mg, 0.490mmol), cesium fluoride (50mg, 0.329mmol) and A1-9 (50mg, 0.198mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, Solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (37mg, 47%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 4.51 (s, 2H), 3.89 (t, J=5.6Hz, 2H), 3.56 (t, J=6.5Hz, 4H), 2.89 (t, J=5.8Hz, 2H), 2.37 (s, 3H), 2.17 (s, 3H), 1.97 (t, J=6.6Hz, 4H)；ESI-MS(m/z)∶420.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 5

The present embodiment provides a kind of new antitumoral compounds A5, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 5-1：

A1-4 (1g, 3.19mmol) and N- methyl 2- ethylaminoethanols (480mg, 6.39mmol) are dissolved in second successively under agitation In alcohol (10mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through the refined (stream of column chromatography It is dynamic to be mutually petroleum ether: ethyl acetate=4: 1) to obtain a white solid (280mg, 28%).

2) synthesis of intermediate A 5-2：

After A5-1 (280mg, 0.91mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to saturated sodium bicarbonate aqueous solution and wash (5mL) and dichloromethane In alkane (20mL), organic phase saturated aqueous common salt (10mL) is washed, anhydrous sodium sulfate drying filtering after a white solid (180mg, 95%).

3) synthesis of product A5：

A5-2 (80mg, 0.384mmol), cesium fluoride (50mg, 0.329mmol) and A1-9 (50mg, 0.198mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (20mg, 24%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.33 (s, 1H), 8.2l (s, 1H), 8.08 (s, 1H), 7.41 (s, 1H), 6.63 (s, 1H), 4.51 (s, 2H), 3.87 (s, 4H), 3.74 (s, 2H), 3.19 (s, 3H), 2.86 (s, 2H), 2.35 (s, 3H), 2.15 (s, 3H)；ESI-MS(m/z)：424.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 6

The present embodiment provides a kind of new antitumoral compounds A6, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 6-1：

A1-4 (1g, 3.19mmol) and 4- hydroxy piperidines (650mg, 6.39mmol) are dissolved in ethanol successively under agitation In (10mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through the refined (flowing of column chromatography It is mutually petroleum ether: ethyl acetate=2: 1) obtain a white solid (400mg, 37.5%).

2) synthesis of intermediate A 6-2：

After A6-1 (400mg, 1.2mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to saturated sodium bicarbonate aqueous solution and wash (5mL) and dichloromethane In alkane (20mL), organic phase saturated aqueous common salt (10mL) is washed, and with anhydrous sodium sulfate drying, a white solid is obtained after filtering and concentrating (210mg, 79%).

3) synthesis of product A6：

A6-2 (200mg, 0.85mmol), cesium fluoride (300mg, 1.98mmol) and A1-9 (80mg, 0.31mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (30mg, 21%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.37 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.47 (s, 1H), 6.66 (s, 1H), 4.53 (s, 2H), 4.43 (s, 2H), 3.40 (s, 3H), 3.31 (s, 2H), 2.89 (s, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 1.94 (s, 2H), 1.55 (s, 2H)；ESI-MS(m/z)：450.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 7

The present embodiment provides a kind of new antitumoral compounds A7, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 7-1：

A1-4 (1g, 3.19mmol) and morpholine (700mg, 8.0mmol) are dissolved in ethanol (10mL) successively under agitation, plus Heat after 12 hours, is cooled to room temperature to flowing back, and solvent is removed in decompression rotation, concentrate through column chromatography it is refined (mobile phase is petroleum ether: Ethyl acetate=2: 1) obtain a white solid (760mg, 75%).

2) synthesis of intermediate A 7-2：

After A7-1 (700mg, 2.3mmol) is dissolved in into a small amount of dichloromethane, the saturation ethyl acetate solution of hydrogen chloride is added (3mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to saturated sodium bicarbonate aqueous solution and wash (5mL) and dichloromethane In alkane (20mL), organic phase saturated aqueous common salt (10mL) is washed, and with anhydrous sodium sulfate drying, a white solid is obtained after filtering and concentrating (434mg, 83%).

3) synthesis of product A7：

A6-2 (50mg, 0.23mmol), cesium fluoride (300mg, 1.98mmol) and A1-9 (20mg, 0.079mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (10mg, 29%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.40 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.52 (s, 1H), 6.69 (s, 1H), 4.56 (s, 2H), 3.91 (s, 3H), 3.78-3.78 (m, 8H), 2.90 (s, 2H), 2.41 (s, 3H), 2.21 (s, 3H)； ESI-MS(m/z)：436.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 8

The present embodiment provides a kind of new antitumoral compounds A8, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 8-1：

A1-4 (854mg, 2.728mmol) and 2,6-dimethyl-piperizine (950mg, 8.333mmol) are molten successively under agitation In ethanol (10mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is refined through column chromatography (mobile phase is petroleum ether: ethyl acetate=5: 1 arrives dichloromethane: methyl alcohol=10: 1) obtains a white solid (245mg, 26.5%). Its chemical shift is as follows：¹H-NMR (400MHz, CDC1₃) δ 7.97 (s, 1H), 4.54 (d, J=13.2Hz, 2H), 4.33 (s, 2H), 3.59 (s, 2H), 2.67 (s, 2H), 2.38-2.29 (m, 2H), 1.97 (s, 2H), 1.41 (s, 9H), 1.06 (d, J=6.0Hz, 6H)。

2) synthesis of intermediate A 8-2：

A8-1 (245mg, 0.706mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a yellow solid (100mg, 57.3%).

3) synthesis of product A8：

(90mg, 0.364mmoll, cesium fluoride (43mg, 0.283mmol) and A1-9 (31mg, 0.123mmol) are respectively for A8-2 It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (36mg, 63.4%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.29 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.36 (s, 1H), 6.59 (s, 1H), 4.82-4.59 (m, 2H), 4.48 (s, 2H), 3.84 (t, J=5.2Hz, 2H), 3.08 (s, 4H), 2.82 (t, J= 6.0Hz, 2H), 2.31 (s, 3H), 2.11 (s, 3H), 1.50 (s, 6H)；ESI-MS(m/z)：463.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 9

The present embodiment provides a kind of new antitumoral compounds A9, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 9-1：

A1-4 (1g, 3.195mmol) and methylethylolamine solution (27%-32%, 1g) are dissolved in ethanol successively under agitation In (10mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through the refined (flowing of column chromatography It is mutually petroleum ether: ethyl acetate=4: 1 to 1: 1) obtain a yellow oil (500mg, 59.3%).Its chemical shift is as follows：¹H- NMR (400MHz, CDCl₃) δ 8.03 (s, 1H), 4.40 (s, 2H), 4.10 (q, J=7.1Hz, 1H), 3.67 (t, J=5.6Hz, 2H), 2.97 (d, J=5.2Hz, 3H), 2.73 (t, J=5.6Hz, 2H), 1.47 (s, 9H).

2) synthesis of intermediate A 9-2：

A9-1 (300mg, 1.14mmol) is dissolved in the dichloromethane of 10mL, at 0 DEG C add triethylamine (487mg, 4.82mmoll, is then added dropwise over dichloromethane (5mL) solution of mesyl chloride (360mg, 3.16mmol).Stirred at 0 DEG C 1 hour, solvent was removed in decompression rotation, solute through column chromatography it is refined (mobile phase is petroleum ether: ethyl acetate=4: 1) a colorless oil Thing (321mg, 82.7%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.23 (s, 1H), 4.46 (s, 2H), 3.65 (t, J=5.8Hz, 2H), 3.43 (s, 3H), 3.40 (s, 3H), 2.82 (t, J=5.6Hz, 2H), 1.41 (s, 9H).

3) synthesis of intermediate A 9-3：

A9-2 (321mg, 0.94mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a white solid (76mg, 33.5%).Its chemical shift is as follows：¹H-NMR (400MHz, DMSO-d6) δ 8.20 (s, 1H), 3.99 (s, 2H), 3.45 (s, 3H), 3.42 (s, 3H), 3.24 (t, J=6.4Hz, 2H), 2.89 (t, J=5.8Hz, 2H).

