CN103524535B - There is the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist - Google Patents

There is the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist Download PDF

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CN103524535B
CN103524535B CN201310485380.8A CN201310485380A CN103524535B CN 103524535 B CN103524535 B CN 103524535B CN 201310485380 A CN201310485380 A CN 201310485380A CN 103524535 B CN103524535 B CN 103524535B
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activity
compound
heterocycle compound
pyridine heterocycle
synthesis
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CN103524535A (en
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张小虎
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Suzhou pharmaceutical Limited by Share Ltd
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SUZHOU YUNXUAN PHARMACEUTICAL Co Ltd
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Priority to EP13871618.8A priority patent/EP2945623B1/en
Priority to PCT/US2013/077305 priority patent/WO2014113191A1/en
Priority to US14/761,166 priority patent/US9695178B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

Present invention is disclosed a kind of Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, including this compound and pharmaceutically acceptable salt, various isotope, various isomer and various crystalline structure, there is the structure shown in formula I:A kind of Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist of the present invention, it is possible to block Nasopharyngeal neoplasms regeneration by hedgehog pathway antagonism, there is obvious antitumor action.

Description

There is the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist
Technical field
The present invention relates to medicine synthesis technical field, particularly relate to a kind of Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist.
Background technology
Malignant tumor is one of main disease of harm human health, the annual malignant tumor new cases about 10,900,000 in the whole world, and annual because of malignant tumor the patient of death about 6,700,000.Antitumor drug research and development experienced by great variety in recent years, is mainly cytotoxic drug with antitumor drug conventional on preclinical therapy, this kind anti-cancer drugs have be difficult to avoid that poor selectivity, toxic and side effects is strong, be easily generated the shortcomings such as drug resistance.Recently as the progress at full speed of life science, the various basic processes such as the interaction of signal transduction in malignant cell, the regulation and control of cell cycle, apoptotic induction, angiogenesis and cell and extracellular matrix are just progressively elucidated with.Using some to tumor cell differentiation the key enzyme of the intracellular signal transduction pathway that propagation is relevant as drug screening target spot, find that selectively acting is in specific target spot, be provided simultaneously with important directions efficient, that low toxicity character pilot compound has become the research and development of current antitumor drug.The successful listing of the targeted drugs such as Herceptin (trastuzumab), imatinib (imatinib), gefitinib (gefitinib) and erlotinib (erlotinib) is exactly typical example.
Transfer and the feature that regeneration is malignant tumor, be also a difficult problem for treatment malignant tumor.Even the targeted drug of a new generation is also very micro-with regeneration curative effect to the transfer of tumor.Based on this; the research of Hedgehog (Hh) signal path-hedgehog pathway in recent years receives scientific circles and more and more payes attention to; it is not only because the generation evolution that Hh signal path abnormal activation includes basal cell carcinoma, the cerebral tumor, breast carcinoma, carcinoma of prostate and some alimentary system malignant tumours in many tumors and all plays very important effect; the more important thing is; Hh signal path is fetal development path; to regulation and control tumor stem cell, thus control neoplasm metastasis and play an important role with regeneration.
Hedgehog signal path is the intercellular signal transduction system of a high conservative, within 1980, find in fruit bat, may result in larva body surface reveal the furcella of many likeness in form Rrinaceus earopaeuss, therefore called after hedgehog pathway Hedgehog (Hh) owing to this pathway gene of fruit bat suddenlys change.Hh signal path is made up of Hh part, two transmembrane proteins receptor patchedmembranereceptor (PTCH) and smoothenedtransmembraneprotein (SMO) and downstream transcription factor Gli albumen etc..PTCH and SMO is in two kinds of transmembrane proteins on target cell membrane, and wherein PTCH is 12 transmembrane proteins encoded by antioncogene PTCH, is a kind of cell surface receptor, has isolation and the dual function of transduction Hh.SMO is 7 transmembrane proteins, highly similar to g protein coupled receptor family in structure, has the effect of transduction Hh signal.PTCH and SMO plays the effect of receptor in Hh signal transduction process, and wherein PTCH is the receptor of Hh.When being absent from Hh, PTCH stops SMO to insert to cell membrane, thus suppressing the activity of SMO, and then suppresses the transcriptional expression of downstream gene；When there is Hh signal, Hh and PTCH combines, multiple serine/threonine residue generation phosphorylations of induction SMO c-terminus, cause that SMO assembles at cell surface and activates, the SMO and kinesin sample molecule Costal2 (Cos2) that activate and serine/threonine kinases fused (Fus), Suppressoroffused (Sufu) form complex and dissociate out from micro-pipe, transcriptional activation is played with the form of total length, sample transcription factor Gli activates finally to cause zinc to refer to, and the latter enters and causes transcribing of target gene in nucleus.Therefore, in Hh signal path, Hh is the starting point of this signal path, and Gli is as the terminal that transcription factor is this signal path, and Hh and SMO is as the exciting factor, and PTCH, as inhibitive factor, regulates and controls the activity of signal path.
Transmembrane protein receptor SMO is as the key members of Hh signal path, it it is the transcriber in Hh signal path, it can convert intracellular Gli1 signal to extracellular Hh signal, transcribes thus active cell core is intragentic, Hh signal path is had activation.Most generations of tumor cell relevant to the activation of Hh cell pathway, evolution all also exist the Functional mutations of SMO.Little molecule SMO protein antagonist is specific inhibition Hh signal path by antagonism SMO, and Hh signal path is in inactivated state at Normal adult, so other positions of body will not be had side effects by antagonist, this is the theoretical basis of magnetic target therapy feasibility of tumor.Therefore, SMO albumen has become as one of target spot of attracting people's attention most in the research and development of current antineoplastic medicine, and the synthesis of the small molecular antagonists of targeting SMO albumen also becomes the research and development focus of Ge great drugmaker in the world.
The small molecular antagonists having at least 5 targeting SMO albumen now is carrying out clinical trial, the little molecule SMO antagonist GDC-0449 that Genentech company of the U.S. and Curis company research and develop jointly, is used for the treatment of basal cell carcinoma patient in late period in January, 2012 by U.S. food Drug Administration FDA approval.This proves that little molecule SMO antagonist has good using value and market prospect as the research and development of anti-cancer agent.
Little molecule SMO antagonist representative in clinical trial includes following several:
Although vismodegib and other clinical compounds have good drug effect, they also have respective problem.Such as vismodegib physicochemical property is poor, and dissolubility is low, has stronger side effect and has produced drug resistance etc..It is therefore desirable to propose a kind of brand-new hedgehog pathway antagonist, avoid falling drug resistance and side effect that prior art Chinese medicine occurs, block Nasopharyngeal neoplasms regeneration better, treat tumor.
Summary of the invention
In view of the defect that above-mentioned prior art exists, the purpose of the present invention is to propose to a kind of Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, it is possible to block Nasopharyngeal neoplasms regeneration, treat tumor disease.