4) synthesis of product A9：

(76mg, 0.364mmoll, cesium fluoride (64mg, 0.42mmol) and A1-9's A9-3 (53mg, 0.21mmol) exist respectively It is dissolved under stirring condition in dimethyl sulfoxide (1mL), is heated to 120 DEG C, is reacted 12 hours.Room temperature is cooled to, ethyl acetate is added (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) is washed, and after anhydrous sodium sulfate drying filtering, solvent, solute are removed in rotation Through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (3 mg, 3.1%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.33 (s, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 7.47 (s, 1H), 6.66 (s, 1H), 4.62 (s, 2H), 3.88 (t, J=5.6Hz, 2H), 3.47 (s, 3H), 3.44 (s, 3H), 2.97 (t, J=5.6Hz, 2H), 2.35 (s, 3H), 2.15 (s, 3H)；ESI-MS(m/z)：458.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 10

The present embodiment provides a kind of new antitumoral compounds A10, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 10-1：

Pyrazoles (435mg, 6.4mmol) is dissolved in the tetrahydrofuran of 15mL, at 0 DEG C add sodium hydride (80%, 221mg, 7.36mmol), it is stirred at room temperature 15 minutes, A1-4 (1g, 3.2mmol) is added, stirred 1 hour at 0 DEG C.Plus it is full It is quenched with aqueous ammonium chloride solution, solvent is removed in decompression rotation, adds dichloromethane (150mL) and water (100mL), the anhydrous sulphur of organic phase After sour sodium dry filter, solvent is removed in rotation, solute through column chromatography it is refined (mobile phase is petroleum ether: ethyl acetate=1: 1) a white Solid (610mg, 63.4%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.52 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 6.43 (s, 1H), 4.57 (s, 2H), 3.72 (t, J=5.8Hz, 2H), 2.99 (t, J=5.6Hz, 2H), 1.45 (s, 9H).

2) synthesis of intermediate A 10-2：

A10-1 (610mg, 2.03mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a white solid (173mg, 42.5%).

3) synthesis of product A10：

A10-2 (140mg, 0.70mmol), cesium fluoride (70mg, 0.46mmol) and A1-9 (59mg, 0.23mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (22mg, 22.6%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.56 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 6.74 (s, 1H), 6.47 (s, 1H), 4.76 (s, 2H), 3.97 (s, 2H), 3.16 (s, 2H), 2.40 (s, 3H), 2.20 (s, 3H)；ESI-MS(m/z)：417.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 11

The present embodiment provides a kind of new antitumoral compounds A11, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 11-1：

A1-4 (625mg, 2mmol) and isopropylamine (2g, 33.9mmol) are dissolved in the tert-butyl alcohol (15mL) successively under agitation, Backflow is heated to, after 36 hours, room temperature is cooled to, solvent is removed in decompression rotation, refined (mobile phase is petroleum ether to concentrate through column chromatography : ethyl acetate=3: 1 to 1: 1) obtain a yellow solid (365mg, 62.6%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 7.97 (s, 1H), 4.75 (d, J=7.2Hz, 1H), 4.35 (s, 2H), 4.04 (m, 1H), 3.61 (t, J=5.2Hz, 2H), 2.66 (s, 2H), 1.42 (s, 9H), 1.16 (d, J=6.4Hz, 6H).

2) synthesis of intermediate A 11-2：

A11-1 (365mg, 1.25mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a yellow solid (157mg, 65.4%).

3) synthesis of product A11：

A11-2 (147mg, 0.77mmol), cesium fluoride (78mg, 0.51mmol) and A1-9 (65mg, 0.255mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (24mg, 22.9%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.43 (s, 1H), 6.64 (s, 1H), 4.93 (d, J=7.6Hz, 1H), 4.53 (s, 2H), 4.13 (m, 1H), 3.90 (s, 2H), 2.84 (t, J=5.6Hz, 2H), 2.36 (s, 3H), 2.18 (s, 3H), 1.23 (d, J=6.4Hz, 6H)；ESI-MS(m/z)：408.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 12

The present embodiment provides a kind of new antitumoral compounds A12, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 12-1：

A1-4 (1g, 3.2mmo1) and tert-butylamine (1.4g, 19.2mmo1) are dissolved in the tert-butyl alcohol (15mL) successively in tube sealing In, 80 DEG C, after 54 hours are heated to, it is cooled to room temperature, solvent is removed in decompression rotation, and through column chromatography, refined (mobile phase is stone to concentrate Oily ether: ethyl acetate=4: 1) obtains a yellow oil (130mg, 13.3%).¹H-NMR (400MHz, CDCl₃) δ 7.97 (s, 1H), 4.98 (s, 1H), 4.37 (s, 2H), 3.65 (s, 2H), 2.68 (s, 2H), 1.45 (s, 9H), 1.39 (s, 9H).

2) synthesis of intermediate A 12-2：

A12-1 (130mg, 0.42mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a yellow oil (43mg, 52.4%).

3) synthesis of product A12：

(43mg, 0.21mmoll, cesium fluoride (32mg, 0.21mmol) and A1-9 (27mg, 0.105mmol) are respectively for A12-2 It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (15mg, 33.3%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 5.15 (s, 1H), 4.51 (s, 2H), 3.88 (t, J=5.2Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.37 (s, 3H), 2.17 (s, 3H), 1.43 (s, 9H)；ESI-MS(m/z)：422.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 13

The present embodiment provides a kind of new antitumoral compounds A13, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 13-1：

A1-4 (1g, 3.2mmol) is dissolved in the aniline of 10mL, 100 DEG C, after 48 hours are heated to, room temperature is cooled to, passed through Column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=8: 1) obtains a brown oil (280mg, 26.9%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.17 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 4.49 (s, 2H), 3.73 (t, J=5.8Hz, 2H), 2.84 (t, J=5.8Hz, 2H), 1.50 (s, 9H)。

2) synthesis of intermediate A 13-2：

A13-1 (280mg, 0.86mmol) is added to the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 is small When, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic phase With anhydrous sodium sulfate drying filter, concentration after a brown solid (140mg, 72.2%).

3) synthesis of product A13：

(80mg, 0.35mmoll, cesium fluoride (81mg, 0.53mmol) and A1-9 (45mg, 0.178mmol) are respectively for A13-2 It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (26mg, 33.1%).Its chemical potential Move as follows：¹H-NMR (400MHz, CDCl₃) δ 8.41 (s, 1H), 8.26 (d, J=5.2Hz, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.34 (t, J=7.2Hz, 2H), 7.06 (t, J=7.8Hz, 1H), 6.73 (s, 1H), 4.63 (s, 2H), 3.95 (s, 2H), 3.01 (t, J=5.4Hz, 2H), 2.42 (s, 3H), 2.22 (s, 3H)；ESI-MS(m/z)∶442.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 14

The present embodiment provides a kind of new antitumoral compounds A14, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 14-1：

A1-3 (1g, 3.56mmol) is added to the Hydrochloride/ethyl acetate ethyl acetate solution (5mL) of 3M, normal temperature Stirring 3 hours, decompression rotation goes solvent, concentrate to be added in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), A brown oil (600mg, 93.2%) is obtained after organic phase anhydrous sodium sulfate drying filtering, concentration.

2) synthesis of product A14：

A14-1 (480mg, 2.65mmol), cesium fluoride (808mg, 5.32mmol) and A1-9 (335mg, 1.33mmol) point It is not dissolved under agitation in dimethyl sulfoxide (7mL), is heated to 120 DEG C, reacts 12 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (100mL) and water (50mL), organic phase saturated aqueous common salt (50mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow oil (270mg, 50.9%). Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.38 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.48 (s, 1H), 6.70 (s, 1H), 4.67 (s, 2H), 3.93 (t, J=5.1Hz, 2H), 3.01 (t, J=5.4Hz, 2H), 2.56 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H)；ESI-MS(m/z)：397.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 15

The present embodiment provides a kind of new antitumoral compounds A15, and the synthetic method of the compound is as follows：

A14 (320mg, 0.81mmol) is dissolved in the tetrahydrofuran of 10mL, peroxosulphuric hydrogen potassium (546mg, 1.78 Mmol) it is dissolved in the water of 2mL.Two solution are merged, is stirred overnight at normal temperatures.Add ethyl acetate (100mL) and water (50mL), organic phase saturated aqueous common salt (50mL) is washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, and solute is through column chromatography It is refined that (mobile phase is methyl alcohol: dichloromethane=1: 100) obtains a yellow oil (150mg, 43.2%).Its chemical shift is as follows ：¹H-NMR (400MHz, CDCl₃) δ 8.69 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.44 (s, 1H), 6.74 (s, 1H), 4.87 (s, 2H), 3.97 (t, J=5.6Hz, 2H), 3.35 (s, 3H), 3.22 (t, J=5.8Hz, 2H), 2.38 (s, 3H), 2.18 (s, 3H)；ESI-MS(m/z)：429.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 16

The present embodiment provides a kind of new antitumoral compounds A16, and the synthetic method of the compound is as follows：

A15 (40mg, 0.093mmol) and cyclopropylmethylamine (14mg, 0.197mmol) are dissolved in the tert-butyl alcohol of 2mL, Be heated to 80 DEG C, overnight, solvent is removed in decompression rotation for reaction, concentrate through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) yellow solid (15.2mg, 38.9%) is obtained.Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 6.64 (s, 1H), 5.16 (t, J=6.0Hz, 1H), 4.52 (s, 2H), 3.89 (t, J=5.0Hz, 2H), 3.25 (t, J=6.2Hz, 2H), 2.86 (t, J=5.4Hz, 2H), 2.37 (s, 3H), 2.17 (s, 3H), 1.07 (m, 1H), 0.51 (d, J=7.6Hz, 2H), 0.24 (d, J=4.8Hz, 2H)；ESI-MS(m/z)：420.8[M+ 1]⁺。