The purpose of the present invention will be achieved by the following technical programs:
A kind of Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, including this compound and pharmaceutically acceptable salt, various isotope, various isomer and various crystalline structure, has the structure shown in formula I:
Wherein, A is nitrogen-atoms, oxygen atom, sulphur atom or C-R9；
R1, R2, R3, R4, R5, R6, R7, R8, R10, R11 is respectively and independently selected from hydrogen atom, halogen, alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl, aliphatic radical, amide groups, urea groups, oxo urea groups, ghiourea group, sulfuryl, sulfoxide group, sulfophenyl, azido, alkane is for thiazolinyl, alkane is for alkynyl, alkane is for amino, alkane is for hydroxyl, alkane is for aliphatic radical, alkane is for sulfuryl, alkane is for sulfoxide group, alkane is for sulfophenyl, alkane is for azido, cyclic alkyl, cyclic alkenyl radical, 3-12 unit heterocycle, aromatic rings or 5-12 unit hetero-aromatic ring, or R10, R11 is carbonyl, thiocarbonyl group, adjacent R groups or with the 3-7 unit carbocyclic ring of the connected together formation of carbon R group or heterocycle；
R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, and alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl, aliphatic radical, amide groups, urea groups, oxo urea groups, ghiourea group, sulfuryl, sulfoxide group, sulfophenyl, azido, alkane is for thiazolinyl, and alkane is for alkynyl, alkane is for amino, and alkane is for hydroxyl, and alkane is for aliphatic radical, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfophenyl, alkane is for azido, cyclic alkyl, cyclic alkenyl radical, 3-12 unit heterocycle, aromatic rings or 5-12 unit hetero-aromatic ring；
N is 0,1,2,3,4,5 or 6.
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, wherein: described R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 are respectively and independently selected from: hydrogen atom, alkyl, thiazolinyl, alkynyl, aromatic rings base or the heterocyclic radical that hydrogen atom is replaced by halogen, cyano group, amino, hydroxyl, sulfydryl, alkoxyl, ester group, sulfuryl, sulfoxide group, sulfophenyl or azido, and cyclic alkyl, cyclic alkenyl radical, 3-12 unit heterocycle or 5-12 membered aromatic heterocycle；The alkyl that described hydrogen atom is optionally substituted by halogen is preferably trifluoromethyl.
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, wherein: alkyl and alkane are for the hydrocarbon alkyl that base is the straight chain of 1-10 carbon atom composition, side chain, ring-type, double-ring or Spirocyclic；Thiazolinyl and alkene are for the Hydrocarbon containing the straight chain of at least one carbon-carbon double bond, side chain, ring-type, double-ring or Spirocyclic that base is 1-10 carbon atom composition；Alkynyl and alkynes are for the Hydrocarbon containing the straight chain of at least one triple carbon-carbon bonds, side chain, ring-type, double-ring or Spirocyclic that base is 1-10 carbon atom composition；Halogen is fluorine, chlorine, bromine or iodine；Hetero atom is nitrogen, oxygen, sulfur or phosphorus, and the quaternary ammonium salt of various oxidation state or nitrogen；Heterocycle is containing including the nonaromatic monocycle of the combination of one or more atoms, dicyclo, three rings or volution in nitrogen, oxygen or sulfur, and the cyclic substituents of various oxidation states；Aromatic rings is phenyl ring, naphthalene nucleus and their substitutive derivative, or is the derivative cyclic substituents of saturated rings and aromatic rings；Aromatic heterocycle is containing including the ring of the combination of one or more atoms in nitrogen, oxygen or sulfur, and the cyclic substituents of various oxidation states, or is the derivative cyclic substituents of saturated rings and aromatic heterocycle.
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, wherein: described isotope includes 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 32P, 35S or 36Cl, described isomer includes stereoisomer, cis-trans-isomer or tautomer.
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, wherein: described formula I is selected from:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, and alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl, aliphatic radical, amide groups, urea groups, oxo urea groups, ghiourea group, sulfuryl, sulfoxide group, sulfophenyl, azido, alkane is for thiazolinyl, alkane is for alkynyl, and alkane is for amino, and alkane is for hydroxyl, and alkane is for aliphatic radical, and alkane is for sulfuryl, and alkane is for sulfoxide group, alkane is for sulfophenyl, and alkane is for azido, cyclic alkyl, cyclic alkenyl radical, 3-12 unit heterocycle, aromatic rings or 5-12 unit hetero-aromatic ring.
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, it includes following compounds and pharmaceutically acceptable salt, various isotope, various isomer and various crystalline structure:
Wherein, R9 is selected from any one in following groups:
Preferably, the above-mentioned Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, it includes following compounds and pharmaceutically acceptable salt, various isotope, various isomer and various crystalline structure:
The present invention also proposes a kind of antitumor medicine composition, comprises the combination of at least two compound composition having in the Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist of formula I structure, its pharmaceutically acceptable salt, various isotope, various isomer and various crystalline structure.
The present invention also proposes the use in conjunction compositions of a kind of antitumor drug, and this use in conjunction compositions is to have the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist and pharmaceutical composition carries out, with the combination of one or more in cisplatin, paclitaxel, camptothecine, Herceptin, imatinib mesylate, imatinib, gefitinib, erlotinib, Lapatinib, the compositions that use in conjunction obtains respectively.
The present invention also proposes a kind of use in conjunction compositions with the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist, antitumor medicine composition or antitumor drug and treats the application in the medicine of tumor in preparation.
The prominent effect of the present invention is: the invention provides a kind of new Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist, it is possible to block Nasopharyngeal neoplasms regeneration, thus treating tumor disease.
Hereinafter just accompanying drawing in conjunction with the embodiments, is described in further detail the specific embodiment of the present invention, so that technical solution of the present invention is more readily understood, grasps.
Accompanying drawing explanation
Fig. 1 is the testing result curve chart of compound C3；
Fig. 2 is the testing result curve chart of compound C4；
Fig. 3 is the testing result curve chart of compound C5；
Fig. 4 is the testing result curve chart of compound C7；
Fig. 5 is the testing result curve chart of compound C9；
Fig. 6 is the testing result curve chart of compound C10；
Fig. 7 is the testing result curve chart of compound C11；
Fig. 8 is the testing result curve chart of compound C21；
Fig. 9 is the testing result curve chart of compound C22.
Detailed description of the invention
Below by specific embodiment, the method for the present invention is illustrated, but the invention is not limited in this.Experimental technique described in following embodiment, if no special instructions, is conventional method；Described reagent and material, if no special instructions, all commercially obtain.Solvent for use and medicine are analytical pure or chemical pure；Solvent is before use all through re-distillation；Anhydrous solvent all processes according to standard method or literature method.Column chromatography silica gel (100-200 order) and tlc silica gel (GF254) are Haiyang Chemical Plant, Qingdao and chemical plant, Yantai product；If not otherwise specified, all adopt petroleum ether (60-90 DEG C)/ethyl acetate (v/v) as eluant；The alcoholic solution of developer iodine or phosphomolybdic acid；All extractant unexplained reference are used that anhydrous Na2SO4Dry.1HNMR U.S. VarianunityINOVA400NB and Vnmrs high resolution NMR instrument record, TMS is interior mark.LC-MS Agilent company 1100 of U.S. type HPLC-ESI-MSn combined instrument (LC-MSDTrap) record, diode array detector (DAD), detects wavelength 214nm and 254nm, ion trap mass spectrometry (ESI source).HPLC column is AgelaDurashellC18 (4.6 × 50mm, 3.5 μm)；Mobile phase is 0.1%TFA aqueous solution: acetonitrile (from 5: 95 to 95: 5 in 6 minutes)；Flow velocity is 1.2ml/min.