The solid spectrum analysis of gained are

Embodiment 17

The present embodiment provides a kind of new antitumoral compounds A17, and the synthetic method of the compound is as follows：

A15 (44mg, 0.103mmol) and 3- pyrrolidinols (36mg, 0.414mmol) are dissolved in the tert-butyl alcohol of 2mL, Be heated to 80 DEG C, overnight, solvent is removed in decompression rotation for reaction, concentrate through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) colorless oil (7.4mg, 16.5%) is obtained.Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.34 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.42 (s, 1H), 6.64 (s, 1H), 4.57 (s, 1H), 4.51 (s, 2H), 3.89 (t, J=5.2Hz, 2H), 3.73-3.62 (m, 2H), 2.88 (t, J=5.8Hz, 2H), 2.37 (s, 3H), 2.17 (s, 3H), 2.13- 2.01 (m, 2H)；ESI-MS(m/z)∶436.8[M+1]⁺。

The grease of gained is through resolving to

Embodiment 18

The present embodiment provides a kind of new antitumoral compounds A18, and the synthetic method of the compound is as follows：

A15 (40mg, 0.093mmol) and caustic alcohol (19mg, 0.279mmol) are dissolved in the ethanol of 2mL, at 0 DEG C Solvent is removed in reaction 1 hour, decompression rotation, concentrate through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) it is one white Color solid (20mg, 54.3%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.43 (s, 1H), 6.67 (s, 1H), 4.64 (s, 2H), 4.39 (q, J=7.2Hz, 2H), 3.91 (s, 2H), 2.98 (t, J=5.6Hz, 2H), 2.37 (s, 3H), 2.17 (s, 3H), 1.42 (t, J=7.1Hz, 3H)；ESI-MS(m/z)：395.9 [M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 19

The present embodiment provides a kind of new antitumoral compounds A19, and the synthetic method of the compound is as follows：

By A15 (40mg, 0.093mmol), 4- methoxy piperides hydrochloride (29mg, 0.186mmol) and triethylamine (21mg, 0.205mmol) is dissolved in the tert-butyl alcohol of 2mL, is heated to 80 DEG C, and overnight, solvent is removed in decompression rotation, and concentrate is through post for reaction Chromatography is refined, and (mobile phase is methyl alcohol: dichloromethane=1: 100) obtains a colorless oil (7.5mg, 17.4%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.37 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.44 (s, 1H), 6.65 (s, 1H), 4.52 (s, 2H), 4.32 (d, J=6.0Hz, 2H), 3.90 (s, 2H), 3.45 (m, 1H), 3.40 (s, 3H), 3.38-3.34 (m, 2H), 2.87 (s, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.93-1.93 (m, 2H), 1.61-1.54 (m, 2H)；ESI- MS(m/z)：464.8[M+1]⁺。

The grease spectrum analysis of gained are

Embodiment 20

The present embodiment provides a kind of new antitumoral compounds A20, and the synthetic method of the compound is as follows：

In the isopropanol that sodium hydride (80%, 9mg, 0.28mmol) is added into 5mL at 0 DEG C, kept for 0 DEG C react 15 points Clock, then A15 (40mg, 0.093mmol) is added in reaction solution, keep 0 DEG C of reaction 2h, plus saturated ammonium chloride solution to be quenched, Decompression rotation goes solvent, concentrate to be diluted with ethyl acetate, family's saturated common salt washing, and organic phase dries concentration, refined through column chromatography (mobile phase is methyl alcohol: dichloromethane=1: 100) obtains a colorless oil (18mg, 47.4%).Its chemical shift is as follows：¹H- NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.43 (s, 1H), 6.68 (s, 1H), 5.26 (m, 1H), 4.64 (s, 2H), 3.91 (s, 2H), 2.98 (s, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.38 (d, J=4.4Hz, 6H)；ESI-MS(m/z)：409.8[M+1]⁺。

The grease spectrum analysis of gained are

Embodiment 21

The present embodiment provides a kind of new antitumoral compounds A21, and the synthetic method of the compound is as follows：

A15 (44mg, 0.10mmol) and cyclopentamine (27mg, 0.31mmol) are dissolved in the tert-butyl alcohol of 2mL, 80 are heated to DEG C, overnight, solvent is removed in decompression rotation for reaction, concentrate through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) one Yellow solid (4.2mg, 9.4%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.33 (s, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 5.13 (d, J=8.8Hz, 1H), 4.50 (s, 2H), 4.23 (m, 1H), 3.87 (t, J=5.8Hz, 2H), 2.83 (t, J=5.8Hz, 2H), 2.35 (s, 3H), 2.15 (s, 3H), 2.05-1.98 (m, 2H), 1.70-1.61 (m, 4H), 1.48-1.41 (m, 2H)；ESI-MS(m/z)：434.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 22

The present embodiment provides a kind of new antitumoral compounds A22, and the synthetic method of the compound is as follows：

Cyclopentanol (27mg, 0.31mmol) is added in the tetrahydrofuran of 2mL, at 0 DEG C add sodium hydride (80%, 10mg, 0.33mmol), kept for 0 DEG C react 15 minutes, then A15 (43mg, 0.10mmol) is added in reaction solution, kept for 0 DEG C Reaction 2h, is quenched with saturated ammonium chloride solution, and solvent is removed in decompression rotation, and add water 30mL, is extracted with ethyl acetate (30mL × 3) Take, after organic phase is filtered with anhydrous sodium sulfate drying, solvent is removed in rotation, through column chromatography, refined (mobile phase is methyl alcohol to solute: dichloromethane Alkane=1: 100) obtains a colorless oil (2.3mg, 5.2%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)δ8.36 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 7.44 (s, 1H), 6.68 (s, 1H), 5.41 (m, 1H), 4.65 (s, 2H), 3.92 (t, J=5.0Hz, 2H), 2.99 (t, J=5.6Hz, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.98-1.95 (m, 2H), 1.88 (s, 2H), 1.63 (s, 4H)；ESI-MS(m/z)：435.8[M+1]+.

The solid spectrum analysis of gained are

Embodiment 23

The present embodiment provides a kind of new antitumoral compounds A23, and the synthetic method of the compound is as follows：

By A15 (42mg, 0.098mmol), 3- hydroxyazetidiniums hydrochloride (55mg, 0.5mmol) and triethylamine (60mg, 0.205mmol) it is dissolved in the tert-butyl alcohol of 2mL, is heated to 80 DEG C, overnight, solvent is removed in decompression rotation, and concentrate is through column chromatography essence for reaction (mobile phase is methyl alcohol to system: dichloromethane=1: 100) obtains a colorless oil (6.9mg, 16.8%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.43 (s, 1H), 6.65 (s, 1H), 4.86-4.67 (m, 1H), 4.54 (s, 2H), 4.39 (t, J=8.0Hz, 2H), 3.99-3.96 (m, 2H), 3.90 (t, J=5.6Hz, 2H), 2.90 (t, J=6.0Hz, 2H), 2.38 (s, 3H), 2.18 (s, 3H)；ESI-MS(m/z)：422.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 24

The present embodiment provides a kind of new antitumoral compounds A24, and the synthetic method of the compound is as follows：

Cyclopropyl-carbinol (72mg, 1mmol) is added in the tetrahydrofuran of 2mL, at 0 DEG C add sodium hydride (80%, 33mg, 1.1mmol), kept for 0 DEG C react 15 minutes, then A15 (44mg, 0.103mmol) is added in reaction solution, normal temperature is anti- 3h is answered, is quenched with saturated ammonium chloride solution, solvent is removed in decompression rotation, and add water 30mL, is extracted with ethyl acetate (30mL × 3), After organic phase is filtered with anhydrous sodium sulfate drying, solvent is removed in rotation, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane= 1: 100) obtain a colorless oil (2.8mg, 6.5%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.44 (s, 1H), 6.68 (s, 1H), 4.65 (s, 2H), 4.18 (d, J=7.6Hz, 2H), 3.92 (t, J=4.6Hz, 2H), 2.99 (t, J=5.6Hz, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.32 (m, 1H), 0.61 (d, J=7.2Hz, 2H), 0.37 (d, J=4.8Hz, 2H)；ESI-MS(m/z)：421.9[M+1]⁺。

The grease spectrum analysis of gained are

Embodiment 25

The present embodiment provides a kind of new antitumoral compounds A25, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 25-1：

4- t-butoxycarbonylpiperidins ketone (1g, 5.0mmol) are dissolved in anhydrous tetrahydro furan, cool under nitrogen protection- 78 DEG C, lithium diisopropyl amido (3mL, 6.0mmol) is added drop-wise in above-mentioned solution at this temperature；After 30 minutes, iodomethane (852mg, 6.0mmol) is added at -78 DEG C, and reaction continues to stir 3 hours at room temperature.Quenched with the aqueous ammonium chloride solution of saturation Go out, add ethyl acetate (20mL) extraction, after organic phase is filtered with anhydrous sodium sulfate drying, solvent is removed in rotation, and solute is through column chromatography It is refined that (mobile phase is petroleum ether: ethyl acetate=20: 1) obtains a colourless oil liquid (500mg, 45.5%).Its chemical shift is such as Under：¹H-NMR (400MHz, CDCl₃) δ 4.11 (m, 1H), 3.71 (m, 1H), 3.23 (m, 1H), 2.81 (brs, 1H), 2.47 (m, 3H), 1.47 (s, 9H), 1.03 (d, J=6.8Hz, 3H).