Embodiment 1
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C1, and it is prepared by method synthesis:
1) synthesis of intermediate C1-1:
By N-t-butoxycarbonylpiperidin ketone (20g, 100.5mmol), cyanamide (8.7g, 200.9mmol), Sublimed Sulfur (6.4g, 200mmol) join in the pyridine of 100mL, react 90 minutes at 130 DEG C, be cooled to room temperature and precipitate out crystal, filter, gained solid ether (100mL) is washed twice, obtains a light yellow solid (19g, 74.2%).1HNMR(400MHz,DMSO-d6)δ6.83(s,2H),4.29(s,2H),3.56(s,2H),2.43(s,2H),1.41(s,9H)。
2) synthesis of intermediate C1-2:
By C1-1(200mg, 0.78mmol) join the ethyl acetate solution (3mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic facies obtains a white solid (155mg, 87%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C1:
C1-2(55mg, 0.35mmol), cesium fluoride (152mg, 1mmol) and A1-9(180mg, 0.7mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow oil C1 (50mg, 37.8%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:100).1HNMR(400MHz,CDCl3)δ8.35(s,1H),8.21(s,1H),7.44(s,1H),6.65(s,1H),4.56(s,2H),3.86(s,2H),2.75(s,2H),2.38(s,3H),2.17(s,3H)；ESI-MS(m/z):371.8[M+1]+.Material through spectrum analysis gained is
Embodiment 2
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C2, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C2.
C1 (40mg, 0.11mmol), acetic acid (9mg, 0.14mmol), N, N`-diisopropylethylamine (28mg, 0.22mmol) are dissolved in N, N`-dimethylformamide (1.5mL).HATU(53mg, 0.14mmol) add in solution, stir 24 hours under room temperature.Reactant liquor adds in ethyl acetate (40mL), washs with saturated aqueous common salt (15mL × 3).Organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C2 (20mg, 45%) through silicagel column (dichloromethane: methanol=70:1) purification.1HNMR(400MHz,CDCl3)δ9.55(s,1H),8.35(s,1H),8.22(s,1H),7.43(s,1H),6.66(s,1H),4.68(s,2H),3.96(t,J=5.6Hz,2H),2.83(t,J=5.4Hz,2H),2.38(s,3H),2.23(s,3H),2.17(s,3H)；ESI-MS(m/z):413.8[M+1]+.Material through spectrum analysis gained is
Embodiment 3
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C3, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C3.
C1 (35mg, 0.094mmol), isopropylformic acid. (11mg, 0.125mmol), N, N`-diisopropylethylamine (20mg, 0.155mmol) are dissolved in N, N`-dimethylformamide (1.5mL).HATU(49mg, 0.129mmol) add in solution, stir 24 hours under room temperature.Reactant liquor adds in ethyl acetate (40mL), washs with saturated aqueous common salt (15mL × 3).Organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains white solid C3(13.3mg through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, and 32%).1HNMR(400MHz,CDCl3)δ9.89(s,1H),8.36(s,1H),8.22(s,1H),7.43(s,1H),6.67(s,1H),4.67(s,2H),3.96(t,J=5.6Hz,2H),2.82(t,J=5.4Hz,2H),2.59(m,1H),2.38(s,3H),2.17(s,3H),1.24(d,J=6.8Hz,6H)；ESI-MS(m/z):441.8[M+1]+.Material through spectrum analysis gained is
Embodiment 4
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C4, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C4.
C1 (35mg, 0.094mmol), propanoic acid (9mg, 0.122mmol), N, N`-diisopropylethylamine (20mg, 0.155mmol) are dissolved in N, N`-dimethylformamide (1.5mL).HATU(49mg, 0.129mmol) add in solution, stir 24 hours under room temperature.Reactant liquor adds in ethyl acetate (40mL), washs with saturated aqueous common salt (15mL × 3).Organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains white solid C4 (9.6mg, 23.8%) through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification.1HNMR(400MHz,CDCl3)δ10.11(s,1H),8.36(s,1H),8.23(s,1H),7.43(s,1H),6.67(s,1H),4.67(s,2H),3.96(t,J=5.6Hz,2H),2.82(t,J=5.0Hz,2H),2.45(q,J=7.5Hz,2H),2.38(s,3H),2.17(s,3H),1.24(t,J=7.4Hz,3H)；ESI-MS(m/z):427.8[M+1]+.Material through spectrum analysis gained is
Embodiment 5
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C5, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C5.
C1 (35mg, 0.094mmol), ethylene-acetic acid (11mg, 0.128mmol), N, N`-diisopropylethylamine (20mg, 0.155mmol) are dissolved in N, N`-dimethylformamide (1.5mL).HATU(49mg, 0.129mmol) add in solution, stir 24 hours under room temperature.Reactant liquor adds in ethyl acetate (40mL), washs with saturated aqueous common salt (15mL × 3).Organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains white solid C5(7.1mg through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, and 17.1%).1HNMR(400MHz,CDCl3)δ10.25(s,1H),8.36(s,1H),8.23(s,1H),7.43(s,1H),6.67(s,1H),4.66(s,2H),3.96(t,J=5.6Hz,2H),2.83(t,J=5.2Hz,2H),2.38(s,3H),2.17(s,3H),1.60(m,1H),1.19-1.16(m,2H),0.98-0.94(m,2H)；ESI-MS(m/z):439.7[M+1]+.Material through spectrum analysis gained is
Embodiment 6
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C6, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C6.
C1 (35mg, 0.094mmol), 2-2-Methoxyacetic acid (11mg, 0.122mmol), N, N`-diisopropylethylamine (20mg, 0.155mmol) are dissolved in N, N`-dimethylformamide (1.5mL).HATU(49mg, 0.129mmol) add in solution, stir 24 hours under room temperature.Reactant liquor adds in ethyl acetate (40mL), washs with saturated aqueous common salt (15mL × 3).Organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow oil C6 (24mg, 50%) through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification.1HNMR(400MHz,CDCl3)δ9.65(s,1H),8.35(s,1H),8.22(s,1H),7.43(s,1H),6.67(s,1H),4.71(s,2H),4.11(s,2H),3.96(s,2H),3.49(s,3H),2.85(s,2H),2.37(s,3H),2.16(s,3H)；ESI-MS(m/z):443.8[M+1]+.Material through spectrum analysis gained is
Embodiment 7
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C7, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C7.
C1 (35mg, 0.094mmol), N, N`-diisopropylethylamine (20mg, 0.155mmol) are dissolved in dichloromethane (3mL).Dichloromethane (1mL) solution of 2,2-dimethylpropionic acid chloride (14mg, 0.116mmol) is slowly dripped at 0 DEG C, and keep 0 DEG C to react 2 hours, concentrating under reduced pressure, obtains yellow oil C7(22.8mg through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, and 53%).1HNMR(400MHz,CDCl3)δ9.55(s,1H),8.36(s,1H),8.23(s,1H),7.43(s,1H),6.67(s,1H),4.69(s,2H),3.97(t,J=5.6Hz,2H),2.83(t,J=5.6Hz,2H),2.38(s,3H),2.17(s,3H),1.32(s,9H)；ESI-MS(m/z):455.8[M+1]+.Material through spectrum analysis gained is
Embodiment 8
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C8, and it is prepared by method synthesis:
1) synthesis of intermediate C8-1:
At 0 DEG C, amyl nitrite (8.8mL, 62.8mmol) and copper bromide (10.7g, 48mmol) being joined N, N`-dimethylformamide (100mL), C1-1 (10g, 39.2mmol) is added in solution, stirs 30 minutes at 40 DEG C.Concentrating under reduced pressure adds water (50mL), extracts with dichloromethane (100mL × 2), and organic facies merging saturated common salt washes (30mL × 2), after anhydrous sodium sulfate dry filter, solvent is removed in rotation, and solute obtains yellow solid C8-1 (5.3g, 42.4%) through column chromatography refining (dichloromethane).
2) synthesis of intermediate C8-2:
C8-1(200mg, 0.629mmol), morpholine (231mg, 2.656mmol), N, N`-diisopropylethylamine (428mg, 3.32mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.It is cooled to room temperature, reactant liquor adds in ethyl acetate (40mL), wash with saturated aqueous common salt (15mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, white solid C8-2 (130mg, 63.7%) is obtained through silicagel column (petroleum ether: ethyl acetate=4:1) purification.
3) synthesis of intermediate C8-3:
By C8-2 (130mg, 0.4mmol) join the Hydrochloride/ethyl acetate (3mL) of 3M, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (5mL) and dichloromethane (20mL), organic facies obtains a white solid C8-3 (50mg, 55.5%) after concentrating with anhydrous sodium sulfate dry filter.
4) synthesis of product C8:
C8-3(50mg, 0.22mmol), cesium fluoride (100mg, 0.66mmol) and A1-9(111mg, 0.44mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a white solid C8 (33mg, 33.6%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:70).1HNMR(400MHz,CDCl3)δ8.38(s,1H),8.24(s,1H),7.45(s,1H),6.68(s,1H),4.63(s,2H),3.93(t,J=5.7Hz,2H),3.82(t,J=4.8Hz,4H),3.44(t,J=4.8Hz,4H),2.80(t,J=5.4Hz,2H),2.40(s,3H),2.19(s,3H)；ESI-MS(m/z):441.8[M+1]+.Material through spectrum analysis gained is
Embodiment 9
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C9, and it is prepared by method synthesis:
1) synthesis of intermediate C9-1:
C8-1(400mg, 1.25mmol), 2,6-dimethyl-piperizine (428mg, 3.75mmol), N, N`-diisopropylethylamine (650mg, 5.04mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C9-1(400mg through silicagel column (methanol: dichloromethane=1:50) purification, and 90.7%).
2) synthesis of intermediate C9-2:
By C9-1 (400mg, 1.136mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C9-2 (212mg, 74%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C9:
C9-2(50mg, 0.198mmol), cesium fluoride (76mg, 0.5mmol) and A1-9(76mg, 0.3mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow oil C9 (17.4mg, 18.7%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:50 to 1:20).1HNMR(400MHz,CDCl3)δ8.34(s,1H),8.20(s,1H),7.41(s,1H),6.64(s,1H),4.58(s,2H),3.90(t,J=5.6Hz,2H),3.77-3.73(m,2H),3.04-2.95(m,2H),2.76(t,J=5.6Hz,2H),2.63-2.57(m,2H),2.36(s,3H),2.16(s,3H),1.14(d,J=6.4Hz,6H)；ESI-MS(m/z):468.8[M+1]+.Material through spectrum analysis gained is
Embodiment 10
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C10, and it is prepared by method synthesis:
1) synthesis of intermediate C10-1:
C8-1(400mg, 1.25mmol), cyclopropylmethylamine (267mg, 3.76mmol), N, N`-diisopropylethylamine (650mg, 5.04mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C10-1(310mg through silicagel column (petroleum ether: ethyl acetate=4:1) purification, and 80.1%).
2) synthesis of intermediate C10-2:
By C10-1(310mg, 1.003mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C10-2(150mg after concentrating with anhydrous sodium sulfate dry filter, and 77%).
3) synthesis of product C10:
C10-2(50mg, 0.24mmol), cesium fluoride (91mg, 0.6mmol) and A1-9(91mg, 0.36mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a white solid C10 (27mg, 26.4%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:100 to 1:50).1HNMR(400MHz,CDCl3)δ8.34(s,1H),8.20(s,1H),7.41(s,1H),6.63(s,1H),5.50(s,1H),4.56(s,2H),3.89(t,J=5.6Hz,2H),3.08(d,J=7.2Hz,2H),2.73(t,J=5.4Hz,2H),2.36(s,3H),2.15(s,3H),1.10(brs,1H),0.54(d,J=7.7Hz,2H),0.24(d,J=5.1Hz,2H)；ESI-MS(m/z):425.8[M+1]+.Material through spectrum analysis gained is
Embodiment 11
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C11, and it is prepared by method synthesis:
1) synthesis of intermediate C11-1:
C8-1 (400mg, 1.25mmol), 4-piperidine alcohols (379mg, 3.75mmol), N, N`-diisopropylethylamine (650mg, 5.04mmol) are dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C11-1(370mg through silicagel column (petroleum ether: ethyl acetate=1:1) purification, and 87%).
2) synthesis of intermediate C11-2:
By C11-1(370mg, 1.09mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C11-2(150mg after concentrating with anhydrous sodium sulfate dry filter, and 57.7%).
3) synthesis of product C11:
C11-2(50mg, 0.21mmol), cesium fluoride (80mg, 0.525mmol) and A1-9(80mg, 0.315mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow oil C11(9mg through column chromatography refining (mobile phase is methanol: dichloromethane=1:100 to 1:20), and 9.4%).1HNMR(400MHz,CDCl3)δ8.33(s,1H),8.20(s,1H),7.42(s,1H),6.64(s,1H),4.58(s,2H),3.89(t,J=5.6Hz,2H),3.87-3.84(m,1H),3.78-3.73(m,2H),3.20-3.14(m,2H),2.75(t,J=5.6Hz,2H),2.36(s,3H),2.15(s,3H),1.95-1.89(m,2H),1.65-1.56(m,2H)；ESI-MS(m/z):455.8[M+1]+.Material through spectrum analysis gained is
Embodiment 12
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C12, and it is prepared by method synthesis:
1) synthesis of intermediate C12-1:
C8-1(400mg, 1.25mmol), 2,6-thebaines (431mg, 3.75mmol), N, N`-diisopropylethylamine (650mg, 5.04mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C12-1(300mg through silicagel column (petroleum ether: ethyl acetate=2:1) purification, and 67.7%).
2) synthesis of intermediate C12-2:
By C12-1(300mg, 0.848mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C12-2(193mg after concentrating with anhydrous sodium sulfate dry filter, and 90%).
3) synthesis of product C12:
C12-2(50mg, 0.2mmol), cesium fluoride (76mg, 0.5mmol) and A1-9(76mg, 0.3mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a white solid C12 (28mg, 30.1%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:80 to 1:40).1HNMR(400MHz,CDCl3)δ8.34(s,1H),8.21(s,1H),7.42(s,1H),6.65(s,1H),4.60(s,2H),3.91(t,J=5.8Hz,2H),3.78-3.71(m,2H),3.68(d,J=12.8Hz,2H),2.77(t,J=5.6Hz,2H),2.70(t,J=11.6Hz,2H),2.37(s,3H),2.16(s,3H),1.24(d,J=6.4Hz,6H)；ESI-MS(m/z):469.8[M+1]+.Material through spectrum analysis gained is
Embodiment 13
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C13, and it is prepared by method synthesis:
1) synthesis of intermediate C13-1:
C8-1(400mg, 1.25mmol), nafoxidine (266mg, 3.75mmol), N, N`-diisopropylethylamine (650mg, 5.04mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C13(320mg through silicagel column (petroleum ether: ethyl acetate=4:1) purification, and 82.6%).