2) synthesis of intermediate A 25-2：

By the molten 2 milliliters of DMF dimethylacetals of A25-1 (200mg, 0.94mmol), finish, 80 DEG C anti- Answer 12 hours.Be cooled to room temperature, rotate an orange crude product directly casts single step reaction.Under normal temperature, by the methyl thiourea of sulfuric acid half (88mg, 0.47mmol) and caustic alcohol (64mg, 0.94mmol) are dissolved in 4 milliliters of ethanol, are walked after stirring half an hour, in addition and closed Into orange crude product 1 milliliter of ethanol solution, flow back 12h, be cooled to room temperature, vacuum distillation, concentrate dilute with water, acetic acid Ethyl ester is extracted, and organic phase is washed with saturated common salt, after anhydrous sodium sulfate drying filtering, evaporated under reduced pressure, through the refined (flowing of column chromatography It is mutually ethyl acetate: petroleum ether=1: 5) obtain an orange (100mg, 36%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.25 (s, 1H), 3.75-3.70 (m, 3H), 3.49 (m, 1H), 2.94 (m, 1H), 2.56 (s, 3H), 1.41 (s, 9H), 1.26 (t, J=7.2Hz, 3H).

3) synthesis of intermediate A 25-3：

A25-2 (900mg, 3.1mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (450mg, 74%) it is directly used in next step.

4) synthesis of product A25：

A25-3 (450mg, 2.3mmol), cesium fluoride (700mg, 4.6mmol) and A1-9 (580mg, 2.3mmol) exist respectively It is dissolved under stirring condition in dimethyl sulfoxide (2.5mL), is heated to 120 DEG C, is reacted 24 hours.Room temperature is cooled to, acetic acid second is added Ester (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, Solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (450mg, 48%).Its chemistry Displacement is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.44 (s, 1H), 6.67 (s, 1H), 4.63 (m, 2H), 3.99 (m, 1H), 3.58 (m, 1H), 3.12 (m, 1H), 2.57 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H), 1.38 (d, J=5.0Hz, 3H)；ESI-MS(m/z)：411.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 26

The present embodiment provides a kind of new antitumoral compounds A26, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 26-1：

A25 (50mg, 0.12mmol) is dissolved in mixed solvent of the tetrahydrofuran with water, persulfuric acid is added in ice-water bath Hydrogen potassium (72mg, 0.24mmol), reaction continues to stir l6 hours at room temperature, is filtered to remove not tolerant, the concentrated post (two of filtrate Chloromethanes: methyl alcohol=50: 1) purifying obtains product (10mg, 19%).

2) synthesis of compound A26：

A26-1 (20mg, 0.045mmol) and cyclopropylamine (5.1mg, 0.09mmol) are dissolved in the tert-butyl alcohol successively under agitation In (1mL), backflow is heated to, after 12 hours, is cooled to room temperature, decompression rotation goes solvent, concentrate to refine (mobile phase through column chromatography It is dichloromethane: methyl alcohol=50: 1) obtain a yellow solid (8mg, 42%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.34 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 5.21 (s, 1H), 4.53 (s, 2H), 3.92 (m, 1H), 3.59 (m, 1H), 2.95 (m, 1H), 2.21 (m, 1H), 2.37 (s, 3H), 2.17 (s, 3H), 1.32 (d, J=6.8Hz, 3H), 0.87-079 (m, 2H), 0.58-0.52 (m, 2H)；ESI-MS(m/z)：443.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 27

The present embodiment provides a kind of new antitumoral compounds A27, and the synthetic method of the compound is as follows：

A26-1 (20mg, 0.045mmol) and 2,6-dimethyl-piperizine (10.3mg, 0.09mmol) are molten successively under agitation In the tert-butyl alcohol (1mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through column chromatography essence (mobile phase is dichloromethane to system: methyl alcohol=50: 1) obtains a yellow solid (7mg, 32.5%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.37 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 6.64 (s, 1H), 4.73 (m, 2H), 4.53 (m, 2H), 4.01 (m, 1H), 3.52 (m, 1H), 3.01 (br, 3H), 2.71 (b r, 2H), 2.38 (s, 3H), 2.19 (s, 3H), 1.35-1.26 (m, 9H)；ESI-MS(m/z)：477.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 28

The present embodiment provides a kind of new antitumoral compounds A28, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 28-1：

After A25-2 (2g, 6.8mmol) is dissolved in 0 DEG C of 20 milliliters of dichloromethane, it is slowly added to ask chlorine mistake while stirring Oxybenzoic acid (75%, 3.16g, 13.6mmol), stirring at normal temperature adds sodium acid carbonate (5mL) and sodium thiosulfate after 12 hours Saturated aqueous solution (5mL), stirring at normal temperature 30 minutes, organic phase vacuum distillation concentration, through column chromatography, refined (mobile phase is oil Ether: ethyl acetate=3: 1) obtains a white solid (1.5g, 67%).

2) synthesis of intermediate A 28-2：

A28-1 (250mg, 0.76mmol) and nafoxidine (216mg, 3.04mmol) are dissolved in the tert-butyl alcohol successively under agitation In (2mL), backflow is heated to, after 12 hours, is cooled to room temperature, decompression rotation goes solvent, concentrate to refine (mobile phase through column chromatography It is petroleum ether: ethyl acetate=4: 1) obtain a white solid (190mg, 78%).

3) synthesis of intermediate A 28-3：

A28-2 (190mg, 0.6mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (110mg, 84%) it is directly used in next step.

4) synthesis of product A28：

A28-3 (67mg, 0.31mmol), cesium fluoride (96mg, 0.63mmol) and A1-9 (78mg, 0.31mmol) exist respectively It is dissolved under stirring condition in dimethyl sulfoxide (1mL), is heated to 120 DEG C, is reacted 24 hours.Room temperature is cooled to, ethyl acetate is added (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) is washed, and after anhydrous sodium sulfate drying filtering, solvent, solute are removed in rotation Through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a white solid (50 mg, 37%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.39 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.46 (s, 1H), 6.66 (s, 1H), 4.54 (s, 2H), 4.02 (m, 1H), 3.61-3.58 (m, 5H), 3.05 (m, 1H), 2.41 (s, 3H), 2.11 (s, 3H), 2.01-1.99 (m, 4H), 1.37 (d, J=6.8Hz, 3H)；ESI-MS(m/z)：434.9[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 29

The present embodiment provides a kind of new antitumoral compounds A29, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 29-1：

A28-1 (250mg, 0.76mmol) and 4- hydroxy piperidines (232mg, 2.3mmol) are dissolved in tertiary fourth successively under agitation In alcohol (2mL), backflow is heated to, after 12 hours, is cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through the refined (flowing of column chromatography It is mutually petroleum ether: ethyl acetate=1: 1) obtain a white solid (200mg, 75%).

3) synthesis of intermediate A 29-2：

A29-1 (200mg, 0.57mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain white solid (100mg, 71%) it is directly used in next step.

3) synthesis of product A29：

A29-1 (77mg, 0.31mmol), cesium fluoride (96mg, 0.63mmol) and A1-9 (78mg, 0.31mmol) exist respectively It is dissolved under stirring condition in dimethyl sulfoxide (1mL), is heated to 120 DEG C, is reacted 24 hours.Room temperature is cooled to, ethyl acetate is added (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) is washed, and after anhydrous sodium sulfate drying filtering, solvent, solute are removed in rotation Through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a colorless oil, place and change within 24 hours in air It is yellow solid, purifying again obtains white solid (10mg, 6.7%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.89 (s, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.44 (s, 1H), 4.52-4.48 (m, 2H), 4.42-4.38 (m, 1H), 4.02-4.00 (m, 2H), 3.55-3.50 (m, 1H), 3.12-3.10 (m, 1H), 2.37 (s, 3H), 2.23 (s, 3H), 1.97 (m, 2H), 1.62 (m, 2H), 1.39 (d, J=6.8Hz, 3H)；ESI-MS(m/z)∶478.8[M+ 1]⁺。

The solid spectrum analysis of gained are

Embodiment 30

The present embodiment provides a kind of new antitumoral compounds A30, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 30-1：

4- t-butoxycarbonylpiperidins ketone (1g, 5.0mmol) are dissolved in anhydrous tetrahydro furan, and zero is cooled under nitrogen protection Degree, sodium hydride (80%, 332mg, 11mmol) is added drop-wise in above-mentioned solution at this temperature；After 30 minutes, iodomethane (1.56g, 11mmol) added under zero degree, reaction continues to stir 3 hours at room temperature.It is quenched with the aqueous ammonium chloride solution of saturation, adds second Acetoacetic ester (20mL) is extracted, and after organic phase is filtered with anhydrous sodium sulfate drying, solvent is removed in rotation, and solute is through the refined (flowing of column chromatography It is mutually petroleum ether: ethyl acetate=20: 1) obtain a colourless oil liquid (600mg, 53%).