2) synthesis of intermediate C13-2:
By C13-1(320mg, 1.04mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C13-2 (194mg, 90%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C13:
C13-2(50mg, 0.24mmol), cesium fluoride (92mg, 0.6mmol) and A1-9(91mg, 0.36mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a white solid C13 (13.5mg, 13.2%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:80 to 1:40).1HNMR(400MHz,CDCl3)δ8.34(s,1H),8.20(s,1H),7.41(s,1H),6.64(s,1H),4.59(s,2H),3.91(t,J=5.6Hz,2H),3.43(t,J=6.4Hz,4H),2.79(t,J=5.4Hz,2H),2.36(s,3H),2.16(s,3H),2.03-2.00(m,4H)；ESI-MS(m/z):425.8[M+1]+.Material through spectrum analysis gained is
Embodiment 14
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C14, and it is prepared by method synthesis:
1) synthesis of intermediate C14-1:
C8-1(400mg, 1.25mmol), ethylamine hydrochloride (307mg, 3.74mmol), N, N`-diisopropylethylamine (1.13g, 8.8mmol) be dissolved in dimethyl sulfoxide (2mL), stir 2 days at 130 DEG C.Being cooled to room temperature, reactant liquor adds in ethyl acetate (60mL), washs with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains yellow solid C14-1(100mg through silicagel column (petroleum ether: ethyl acetate=4:1) purification, and 28.1%).
2) synthesis of intermediate C14-2:
By C14-1(100mg, 0.353mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a brown solid C14-2 (53mg, 82%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C14:
C14-2 (53mg, 0.29mmol), cesium fluoride (112mg, 0.73mmol) and A1-9(112mg, 0.44mmol) it is dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow oil C14 (34mg, 29.3%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:80 to 1:40).1HNMR(400MHz,CDCl3)δ8.36(s,1H),8.20(s,1H),7.42(s,1H),6.63(s,1H),4.55(s,2H),3.86(s,2H),3.24(s,2H),2.72(s,2H),2.37(s,3H),2.16(s,3H),1.31(t,J=6.6Hz,3H)；ESI-MS(m/z):399.8[M+1]+.Material through spectrum analysis gained is
Embodiment 15
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C15, and it is prepared by method synthesis:
1) synthesis of intermediate C15-1:
Pyrazoles (255mg, 3.75mmol) is dissolved in DMF (5mL), adds sodium hydride (80%, 135mg, 4.5mmol) and react 15 minutes at 0 DEG C.By C8-1(400mg, 1.25mmol) join in reactant liquor, stir 5 hours at 100 DEG C, it is cooled to room temperature, adds in ethyl acetate (60mL) after reactant liquor cancellation, wash with saturated aqueous common salt (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, obtains white solid C15-1(280mg through silicagel column (petroleum ether: ethyl acetate=40:1 to 10:1) purification, and 72.9%).
2) synthesis of intermediate C15-2:
By C15-1(280mg, 0.915mmol) join the Hydrochloride/ethyl acetate (6mL) of 3M, stirring at normal temperature 3 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C15-2 (138mg, 73.4%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C15:
C15-2(50mg, 0.243mmol), cesium fluoride (94mg, 0.618mmol) and A1-9(94mg, 0.372mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow solid C15 (35.8mg, 34.9%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:80 to 1:40).1HNMR(400MHz,CDCl3)δ8.36(s,1H),8.28(s,1H),8.24(s,1H),7.70(s,1H),7.44(s,1H),6.70(s,1H),6.46(s,1H),4.77(s,2H),3.99(s,2H),2.93(s,2H),2.38(s,3H),2.17(s,3H)；ESI-MS(m/z):422.7[M+1]+.Material through spectrum analysis gained is
Embodiment 16
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C16, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C16.
C1 (50mg, 0.134mmol), N, N`-diisopropylethylamine (35mg, 0.268mmol) are dissolved in dichloromethane (3mL).Ethyl chloroformate (17.5mg is slowly dripped at 0 DEG C, dichloromethane (2mL) solution 0.161mmol), and keep 0 DEG C to react 5 hours, concentrating under reduced pressure, yellow solid C16(34mg is obtained through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, 56.7%).1HNMR(400MHz,CDCl3)δ9.95(s,1H),8.35(s,1H),8.23(s,1H),7.43(s,1H),6.67(s,1H),4.67(s,2H),4.30(q,J=6.9Hz,2H),3.95(s,2H),2.86(s,2H),2.38(s,3H),2.17(s,3H),1.34(t,J=6.9Hz,3H)；ESI-MS(m/z):443.8[M+1]+.Material through spectrum analysis gained is
Embodiment 17
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C17, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C17.
C1 (50mg, 0.134mmol), N, N`-diisopropylethylamine (60mg, 0.465mmol) are dissolved in dichloromethane (3mL).Slowly drip dichloromethane (2mL) solution of trifluoroacetic anhydride (62mg, 0.296mmol) at 0 DEG C, stir 5 hours under room temperature, concentrating under reduced pressure, obtain yellow solid C17(15mg through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, 23.8%).1HNMR(400MHz,CDCl3)δ8.42(s,1H),8.21(s,1H),7.47(s,1H),6.70(s,1H),4.67(s,2H),3.86(s,2H),2.66(s,2H),2.39(s,3H),2.17(s,3H)；ESI-MS(m/z):467.7[M+1]+.Material through spectrum analysis gained is
Embodiment 18
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C18, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C18.
1) synthesis of intermediate C18-1:
C1(200mg, 0.537mmol), triethylamine (108mg, 1.074mmol) be dissolved in dichloromethane (8mL).3-chlorpromazine chloride (82mg is slowly dripped at 0 DEG C, dichloromethane (3mL) solution 0.645mmol), stirs 2 hours at 0 DEG C, concentrating under reduced pressure, white solid C18-1 (88mg, 35.4%) is obtained through silicagel column (dichloromethane: methanol=80:1 to 60:1) purification.
2) synthesis of product C18:
C18-1(60mg, 0.13mmol), potassium iodide (17mg, 0.104mmol), morpholine (45mg, 0.517mmol) it is dissolved in dehydrated alcohol (2mL), stir 2 hours at 80 DEG C, concentrating under reduced pressure, obtains yellow solid C18(60mg through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification, and 90.9%).1HNMR(400MHz,CDCl3)δ8.35(s,1H),8.22(s,1H),7.43(s,1H),6.66(s,1H),4.68(s,2H),3.95(t,J=5.2Hz,2H),3.85(s,4H),2.84(s,2H),2.78(t,J=5.6Hz,2H),2.64(s,6H),2.37(s,3H),2.16(s,3H)；ESI-MS(m/z):512.7[M+1]+.Material through spectrum analysis gained is
Embodiment 19
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C19, and it is prepared by method synthesis:
It is synthetically derived intermediate C18-1 according to the method in embodiment 1 and 18, then prepares product C19.
C18-1(50mg, 0.108mmol), potassium iodide (15mg, 0.09mmol), piperidines (54mg, 0.635mmol) it is dissolved in dehydrated alcohol (2mL), stir 2 hours at 80 DEG C, concentrating under reduced pressure, obtains yellow oil C19(44mg through silicagel column (dichloromethane: methanol=50:1 to 25:1) purification, and 79.7%).1HNMR(400MHz,CDCl3)δ8.36(s,1H),8.22(s,1H),7.43(s,1H),6.67(s,1H),4.68(s,2H),3.95(t,J=5.2Hz,2H),2.85(s,4H),2.73(t,J=5.8Hz,2H),2.68(s,4H),2.38(s,3H),2.17(s,3H),1.80(t,J=5Hz,4H),1.57(s,2H)；ESI-MS(m/z):510.7[M+1]+.Material through spectrum analysis gained is
Embodiment 20
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C20, and it is prepared by method synthesis:
It is synthetically derived intermediate C18-1 according to the method in embodiment 1 and 18, then prepares product C20.
C18-1(50mg, 0.108mmol), potassium iodide (15mg, 0.09mmol), dimethylamine hydrochloride (34mg, 0.42mmol), N, N`-diisopropylethylamine (120mg, 0.93mmol) is dissolved in dehydrated alcohol (2mL), stir 2 hours at 80 DEG C, concentrating under reduced pressure, obtains yellow solid C19 (6.3mg, 12.4%) through silicagel column (dichloromethane: methanol=80:1 to 25:1) purification.1HNMR(400MHz,CDCl3)δ8.35(s,1H),8.22(s,1H),7.43(s,1H),6.66(s,1H),4.66(s,2H),3.94(t,J=5.2Hz,2H),3.02(s,2H),2.89-2.83(m,4H),2.61(s,6H),2.38(s,3H),2.17(s,3H)；ESI-MS(m/z):470.8[M+1]+.Material through spectrum analysis gained is
Embodiment 21
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C21, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C21.
C1 (40mg, 0.108mmol), ethyl isocyanate (33mg, 0.465mmol) it is dissolved in 1, in 4-dioxane (1.5mL), stirring overnight at 80 DEG C, concentrating under reduced pressure, with normal hexane (20mL) concentrating under reduced pressure twice again, yellow oil (24mg, 50.5%) is obtained through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification.1HNMR (400MHz, CDCl3) δ 8.36 (s, 1H), 8.22 (s, 1H), 7.44 (s, 1H), 6.67 (s, 1H), 4.61 (s, 2H), 3.95 (s, 2H), 3.39-3.32 (m, 2H), 2.82 (s, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.21 (t, J=7.2Hz, 3H)；ESI-MS(m/z):442.8[M+1]+.Material through spectrum analysis gained is
Embodiment 22
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C22, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C22.
C1 (40mg, 0.108mmol), 2-Isocyanato-propane 1-Methylethyl isocyanate (40mg, 0.471mmol) it is dissolved in 1, in 4-dioxane (1.5mL), stirring overnight at 80 DEG C, concentrating under reduced pressure, with normal hexane (20mL) concentrating under reduced pressure twice again, yellow oil (26mg, 53.06%) is obtained through silicagel column (dichloromethane: methanol=80:1 to 50:1) purification.1HNMR(400MHz,CDCl3)δ8.35(s,1H),8.23(s,1H),7.43(s,1H),6.67(s,1H),4.62(s,2H),4.01(m,1H),3.95(s,2H),2.82(s,2H),2.38(s,3H),2.17(s,3H),1.23(s,6H)；ESI-MS(m/z):456.8[M+1]+.Material through spectrum analysis gained is
Embodiment 23
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C23, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C23.
C1 (56mg, 0.151mmol), triethylamine (30mg, 0.297mmol) it is dissolved in dichloromethane (3mL), acryloyl chloride (17mg is slowly dripped at 0 DEG C, dichloromethane (1mL) solution 0.189mmol), stirs 4 hours at 0 DEG C, concentrating under reduced pressure, white solid (7.3mg, 11.4%) is obtained through silicagel column (petroleum ether: ethyl acetate=2:1 to 1:1) purification.1HNMR(300MHz,DMSO-d6)δ12.24(s,1H),8.30(s,1H),8.23(s,1H),7.57(s,1H),6.90(s,1H),6.52-6.43(m,1H),6.35(d,J=17.4Hz,1H),5.86(d,J=9.3Hz,1H),4.71(s,2H),3.95(t,J=5.0Hz,2H),2.71(s,2H),2.31(s,3H),2.07(s,3H)；ESI-MS(m/z):425.8[M+1]+.Material through spectrum analysis gained is
Embodiment 24
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C24, and it is prepared by method synthesis:
It is synthetically derived intermediate C1 according to the method in embodiment 1, then prepares product C24.
C1 (42mg, 0.113mmol), triethylamine (34mg, 0.337mmol) it is dissolved in dichloromethane (3mL), mesyl chloride (26mg is slowly dripped at 0 DEG C, dichloromethane (1mL) solution 0.227mmol), stir 4 hours at 0 DEG C, concentrating under reduced pressure, stir 3 hours in the mixed solution of saturated sodium bicarbonate aqueous solution (4mL) and acetonitrile (0.5mL) under room temperature, extract by ethyl acetate (10mL × 2), organic facies filters after drying at anhydrous sodium sulfate, filtrate reduced in volume, yellow solid (19mg is obtained through silicagel column (petroleum ether: ethyl acetate=2:1 to 1:1) purification, 37.4%).1HNMR(300MHz,CDCl3)δ8.35(s,1H),8.22(s,1H),7.44(s,1H),6.65(s,1H),4.53(s,2H),3.90(s,2H),2.99(s,3H),2.78(s,2H),2.38(s,3H),2.16(s,3H)；ESI-MS(m/z):449.7[M+1]+.Material through spectrum analysis gained is
Embodiment 25
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C25, and it is prepared by method synthesis:
It is synthetically derived intermediate C8-1 according to the method in embodiment 1 and 8, then prepares product C25.
1) synthesis of intermediate C25-1:
By sodium hydride (80% at 0 DEG C, 90mg, 3mmol) join in ethanol (3mL) and react 30 minutes, C8-1(320mg, 1mmol) it is added in reactant liquor, reacts at 80 DEG C overnight, concentrating under reduced pressure, green oil thing (180mg, 63.3%) is obtained through silicagel column (petroleum ether: ethyl acetate=15:1) purification.1HNMR(400MHz,CDCl3)δ4.36(s,2H),4.34-4.31(m,2H),3.63(s,2H),2.60(s,2H),1.41(s,9H),1.34(t,J=7.0Hz,3H)。
2) synthesis of intermediate C25-2:
C25-1 (107mg, 0.377mmol) is dissolved in dichloromethane (3mL), drips trifluoroacetic acid (0.37mL, 4.9mmol) and stirs 4 hours, be added in reactant liquor by frozen water (3mL) at 0 DEG C, and the sodium hydrate aqueous solution with 40% regulates pH to 10.Extracting with dichloromethane (10mL × 3), organic facies filters after drying at anhydrous sodium sulfate, and filtrate reduced in volume obtains yellow solid (62mg, 88.6%).1HNMR(400MHz,CDCl3)δ4.40(q,J=7.2Hz,2H),3.86(t,J=1.8Hz,2H),3.16(t,J=5.8Hz,2H),2.65-2.60(m,2H),1.41(t,J=7.0Hz,3H)。
3) synthesis of product C25:
C25-2 (50mg, 0.272mmol), cesium fluoride (103mg, 0.678mmol) and A1-9(103mg, 0.407mmol) it is dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow solid (26mg, 23.9%) through column chromatography refining (mobile phase is ethyl acetate: dichloromethane=1:20).1HNMR(300MHz,CDCl3)δ8.35(s,1H),8.21(s,1H),7.42(s,1H),6.65(s,1H),4.59(s,2H),4.41(q,J=7.1Hz,2H),3.92(t,J=5.6Hz,2H),2.77(t,J=5.3Hz,2H),2.37(s,3H),2.16(s,3H),1.41(t,J=7.1Hz,3H)；ESI-MS(m/z):400.8[M+1]+.Material through spectrum analysis gained is
Embodiment 26
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C26, and it is prepared by method synthesis:
It is synthetically derived intermediate C8-1 according to the method in embodiment 1 and 8, then prepares product C26.