2) synthesis of intermediate A 30-2：

By in the molten 50 milliliters of DMFs of A30-1 (7g, 31mmol), DMF two is added Methyl acetal (7.4g, 62mmol), is finished, and 80 DEG C are reacted l2 hours.Be cooled to room temperature, rotate an orange crude product is directly thrown Next step is reacted.Under normal temperature, the methyl thiourea of sulfuric acid half (4.3g, 15.4mmol) and caustic alcohol (2.1g, 31mmol) are dissolved in 80 millis Rise in ethanol, after stirring half an hour, 20 milliliters of the ethanol solution of the orange crude product of synthesis is walked in addition, flow back 12h, is cooled to Room temperature, vacuum distillation, concentrate dilute with water, ethyl acetate extraction, organic phase is washed with saturated common salt, anhydrous sodium sulfate drying After filtering, evaporated under reduced pressure, through column chromatography it is refined (mobile phase is ethyl acetate: petroleum ether=1: 5) a colorless oil (6g, 62%).

3) synthesis of intermediate A 30-3：

A30-2 (200mg, 0.64mmol) is dissolved in 3M ethyl acetate solutions (5mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (110mg, 82.5%) it is directly used in next step.

4) synthesis of product A30：

A30-3 (106mg, 0.51mmol), cesium fluoride (156mg, 1.02mmol) and A1-9 (129mg, 0.51mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 24 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (62mg, 29%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.37 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.45 (s, 1H), 6.68 (s, 1H), 4.62 (s, 2H), 3.68 (s, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H), 1.34 (s, 6H)； ESI-MS(m/z)：425.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 31

The present embodiment provides a kind of new antitumoral compounds A31, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 31-1：

After A30-2 (5g, 16mmol) is dissolved in 0 DEG C of 100 milliliters of dichloromethane, it is slowly added to ask chlorine mistake while stirring Oxybenzoic acid (85%, 5.6g, 32mmol), stirring at normal temperature is after 12 hours, adds sodium acid carbonate (20mL) and sodium thiosulfate Saturated aqueous solution (20mL), stirring at normal temperature 30 minutes, organic phase vacuum distillation concentration, through column chromatography, refined (mobile phase is oil Ether: ethyl acetate=3: 1) obtains a white solid (2.5g, 46%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) 68.62 (s, 1H), 4.74 (s, 2H), 3.56 (s, 2H), 3.41 (s, 3H), 1.50 (s, 9H), 1.40 (s, 6H).

2) synthesis of intermediate A 31-2：

A31-1 (400mg, 1.2mmol) and cyclopropylamine (342mg, 5mmol) are dissolved in the tert-butyl alcohol (2mL) successively under agitation In, 90 DEG C, after 12 hours are heated, it is cooled to room temperature, solvent is removed in decompression rotation, and through column chromatography, refined (mobile phase is oil to concentrate Ether: ethyl acetate=4: 1) obtains a white solid (300mg, 79%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)δ 8.24 (s, 1H), 4.47 (s, 2H), 3.44 (s, 2H), 2.74 (m, 1H), 1.49 (s, 9H), 1.25 (s, 6H), 0.79 (m, 2H), 0.52 (m, 2H).

3) synthesis of intermediate A 31-3：

A31-2 (300mg, 0.94mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (200mg, 97%) it is directly used in next step.Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 7.99 (s, 1H), 5.17 (s, 1H), 3.86 (s, 2H), 2.89 (s, 2H), 2.73 (m, 1H), 1.25 (s, 6H), 0.75 (m, 2H), 0.53 (m, 2H).

4) synthesis of product A31：

A31-3 (111mg, 0.51mmol), cesium fluoride (156mg, 1.02mmol) and A1-9 (129mg, 0.51mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 24 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (60mg, 27%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.44 (s, 1H), 6.64 (s, 1H), 5.38 (s, 1H), 4.53 (s, 2H), 3.65 (s, 2H), 2.68 (m, 1H), 2.38 (s, 3H), 2.19 (s, 3H), 1.30 (s, 6H), 0.81 (m, 2H), 0.55 (m, 2H)；ESI-MS(m/z)：434.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 32

The present embodiment provides a kind of new antitumoral compounds A32, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 32-1：

A31-1 (150mg, 0.44mmo1) and nafoxidine (156mg, 2.2mmol) are dissolved in the tert-butyl alcohol successively under agitation In (2mL), 90 DEG C, after 12 hours are heated, be cooled to room temperature, solvent is removed in decompression rotation, refined (mobile phase is concentrate through column chromatography Petroleum ether: ethyl acetate=4: 1) obtains a white solid (110mg, 75%).

2) synthesis of intermediate A 32-2：

A32-1 (110mg, 0.33mmol) is dissolved in 3M ethyl acetate solutions (5mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain white solid (60mg, 78%) it is directly used in next step.

3) synthesis of product A32：

A32-2 (47.6mg, 0.21mmol), cesium fluoride (64mg, 0.42mmol) and A1-9 (54mg, 0.21mmol) are respectively It is dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 24 hours.Room temperature is cooled to, acetic acid second is added Ester (10mL) and water (5mL), organic phase saturated aqueous common salt (5mL) are washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 100) a yellow solid (30mg, 32%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.43 (s, 1H), 6.63 (s, 1H), 4.50 (s, 2H), 3.66 (br s, 2H), 3.58 (br, 4H), 2.38 (s, 3H), 2.19 (s, 3H), 1.98 (m, 4H), 1.31 (s, 6H)；ESI-MS(m/z)：448.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 33

The present embodiment provides a kind of new antitumoral compounds A33, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 33-1：

A31-1 (400mg, 1.2mmol) and 2,6-dimethyl-piperizine (399mg, 3.6mmol) are dissolved in uncle successively under agitation In butanol (2mL), 90 DEG C, after 12 hours are heated, be cooled to room temperature, solvent is removed in decompression rotation, and concentrate is through the refined (flowing of column chromatography It is mutually dichloromethane: methyl alcohol=25: 1) obtain a white solid (240mg, 53%).

2) synthesis of intermediate A 33-2：

A33-1 (240mg, 0.64mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (130mg, 74%) it is directly used in next step.

3) synthesis of product A33：

A33-2 (130mg, 0.47mmol), cesium fluoride (156mg, 1.02mmol) and A1-9 (129mg, 0.51 mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 24 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 25) a yellow solid (65mg, 28%).Its chemistry Displacement is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.36 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 6.64 (s, 1H), 4.80-4.77 (m, 2H), 4.53 (br, 2H), 3.66 (s, 2H), 3.14 (br, 2H), 2.89 (m, 2H), 2.38 (s, 3H), 2.19 (s, 3H), 1.47 (d, J=5.2Hz, 6H), 1.31 (s, 6H)；ESI-MS(m/z)：491.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 34

The present embodiment provides a kind of new antitumoral compounds A34, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 34-1：

A31-1 (400mg, 1.2mmol) and 4- hydroxy piperidines (360mg, 3.6mmol) are dissolved in the tert-butyl alcohol successively under agitation In (2mL), 90 DEG C, after 12 hours are heated, be cooled to room temperature, solvent is removed in decompression rotation, refined (mobile phase is concentrate through column chromatography Dichloromethane: methyl alcohol=25: 1) obtains a white solid (200mg, 46%).

2) synthesis of intermediate A 34-2：

A34-1 (200mg, 0.55mmol) is dissolved in 3M ethyl acetate solutions (10mL), stirring at normal temperature 3 hours, filtering.Filter Cake be dissolved in water saturated aqueous sodium carbonate adjust PH=7.0, solution reversed-phase preparative chromatography purifying obtain yellow solid (120mg, 83%) it is directly used in next step.Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 7.97 (s, 1H), 4.45-4.42 (m, 2H), 3.92 (s, 1H), 3.85 (s, 2H), 3.23 (t, J=6.8Hz, 2H), 2.90 (s, 2H), 1.95-1.93 (m, 2H), 1.51-1.49 (m, 2H), 1.26 (s, 6H).