1) synthesis of intermediate C26-1:
By sodium hydride (80% at 0 DEG C, 283mg, 9.43mmol) join in cyclopropyl-carbinol (4mL) and react 30 minutes, C8-1(500mg, 1.57mmol) it is added in reactant liquor, reacts at 80 DEG C overnight, concentrating under reduced pressure, yellow oil (250mg, 51.4%) is obtained through silicagel column (petroleum ether: ethyl acetate=15:1) purification.1HNMR(400MHz,CDCl3)δ4.43(s,2H),4.18(d,J=7.2Hz,2H),3.70(t,J=4.6Hz,2H),2.66(s,2H),1.48(s,9H),1.29(m,1H),0.66-0.61(m,2H),0.38-0.34(m,2H)。
2) synthesis of intermediate C26-2:
C26-1 (250mg, 0.806mmol) is dissolved in dichloromethane (5mL), drips trifluoroacetic acid (0.8mL, 10.8mmol) and stirs 4 hours, be added in reactant liquor by frozen water (4mL) at 0 DEG C, and the sodium hydrate aqueous solution with 40% regulates pH to 10.Extracting with dichloromethane (20mL × 3), organic facies filters after drying at anhydrous sodium sulfate, and filtrate reduced in volume obtains yellow oil (21mg, 12.4%).
3) synthesis of product C26:
C26-2 (21mg, 0.1mmol), cesium fluoride (38mg, 0.25mmol) and A1-9(38mg, 0.15mmol) it is dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.It is cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains a yellow solid (6mg, 14.08%) through column chromatography refining (mobile phase is ethyl acetate: dichloromethane=1:20).1HNMR(300MHz,CDCl3)δ8.34(s,1H),8.21(s,1H),7.42(s,1H),6.64(s,1H),5.08(m,1H),4.59(s,2H),3.91(t,J=5.6Hz,2H),2.76(t,J=5.1Hz,2H),2.5-2.40(m,2H),2.37(s,3H),2.27-2.18(m,2H),2.16(s,3H),1.91-1.77(m,1H),1.71-1.64(m,1H)；ESI-MS(m/z):426.8[M+1]+.Material through spectrum analysis gained is
Embodiment 27
The present embodiment provides a kind of Amido thiazole-pyridine heterocycle compound C27, and it is prepared by method synthesis:
It is synthetically derived intermediate C8-1 according to the method in embodiment 1 and 8, then prepares product C27.
1) synthesis of intermediate C27-1:
Sodium hydride (80%, 188mg, 6.25mmol) is joined in oxolane (10mL) solution of aniline (581mg, 6.25mmol), stir 30 minutes at 60 DEG C, be cooled to room temperature, C8-1 added in reactant liquor, stir 4 hours under room temperature.Saturated aqueous common salt (20mL) is added in reactant liquor, extracting by ethyl acetate (30mL × 3), organic facies is with after anhydrous sodium sulfate dry filter, and solvent is removed in rotation, solute obtains a yellow solid (287mg, 69.1%) through column chromatography refining (petroleum ether: ethyl acetate=6:1).1HNMR(300MHz,CDCl3)δ7.32(s,3H),7.26(s,1H),7.06(s,1H),4.48(s,2H),3.72(s,2H),2.71(s,2H),1.48(s,9H)。
2) synthesis of intermediate C27-2:
By C27-1(287mg, 0.867mmol) join the ethyl acetate solution (6mL) of 3M hydrogen chloride, stirring at normal temperature 4 hours, solvent is removed in decompression rotation, concentrate joins in saturated sodium bicarbonate aqueous solution (10mL) and dichloromethane (40mL), organic facies obtains a yellow solid C27-2 (174mg, 87%) after concentrating with anhydrous sodium sulfate dry filter.
3) synthesis of product C27:
C27-2(50mg, 0.216mmol), cesium fluoride (82mg, 0.541mmol) and A1-9(82mg, 0.324mmol) be dissolved in dimethyl sulfoxide (1mL) respectively under agitation, heating, to 120 DEG C, is reacted 36 hours.Being cooled to room temperature, add ethyl acetate (10mL) and water (5mL), organic facies saturated aqueous common salt (5mL) is washed, after anhydrous sodium sulfate dry filter, solvent is removed in rotation, and solute obtains a yellow oil (9mg, 9%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:100 to 1:80).1HNMR(400MHz,CDCl3)δ8.36(s,1H),8.22(s,1H),7.43(s,1H),7.36-7.32(m,4H),7.06(t,J=6Hz,1H),6.66(s,1H),4.63(s,2H),3.93(s,2H),2.81(s,2H),2.38(s,3H),2.17(s,3H)；ESI-MS(m/z):447.8[M+1]+.Material through spectrum analysis gained is
Embodiment 28
1) synthesis of intermediate C28-1:
By malonic acid ring isopropyl ester (5g, 34.72mmol), N-(tertbutyloxycarbonyl)-Beta-alanine (5.96g, 31.57mmol) and DMAP (5.8g, 47.36mmol) be dissolved in the dichloromethane of 40 milliliters, dicyclohexylcarbodiimide (7.8g is slowly dripped at 0 DEG C, 37.88mmol) dichloromethane (20mL) solution, stirred overnight at room temperature.Filtering, filtrate is washed twice with water (100mL) solution of citric acid (5g, 26mmol), then washes once with water (100mL), and organic facies obtains a yellow solid crude product (11g) after concentrating with anhydrous sodium sulfate dry filter, can be directly used for next reaction.
2) synthesis of intermediate C28-2:
By C28-1(11g) it is dissolved in the toluene of 200mL, stir at 80 DEG C overnight, concentrating under reduced pressure, solute obtains a white solid (2.5g, 33.7%) through column chromatography refining (mobile phase is methanol: dichloromethane=1:100).1HNMR(400MHz,CDCl3)δ4.13(t,J=6.0Hz,2H),3.54(s,2H),2.65(t,J=6.0Hz,2H),1.58(s,9H)。
3) synthesis of intermediate C28-3:
By C28-2(213mg, 1mmol) it is dissolved in the oxolane of 4mL, it is dividedly in some parts N-bromo-succinimide (178mg, 1mmol) at 0 DEG C, stirs 2 hours under room temperature.Adding saturated aqueous common salt (5mL) in reactant liquor, extract by ethyl acetate (10mL), organic facies obtains a crude white solid (292mg) after concentrating with anhydrous sodium sulfate dry filter, can be directly used for next reaction.
4) synthesis of intermediate C28-4:
By C28-3(292mg, 1mmol), thiourea (76mg, 1mmol) and sodium bicarbonate (84mg, 1mmol) be dissolved in the ethanol of 4 milliliters, stir 2 hours at 80 DEG C, be cooled to room temperature, filter, concentrating under reduced pressure filtrate, solute obtains a white solid (200mg, 74.3%) through recrystallization from ethanol.1HNMR(400MHz,DMSO)δ8.08(s,2H),3.89(t,J=6.4Hz,2H),2.75(t,J=6.4Hz,2H),1.44(s,9H)。
5) synthesis of intermediate C28-5:
At 0 DEG C, amyl nitrite (176mg, 1.5mmol) and copper bromide (268mg, 1.2mmol) being joined N, N`-dimethylformamide (2.5mL), C28-4 (269mg, 1mmol) is added in solution, stirs 30 minutes at 40 DEG C.Saturated aqueous common salt (20mL) is added in reactant liquor, extract by ethyl acetate (30mL*2), organic facies merging saturated common salt washes (10mL*2), after anhydrous sodium sulfate dry filter, solvent is removed in rotation, solute obtains white solid C28-5 (150mg, 45%) through column chromatography refining (mobile phase is petroleum ether: ethyl acetate=20:1).1HNMR(400MHz,CDCl3)δ4.12(t,J=6.4Hz,2H),3.10(t,J=6.4Hz,2H),1.56(s,9H)。
6) synthesis of intermediate C28-6:
C28-5(111mg, 0.333mmol), nafoxidine (71mg, 1mmol), N, N`-diisopropylethylamine (156mg, 1.2mmol) be dissolved in dimethyl sulfoxide (2mL), stir 6 hours at 130 DEG C.It is cooled to room temperature, reactant liquor adds in saturated aqueous common salt (20mL), extract with dichloromethane (20mL × 3), organic facies merges with saturated aqueous common salt (15mL*2) washing, filter after drying through anhydrous sodium sulfate, filtrate reduced in volume, obtains a yellow solid (70mg, 94%) through silicagel column (dichloromethane: methanol=60:1) purification.1HNMR(400MHz,CDCl3)δ5.61(s,1H),3.59-3.55(m,2H),3.51(s,4H),2.89(t,J=7Hz,2H),2.09-2.06(m,4H)。
7) synthesis of product C28:
By A1-9(20mg; 0.079mmol), C28-6 (20mg; 0.096mmol), tetrakis triphenylphosphine palladium (4mg; 0.0034mmol), 4; double; two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (4mg, 0.0068mmol) and cesium carbonate (40mg; 0.123mmol) adding in the dioxane of 4mL, 110 DEG C of stirrings are overnight under nitrogen protection.It is cooled to room temperature, concentrating under reduced pressure, obtains a yellow solid (16mg, 47.6%) through silicagel column (petroleum ether: ethyl acetate=4:1) purification.1HNMR(400MHz,CDCl3)δ8.43(s,1H),8.33(s,1H),7.93(s,1H),7.42(s,1H),4.37(t,J=6.6Hz,2H),3.53(s,4H),3.01(t,J=6.6Hz,2H),2.36(s,3H),2.22(s,3H),2.10-2.07(m,4H)；ESI-MS(m/z):440.3[M+1]+.Material through spectrum analysis gained is
Embodiment 29
The compound of embodiment 1-28 gained is carried out biological test by the present embodiment, with the vismodegib of success listing in 2012 for standard control thing:
NIH3T3-GRE-Luc luciferase reporter gene test experience
NIH3T3 cell is to cultivate in the DMEM (11965, Gibico) containing 10%FBS (Hyclone).GRE-firefly luciferin plasmid is to respond element via the cell transcription factor GLI-1 amplifying octuple to implant acquisition in MCS.Monoclonal is the small molecule agonist SAG checking being shown below through restructuring Su Nike hedgehog pathway albumen and structural formula.The selected clone being verified is for detecting hedgehog pathway signal.
The NIH3T3 cell expressing GRE-Lampyridea element is to maintain in complete culture fluid.When needs do analysis detection, cell is added in 96 orifice plates, and final every hole is containing cell about 15,000.96 orifice plates are being cultured 48 hours.Detected compound is by DMSO and detects buffer by serial dilution.10nMSAG is as hedgehog pathway agonist.100 microlitres include the analysis buffer of test compound and agonist and are carefully added into containing in 96 orifice plates in cell subsequently, and cultivate 48 hours at 37 degrees Celsius.
After 48 hours of incubation, 40 microlitre LUC Photinus pyralis LUC Photinus pyralis FL are added in each hole.96 orifice plates are jog 5 minutes at room temperature.Luminous signal is by plate reader record.The blocking-up of luminous signal is calculated by it and goes out by the activity of compound, and synthesized compound is tested, and result is following table such as:
The above results shows, that has surveyed in 28 compounds has 23, and wherein 22 have activity, wherein 9 (C3, C4, C5, C7, C9, C10, C11, C21, C22) it is better than as shown in figs 1-9 or suitable with the effect value of vismodegib, there is good hedgehog pathway antagonistic effect.As can be seen here, the Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist that the present invention is new, it is possible to block Nasopharyngeal neoplasms regeneration by hedgehog pathway antagonism, thus treating tumor disease.
The present invention still has numerous embodiments, all employing equivalents or equivalent transformation and all technical schemes of being formed, all falls within protection scope of the present invention.

Claims (6)

1. there is an Amido thiazole-pyridine heterocycle compound for activity of hedgehog path antagonist, there is the structure shown in formula I:
Wherein, R1For NR2R3；R2、R3Separately selected from hydrogen atom, C1-6Alkyl, C1-6Cycloalkyl, phenyl, C1-6Acyl group, C1-6Urea groups, C1-6Oxo urea groups, C1-6Sulfonyl, or the C replaced by 1-3 substituent group1-6Alkyl, C1-6Cycloalkyl, phenyl, C1-6Acyl group, C1-6Urea groups, C1-6Oxo urea groups, C1-6Sulfonyl；Described substituent group is separately selected from: halogen, C1-6Alkyl, C1-6Cycloalkyl, C1-6Alkoxyl, hydroxyl, amino, C1-6Alkane is for amino, containing 1-2 the heteroatomic C selected from O, N, S1-6Heterocyclylalkyl；It addition, R2, R3And connected atom N also can connect into containing 1-2 the heteroatomic five yuan of hetero-aromatic rings selected from O, N, S, or connect into containing 1-2 the heteroatomic 5-7 unit Heterocyclylalkyl selected from O, N, S；Described 5-7 unit Heterocyclylalkyl can be independently selected from halogen, hydroxyl, amino, oxo, C by 1-21-6Alkyl, C1-6Alkane is for amino, C1-6The substituent group of alkoxyl replaces.
2. the Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist according to claim 1, wherein said compound is selected from following compounds and pharmaceutically acceptable salt thereof:
Wherein, R1Any one in following groups:
。
3. the Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist according to claim 2, wherein said compound is selected from:
4. an antitumor medicine composition, comprises the combination that the arbitrary at least two compound having in the Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist of Formulas I structure, its pharmaceutically acceptable salt described in claim 1-3 forms.
5. a use in conjunction compositions for antitumor drug, this use in conjunction compositions is the arbitrary Amido thiazole-pyridine heterocycle compound with activity of hedgehog path antagonist described in claim 1-4 and pharmaceutical composition carries out, with the combination of one or more in cisplatin, paclitaxel, camptothecine, Herceptin, imatinib mesylate, imatinib, gefitinib, erlotinib, Lapatinib, the compositions that use in conjunction obtains respectively.
6. the arbitrary use in conjunction compositions with the Amido thiazole-pyridine heterocycle compound of activity of hedgehog path antagonist, antitumor medicine composition or antitumor drug according to claim 1-5 treats the application in the medicine of tumor in preparation.
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