3) synthesis of product A34：

A34-2 (120mg, 0.46mmol), cesium fluoride (156mg, 1.02mmol) and A1-9 (129mg, 0.51mmol) point It is not dissolved under agitation in dimethyl sulfoxide (1mL), is heated to 120 DEG C, reacts 24 hours.Room temperature is cooled to, acetic acid is added Ethyl ester (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is methyl alcohol: dichloromethane=1: 25) a colorless oil, place in air 24 small When be changed into yellow solid, again purifying obtain white solid (10mg, 4.4%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.99 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.44 (s, 1H), 4.51- 4.48 (m, 2H), 4.07 (s, 2H), 4.01 (br s, 1H), 3.51 (t, J=6.4Hz, 2H), 2.37 (s, 3H), 2.23 (s, 3H), 1.99-1.97 (m, 2H), 1.59-1.57 (m, 2H), 1.35 (s, 6H)；ESI-MS(m/z)：492.8[M+1]⁺。

The grease spectrum analysis of gained are

Embodiment 35

The present embodiment provides a kind of new antitumoral compounds A35, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 1-2：

By 4- t-butoxycarbonylpiperidins ketone (2g, 10.1mmol) and DMF dimethylacetal (18g, 151.5mmol) stir, 90 DEG C are reacted 12 hours.Room temperature is cooled to, is added in ethyl acetate (150mL) and water (50mL), had Machine is mutually washed twice with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying filtering, rotate an orange crude product (3.10g) directly Cast single step reaction.

2) synthesis of intermediate A 35-1：

Under normal temperature, guanidine hydrochloride (1.92g, 20.1mmol) and caustic alcohol (1.37g, 20.1mmol) are dissolved in ethanol (20mL) In, after stirring half an hour, the intermediate A 1-2 (3.10g, 12.2mmol) of synthesis is walked in addition, flow back reaction overnight.It is cooled to Room temperature, adds ethyl acetate (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) to wash, anhydrous sodium sulfate drying mistake After filter, evaporated under reduced pressure, through column chromatography it is refined (mobile phase is ethyl acetate: petroleum ether=2: 1) an orange (750mg, 25%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 4.95 (s, 2H), 4.44 (s, 2H), 3.69 (t, J=5.8Hz, 2H), 2.75 (t, J=5.4Hz, 2H), 1.49 (s, 9H).

3) synthesis of intermediate A 35-2：

After A35-1 (750mg, 3.0mmol) is dissolved in into the ethyl acetate of 3M, the saturation ethyl acetate solution of hydrogen chloride is added (5mL), stirring at normal temperature 3 hours, decompression rotation goes solvent, solute to be added to (5mL) and dichloromethane in saturated sodium bicarbonate aqueous solution In alkane (20mL), organic phase with saturated common salt wash, anhydrous sodium sulfate drying filtering after, be spin-dried for a white solid (350mg, 78%).

4) synthesis of product A35：

A35-2 (50mg, 0.3mmol), cesium fluoride (125mg, 0.8mmol) and A1-9 (127mg, 0.5mmol) exist respectively It is dissolved under stirring condition in dimethyl sulfoxide (1mL), is heated to 120 DEG C, is reacted 36 hours.Room temperature is cooled to, ethyl acetate is added (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) is washed, and after anhydrous sodium sulfate drying filtering, solvent is removed in rotation, molten Matter through column chromatography it is refined (mobile phase is dichloromethane: methyl alcohol=50: 1) a yellow solid (80mg, 66%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.35 (s, 1H), 8.23 (s, 2H), 8.10 (s, 1H), 7.43 (s, 1H), 6.65 (s, 1H), 4.94 (s, 2H), 4.56 (s, 2H), 3.90 (t, J=5.8Hz, 2H), 2.87 (t, J=5.8Hz, 2H), 2.37 (s.3H) .2.17(s.3H)；ESI-MS(m/z)：366.8[M+1]⁺。

The solid of gained is through resolving to

Embodiment 36

The present embodiment provides a kind of new antitumoral compounds A36, and the synthetic method of the compound is as follows：

A6 (40mg, 0.090mmol) room temperature is placed in atmosphere three days, mixture with prepare plate (solvent is petroleum ether: Ethyl acetate=1: 2) purifying obtains white solid (2mg, 5%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)δ 8.89 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 4.50-4.46 (m, 2H), 4.32 (t, J=7.0Hz, 2H), 4.01 (br s, 2H), 3.53 (t, J=10.0Hz, 2H), 3.02 (t, J=6.4Hz, 2H), 2.37 (s, 3H), 2.23 (s, 3H), 2.00-1.97 (m, 2H), 1.57-1.50 (m, 2H)；ESI-MS(m/z)：464.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 37

The present embodiment provides a kind of new antitumoral compounds A37, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 37-1：

By the chloro- 4- pyridine borates (671mg, 3.5mmol) of 2,5- bis- and 5- methyl -2- bromopyridines (500mg, 2.9mmol) It is added in 5 milliliters of dioxane and 2 milliliters of mixed liquors of water, is subsequently adding Pd (dppf) Cl₂(212mg, 0.29mmol) and Three water potassium phosphates (1.16g, 4.35mmol), reaction system is exchanged three times with nitrogen, heated overnight at reflux.Reaction solution is cooled to room Temperature, adds 10 milliliters of water filtrations, and filtrate is extracted three times with dichloromethane (10mL), and organic phase is filtered with anhydrous sodium sulfate drying, Filtrate was spin-dried for post, and (petroleum ether: ethyl acetate=50: 1) obtains white solid (100mg, 15%).¹H-NMR (400MHz, CDCl₃): δ 8.59 (s, 1H), 8.47 (s, 1H), 7.69-7.63 (m, 3H), 2.44 (s, 3H).

2) synthesis of product A37：

Respectively by A37-1 (30mg, 0.13mmo.), A3-2 (24mg, 0.13mmol) and C_SF (38mg, 0.25mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 24h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is dichloromethane: methyl alcohol=50: 1), obtains a yellow solid (20mg, 39%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.54 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.64-7.59 (m, 2H), 6.96 (s, 1H), 5.82 (br s, 1H), 4.58 (s, 2H), 3.92 (t, J=5.6Hz, 2H), 2.88 (t, J=5.6Hz, 2H), 2.77 (br s, 1H), 2.42 (s, 3H), 0.81 (s, 2H), 0.54 (s, 2H)；ESI-MS(m/z)：392.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 38

The present embodiment provides a kind of new antitumoral compounds A38, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 38-1

In the three-necked bottle of a 25mL, the bromo- 3- picolines (500mg, 2.82mmol) of 2-, A1-8 are separately added into (700mg, 3.64mmol), K₃PO₄·3H₂O (1.50g, 5.64mmol), Pd (dppf) Cl₂(103mg, 0.140mmol) and 1, 4- dioxane/water (7: 1,10mL), with nitrogen displacement three times after, be heated to 100 DEG C, react 16h, be cooled to room temperature, filter, filter Liquid is spin-dried for, and with column chromatography, refined (mobile phase is petroleum ether: ethyl acetate=20: 1), obtains a white solid (40mg, 6%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.55 (d, J=4.4Hz, 1H), 8.48 (s, 1H), 7.65 (d, J=7.6Hz, 1H), 7.34 (s, 1H), 7.33-7.31 (m, 1H), 2.20 (s, 3H).

2) synthesis of product A38

Respectively by A38-1 (40mg, 0.17mmol), A3-2 (50mg, 0.26mmol) and C_SF (64mg, 0.43mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (2mg, 3%).Its chemistry Displacement is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.53 (d, J=4.4Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.62 (d, J=7.6Hz, 1H), 7.29-7.28 (m, 1H), 5.28 (s, 1H), 4.56 (s, 2H), 3.99-3.83 (m, 2H), 2.89 (t, J= 11.2Hz, 2H), 2.83-2.73 (m, 1H), 2.2l (s, 3H), 0.85-0.78 (m, 2H), 0.59-0.48 (m, 2H)；ESI-MS (m/z)：392.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 39

The present embodiment provides a kind of new antitumoral compounds A39, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 39-1：

The chloro- 4- pyridine borates (550mg, 2.9mmol) of 2,5- bis- and 2- bromoquinolines (500mg, 2.3mmol) are added to In 2.4 milliliters of 2N solution of potassium carbonate, 5 milliliters of ethanol and 5 milliliters of mixed liquors of toluene, tetra-triphenylphosphine palladium is subsequently adding (275mg, 0.24mmol), reaction system is exchanged three times with nitrogen, and tube sealing is heated to 105 DEG C.Reaction solution is cooled to room temperature, adds 10 milliliters of water filtrations, filtrate is extracted three times with dichloromethane (10mL), and organic phase is filtered with anhydrous sodium sulfate drying, and filtrate is spin-dried for (petroleum ether: ethyl acetate=25: 1) obtains white solid (210mg, 32%) to cross post.Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃)：δ 8.52 (s, 1H), 8.31 (d, J=8.4Hz, 1H), 8.18 (d, J=8.8Hz, 1H), 7.92 (d, J= 8.0Hz, H), 7.81-7.79 (m, 2H), 7.76 (s, 1H), 7.66 (t, J=7.2Hz, 1H).

2) synthesis of product A39：

Respectively by A39-1 (40mg, 0.15mmol), A3-2 (37mg, 0.15mmol) and C_sF (44mg, 0.29 mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 24h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is dichloromethane: methyl alcohol=50: 1), obtains a light yellow solid (20mg, 32%).Its Chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.23 (s, 1H), 8.19 (d, J=8.4Hz, 1H), 8.14-8.12 (m, 2H), 7.83 (d, J=8.4Hz, 1H), 7.71-7.68 (m, 2H), 7.55 (d, J=7.2Hz, 1H), 6.97 (s, 1H), 5.39 (br S, 1H), 4.54 (s, 2H), 3.89 (t, J=5.6Hz, 2H), 2.83 (t, J=5.6Hz, 2H), 2.69 (br s, 1H), 0.76- 0.74 (m, 2H), 0.46 (s, 2H)；ESI-MS(m/z)：428.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 40

The present embodiment provides a kind of new antitumoral compounds A40, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 40-1

In the three-necked bottle of a 25mL, 2- bromopyridines (100mg, 0.63mmol) are separately added into, A1-8 (240mg, 1.25mmol), K₂CO₃(175mg, 1.27mmol), Pd (dppf) Cl₂(50mg, 0.068mmol) and glycol dimethyl ether/water (7 : 1,5mL), with nitrogen displacement three times after, be heated to 90 DEG C, react 4h, be cooled to room temperature, filter, filtrate is spin-dried for, with column chromatography essence (mobile phase is petroleum ether to system: dichloromethane=2: 1), obtains a white solid (45mg, 32%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.77 (d, J=4.4Hz, 1H), 8.48 (s, 1H), 7.86-7.82 (m, 1H), 7.76 (d, J=8.0Hz, 1H), 7.66 (s, 1H), 7.42-7.39 (m, 1H).

2) synthesis of product A40

Respectively by A40-1 (45mg, 0.20mmol), A3-2 (60mg, 0.32mmol) and C_SF (100mg, 0.67mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (8mg, 14%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.75 (d, J=4.8Hz, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.83- 7.79 (m, 1H), 7.72 (d, J=8.0Hz, 1H), 7.38-7.35 (m, 1H), 6.97 (s, 1H), 5.24 (s, 1H), 4.59 (s, 2H), 3.94 (t, J=11.6Hz, 2H), 2.89 (t, J=11.6Hz, 2H), 2.80-2.74 (m, 1H), 0.85-0.80 (m, 2H), 0.55-0.52 (m, 2H)；ESI-MS(m/z)：378.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 41

The present embodiment provides a kind of new antitumoral compounds A41, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 41-1

In the three-necked bottle of a 25mL, the bromo- 5- trifluoromethyl pyridines (100mg, 0.44mmo1) of 2-, A1-8 are separately added into (150mg, 0.78mmol), K₃PO₄·3H₂O (230mg, 0.86mmol), Pd (dppf) Cl₂(32mg, 0.044mmol) and tetrahydrochysene Furans/water (7: 1,5mL), with nitrogen displacement three times after, be heated to 60 DEG C, react 16h, be cooled to room temperature, filter, filtrate is spin-dried for, With column chromatography, refined (mobile phase is petroleum ether: dichloromethane=3: 2), obtains a white solid (43mg, 33%).Its chemical shift It is as follows：¹H-NMR (400MHz, CDCl₃) δ 9.03 (s, 1H), 8.52 (s, 1H), 8.09 (d, J=8.0Hz, 1H), 7.91 (d, J= 8.0Hz, 1H), 7.67 (s, 1H).

2) synthesis of product A41

Respectively by A41-1 (43mg, 0.15mmol), A3-2 (40mg, 0.21mmol) and C_SF (70mg, 0.47mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (11mg, 17%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDC1₃) δ 9.04 (s, 1H), 8.75-8.71 (m, 1H), 8.65 (d, J=2.0Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 6.96 (s, 1H), 5.48 (br s, 1H), 4.60 (s, 2H), 3.95 (t, J=12.0Hz, 2H), 2.92 (t, J=12.0Hz, 2H), 2.78-2.77 (m, 1H), 0.85-0.81 (m, 2H), 0.56-0.53 (m, 2H)；ESI- MS(m/z)：446.8[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 42

The present embodiment provides a kind of new antitumoral compounds A42, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 42-1：

The chloro- 4- pyridine borates (290mg, 1.5mmol) of 2,5- bis- and 2- Bromopyrimidines (200mg, 1.26mmol) are added to In 1.3 milliliters of 2N solution of potassium carbonate, 3 milliliters of ethanol and 3 milliliters of mixed liquors of toluene, tetra-triphenylphosphine palladium is subsequently adding (146mg, 0.13mmol), reaction system is exchanged three times with nitrogen, and tube sealing is heated to 115 DEG C.Reaction solution is cooled to room temperature, adds 5 milliliters of water filtrations, filtrate is extracted three times with dichloromethane (10mL), and organic phase is filtered with anhydrous sodium sulfate drying, and filtrate is spin-dried for (petroleum ether: ethyl acetate=25: 1) obtains white solid (60mg, 21%) to cross post.Its chemical shift is as follows：¹H-NMR (400MHz, CDC1₃)：δ 8.86 (d, J=4.8Hz, 2H), 8.45 (s, 1H), 7.73 (s, 1H), 7.33 (t, J=4.8Hz, 1H).

2) synthesis of product A42：

Respectively by A42-1 (20mg, 0.09mmol), A3-2 (17mg, 0.09mmol) and C_SF (27mg, 0.18mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 24h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is dichloromethane: methyl alcohol=100: 1), obtains a light yellow solid (7mg, 20%).Its Chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.97 (d, J=4.8Hz, 2H), 8.31 (s, 1H), 8.20 (s, 1H), 7.37 (t, J=4.8Hz, 1H), 7.08 (s, 1H), 5.29 (br s, 1H), 4.59 (s, 2H), 3.94 (t, J=6.0Hz, 2H), 2.90 (t, J=5.6Hz, 2H), 2.77 (br s, 1H), 0.84-0.80 (m, 2H), 0.54 (s, 2H)；ESI-MS(m/z)：380.1 [M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 43

The present embodiment provides a kind of new antitumoral compounds A43, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 43-1

In the tube sealing of a 25mL, 2- chloropyrazines (100mg, 0.87mmol) are separately added into, A1-8 (340mg, 1.77mmol), Na₂CO₃(185mg, 1.74mmol), Pd (PPh₃)₄(170mg, 0.15mmol) and Isosorbide-5-Nitrae-dioxane/water (7: 1,5mL) 10min, is blown with nitrogen, 130 DEG C are heated to, 16h is reacted, is cooled to room temperature, filtered, filtrate is spin-dried for, it is refined with column chromatography (mobile phase is petroleum ether: dichloromethane=3: 2), obtains a white solid (35mg, 18%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 9.09 (s, 1H), 8.78-8.75 (m, 1H), 8.70 (d, J=2.4Hz, 1H), 8.54 (s, 1H), 7.69 (s, 1H).

2) synthesis of product A43

Respectively by A43-1 (35mg, 0.15mmol), A3-2 (40mg, 0.21mmol) and C_SF (70mg, 0.47mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (10mg, 17%).It is changed Displacement study is as follows：¹H-NMR (400MHz, CDCl₃) δ 9.02 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.05 (d, J= 8.0Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 6.98 (s, 1H), 5.88 (br s, 1H), 4.62 (s, 2H), 3.95 (t, J= 11.2Hz, 2H), 296 (t, J=11.2Hz, 2H), 2.83-2.77 (m, 1H), 0.87-0.83 (m, 2H), 0.60-0.56 (m, 2H)；ESI-MS(m/z)：379.9[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 44

The present embodiment provides a kind of new antitumoral compounds A44, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 44-1

After 1,2- Bromofumes (40mg, 0.21mmol) are added in the tetrahydrofuran suspension of zinc, 50 DEG C are heated to, The tetrahydrofuran solution (1mL) of TMSCl (20mg, 0.18mmol) and 2- bromo thiazoles, 50 DEG C of reaction 1h are sequentially added after 5min.Will Tetrahydrofuran solution the injection chloro- 4- iodine pyridines (300mg, 1.09mmol) of 2,5- bis- and the Pd of obtained 2- bromo thiazole zincons (PPh₃)₄In the tetrahydrofuran solution (10mL) of (40mg, 0.035mmol), backflow is heated to, after reaction 12h, is cooled to room temperature, mistake Filter, filtrate is spin-dried for, with column chromatography it is refined (mobile phase is petroleum ether: dichloromethane=3: 2), obtain a white solid (60mg, 24%).Its chemical shift is as follows：¹H-NMR (300MHz, CDCl₃) δ 8.53 (s, 1H), 8.51 (s, 1H), 8.08-8.07 (m, 1H), 7.68-7.67 (m, 1H).

2) synthesis of product A44

Respectively by A44-1 (50mg, 0.22mmol), A3-2 (50mg, 0.26mmol) and C_SF (130mg, 0.85mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (8mg, 10%).It is changed Displacement study is as follows：¹H-NMR (300MHz, CDCl₃) δ 8.31 (s, 1H), 8.24 (s, 1H), 8.02 (d, J=3.0Hz, 1H), 7.62 (s, 1H), 7.61 (d, J=3Hz, 1H), 5.70 (br s, 1H), 4.63 (s, 2H), 3.98 (t, J=11.2Hz, 2H), 2.99- 2.93 (m, 2H), 2.83-2.75 (m, 1H), 0.87-0.81 (m, 2H), 0.61-0.50 (m, 2H).

The solid spectrum analysis of gained are

Embodiment 45

The present embodiment provides a kind of new antitumoral compounds A45, and the synthetic method of the compound is as follows：

By A35 (50mg, 0.1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (1mL) add afterwards DIPEA (53mg, 0.4mmol), ethyl chloroformate (18mg, 0.2mmol) is added under agitation, is heated to 100 DEG C, reaction overnight.It is cooled to Room temperature, adds dichloromethane (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) to wash, anhydrous sodium sulfate drying mistake After filter, solvent is removed in rotation, and through column chromatography, refined (mobile phase is ethyl acetate to solute: petroleum ether=1: 1 to 3: 1), obtains a yellow solid (20mg, 33%).Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.40 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.28 (m, 2H), 3.93 (s, 2H), 3.02 (s, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.32 (t, J=7.0Hz, 3H).

The solid spectrum analysis of gained are

Embodiment 46

The present embodiment provides a kind of new antitumoral compounds A46, and the synthetic method of the compound is as follows：

A35 (50mg, 0.1mmol) and sodium hydride (33mg, l.4mmol) are dissolved in into anhydrous tetrahydro furan (1mL) to stir afterwards 30 minutes, ethyl isocyanate (48.5mg, 0.7mmol) was added under agitation.At normal temperatures after reaction overnight, dichloro is added Methane (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is ethyl acetate: petroleum ether=1: 1 to 3: 1) a yellow solid (15mg, 25%). Its chemical shift is as follows：¹H-NMR (400MHz, CDCl₃) δ 8.92 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.25 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 6.69 (s, 1H), 4.65 (s, 2H), 3.93 (s, 2H), 3.41 (t, J=6.4Hz, 2H), 2.98 (d, J=2.6Hz, 2H), 2.39 (s, 3H), 2.18 (s, 3H), 1.24 (t, J=7.0Hz, 3H).

The solid spectrum analysis of gained are

Embodiment 47

The present embodiment provides a kind of new antitumoral compounds A47, and the synthetic method of the compound is as follows：

A35 (50mg, 0.1mmol) and sodium hydride (8mg, 0.7mmol) are dissolved in anhydrous tetrahydro furan (1mL) and stir 30 afterwards Minute, isopropyl isocyanate (58.10mg, 0.3mmol) is added under agitation.At normal temperatures after reaction overnight, two are added Chloromethanes (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) are washed, and after anhydrous sodium sulfate drying filtering, rotation is gone molten Agent, solute through column chromatography it is refined (mobile phase is ethyl acetate: petroleum ether=1: 1 to 3: 1) a yellow solid (11mg, 17%). Its chemical shift is as follows：¹H-NMR (300MHz, CDCl₃) δ 8.87 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 6.68 (s, 1H), 4.64 (s, 2H), 4.08 (m, 1H), 3.93 (t, J=5.7Hz, 2H), 2.96 (t, J=5.4Hz, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.26 (d, J=3Hz, 6H).

The solid spectrum analysis of gained are

Embodiment 48

The present embodiment provides a kind of new antitumoral compounds A48, and the synthetic method of the compound is as follows：

1) synthesis of intermediate A 48-1

In the three-necked bottle of a 25mL, 3- bromopyridines (100mg, 0.63mmol) are separately added into, A1-8 (240mg, 1.25mmol), Na₂C0₃(135mg, 1.27mmol), Pd (dppf) Cl₂(45mg, 0.061mmol) and glycol dimethyl ether/water (7: 1,5mL), with nitrogen displacement three times after, be heated to 100 DEG C, react 16h, be cooled to room temperature, filter, filtrate is spin-dried for, with post layer Analysis is refined, and (mobile phase is petroleum ether: dichloromethane=3: 2), obtains a white solid (30mg, 21%).¹H-NMR (300MHz, CDCl₃) δ 8.72 (s, 2H), 8.50 (s, 1H), 7.84-7.81 (m, 1H), 7.46-7.42 (m, 1H), 7.35 (s, 1H).

2) synthesis of product A48

Respectively by A48-1 (30mg, 0.13mmol), A3-2 (40mg, 0.21mmol) and C_SF (80mg, 0.53mmol) is molten In 1mL dimethyl sulfoxides, 120 DEG C are heated to, react 12h, be cooled to room temperature, extracted with ethyl acetate and water, organic phase dries rotation Dry, solute column chromatography is refined, and (mobile phase is petroleum ether: ethyl acetate=1: 1), obtains a yellow solid (10mg, 20%).It is changed Displacement study is as follows：¹H-NMR (300MHz, CDCl₃) δ 8.70 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.83 (d, J= 8.1Hz, 1H), 7.43-7.39 (m, 1H), 6.64 (s, 1H), 5.74 (br s, 1H), 4.59 (s, 2H), 3.93 (t, J= 11.2Hz, 2H), 2.94 (t, J=11.7Hz, 2H), 2.82-2.76 (m, 1H), 0.87-0.81 (m, 2H), 0.59-0.54 (m, 2H)；ESI-MS(m/z)：378.9[M+1]⁺。

The solid spectrum analysis of gained are

Embodiment 49

The present embodiment provides a kind of new antitumoral compounds A49, and the synthetic method of the compound is as follows：

A35 (50mg, 0.1mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (1mL) and adds DIPEA afterwards (88.11mg, 0.7mmol), adds trimethyl-aceyl chloride (49.43mg, 0.4mmol) under agitation, is heated to 100 DEG C, Reaction overnight.Room temperature is cooled to, adds dichloromethane (20mL) and water (10mL), organic phase saturated aqueous common salt (10mL) to wash, After anhydrous sodium sulfate drying filtering, solvent is removed in rotation, and through column chromatography, refined (mobile phase is ethyl acetate to solute: petroleum ether=1: 1 to 3 : 1) obtain a yellow solid (20mg, 32%).Its chemical shift is as follows：¹H-NMR (300MHz, CDCl₃) δ 8.40 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 7.43 (s, 1H), 6.68 (s, 1H), 4.67 (s, 2H), 3.93 (t, J=5.7Hz, 2H), 3.04 (t, J=5.8Hz, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.33 (s, 9H).

The solid spectrum analysis of gained are

Embodiment 50

The present embodiment carries out biological NIH3T3-GRE-Luc luciferase reportings base to the compound obtained by embodiment 1-49 Because of test experience, barrier effect of the checking gained compound to hedgehog pathway Hedgehog (Hh).

NIH3T3 cells are the cultures in the DMEM (11965, Gibico) containing 10%FBS (Hyclone).GRE- fireflies Fireworm fluorescein plasmid is to be implanted into MCS to obtain via the cell transcription factor GLI-1 response elements for amplifying eight times.Monoclonal is Verified by restructuring Su Nike hedgehog pathways albumen and small molecule agonist SAG.The selected clone being verified is used to detect thorn Hedgehog path signal.The NIH3T3 cells of expression GRE- firefly elements are maintained in complete nutrient solution.When needs are analyzed During detection, cell is added in 96 orifice plates, final to contain cell about 15,000 per hole.96 orifice plates are being cultured 48 hours.It is tested Compound is surveyed by DMSO and detection buffer solution by serial dilution.10nMSAG is used as hedgehog pathway activator.Subsequent 100 microlitres of bags During analysis buffer containing test compound and activator is carefully added into containing 96 orifice plates in cell, and in 37 degrees Celsius of trainings Support 48 hours.After 48 hours of incubation, 40 microlitres of firefly luciferases are added into each hole.96 orifice plates are at room temperature Jog 5 minutes.Luminous signal is recorded by plate reader.Blocking of the activity of compound by it to luminous signal is calculated and gone out.This Embodiment according to above-mentioned NIH3T3-GRE-Luc luciferase reporter gene test experiences, choose small molecule SMO antagonists GDC-0449 is control drug, and the bioactivity to the compound A1-A49 in embodiment is measured, experimental result such as following table It is shown：Test result indicate that, the IC50 of some of them compound is better than control drug.

As seen from the above-described embodiment, the antitumoral compounds of the embodiment of the present invention are by blocking transmembrane protein acceptor SMO, energy Hedgehog pathway Hedgehog is enough blocked, so that suppress cell abnormal growth, blocking Nasopharyngeal neoplasms regeneration.

All technical sides that the present invention still has numerous embodiments, all use equivalents or an equivalent transformation and formed Case, is within the scope of the present invention.