CN103923085A - Pyridine heterocyclic compounds having Hedgehog pathway antagonist activity, and use thereof - Google Patents

Pyridine heterocyclic compounds having Hedgehog pathway antagonist activity, and use thereof Download PDF

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CN103923085A
CN103923085A CN201410059077.6A CN201410059077A CN103923085A CN 103923085 A CN103923085 A CN 103923085A CN 201410059077 A CN201410059077 A CN 201410059077A CN 103923085 A CN103923085 A CN 103923085A
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alkane
thiazolinyl
group
alkynyl
sulfahydantoin
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CN103923085B (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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention provides pyridine heterocyclic compounds having a Hedgehog pathway antagonist activity. The compounds have a structure represented by general formula I. The pyridine heterocyclic compounds having a Hedgehog pathway antagonist activity can be used for preparing antitumor medicines.

Description

There is pyridine-heterocyclic compound of hedgehog path antagonistic activity and uses thereof
Technical field
The present invention relates to a class and there is pyridine-heterocyclic compound of hedgehog path antagonistic activity and uses thereof, belong to medical synthesis technical field.
Background technology
Malignant tumour is one of main disease of harm humans health, the annual malignant tumour new cases approximately 1,090 ten thousand in the whole world, and every year because of the dead patient approximately 6,700,000 of malignant tumour.Great variety had been experienced in antitumor drug research and development in recent years, was mainly cytotoxic drug with antitumor drug conventional on preclinical therapy, and this kind anti-cancer drugs has the poor selectivity, the toxic side effect that are difficult to avoid and by force, easily produces the shortcomings such as resistance.Along with the progress at full speed of life science, the various primary processes such as the interaction of the signal transduction in malignant cell, the regulation and control of cell cycle, apoptotic induction, vasculogenesis and cell and extracellular matrix are just progressively illustrated in recent years.Using the key enzyme of some intracellular signal transduction pathway relevant to tumour cell differentiation and proliferation as drug screening target spot, find that selectively acting is in specific target spot, possess pilot compound efficient, low toxicity character has become the important directions of current antitumor drug research and development simultaneously; Herceptin (trastuzumab), imatinib (imatinib), the successful listing of the targeted drugs such as Gefitinib (gefitinib) and erlotinib (erlotinib) is exactly typical example.
Shifting with regeneration is the feature of malignant tumour, is also a difficult problem for treatment malignant tumour.Even the targeted drug of a new generation is also very micro-with regeneration curative effect to the transfer of tumour.Based on this; the research of Hedgehog (Hh) signal path-hedgehog path has in recent years been subject to scientific circles and has more and more paid attention to; this is not only because Hh signal path abnormal activation comprises that in many tumours the generation evolution of rodent cancer, cerebral tumor, mammary cancer, prostate cancer and some alimentary system malignant tumours has all played very important effect; the more important thing is; Hh signal path is fetal development path; to regulation and control tumor stem cell, thereby control metastases and regeneration and play an important role.
Hedgehog signal path is the intercellular signal transduction system of a high conservative, within 1980, in fruit bat, find, because this pathway gene sudden change of fruit bat can cause larva body surface to reveal many furcellas that are similar to hedgehogs, therefore called after hedgehog path Hedgehog (Hh).Hh signal path is made up of Hh part, two transmembrane protein acceptor patchedmembranereceptor (PTCH) and smoothenedtransmembraneprotein (SMO) and downstream transcription factor Gli albumen etc.PTCH and SMO are two kinds of transmembrane proteins that are positioned on target cell membrane, and wherein PTCH is 12 transmembrane proteins of being encoded by cancer suppressor gene PTCH, is a kind of cell surface receptor, have the dual function of isolation and 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 play the effect of acceptor, the acceptor that wherein PTCH is Hh in Hh signal transduction process.In the time not there is not Hh, PTCH stops SMO to insert to cytolemma, thereby suppresses the activity of SMO; And then the transcriptional expression of inhibition downstream gene.When Hh signal exists, Hh is combined with PTCH, multiple serine/threonine residue generation phosphorylations of induction SMO carboxyl terminal, cause SMO assemble and activate at cell surface, the SMO activating and kinesin sample molecule Costal2 (Cos2) and serine/threonine kinases fused (Fus), Suppressoroffused (Sufu) form mixture and dissociate out from microtubule, with the form performance transcriptional activation of total length, finally cause that zinc refers to sample transcription factor Gli activation, and the latter enters and in nucleus, causes transcribing of target gene.Therefore, in Hh signal path, Hh is the starting point of this signal path, and Gli is the terminal of this signal path as transcription factor; Hh and SMO are as the exciting factor, and PTCH, as supressor, is regulating and controlling the activity of signal path.
Transmembrane protein acceptor SMO is as the key members of Hh signal path, it is the transcriber in Hh signal path, it can convert intracellular Gli1 signal to extracellular Hh signal, transcribes thereby active cell core is intragentic, and Hh signal path is had to activation.Most and Hh cell pathway activate the functional sudden change that all exists SMO in the generation, evolution of relevant tumour cell.Small molecules SMO protein antagonist is specific inhibition Hh signal path by antagonism SMO, and Hh signal path at normal adult in inactivated state, so antagonist can not have side effects to other positions of body, this is the theoretical basis of the magnetic target therapy feasibility of tumour.Therefore, SMO albumen has become one of target spot attracting people's attention most in current antitumor drug research and development, the synthetic research and development focus of Ge great drugmaker in the world that also becomes of the small molecular antagonists of target SMO albumen.
Have at least now the small molecular antagonists of 5 target SMO albumen carrying out clinical trial, the small molecules SMO antagonist GDC-0449 of the common research and development of Genentech company of the U.S. and Curis company, the treatment for rodent cancer patient in late period by the FDA of U.S. food Drug Administration approval in January, 2012.This proves that small molecules SMO antagonist has good using value and market outlook as the research and development of anti-cancer agent.
Small molecules SMO antagonist representative in clinical trial comprises following several:
Although vismodegib and other clinical compounds have good drug effect, they also have problem separately.Such as vismodegib physico-chemical property is poor, solubleness is low, has stronger side effect and has produced resistance etc.We have synthesized the brand-new hedgehog path antagonist of a class, are expected to solve the above problems.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art part, pyridine-heterocyclic compound that a class has hedgehog path antagonistic activity and uses thereof is provided.
Pyridine-heterocyclic compound of the present invention, it has the structure as shown in formula I:
Wherein,
A is N or C-R9;
R1, R2, R3, R4, R5, R6, R7, R8, R9 is selected from hydrogen atom, halogen, alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl group, fat base, sulfuryl, sulfoxide group, sulfahydantoin, azido-, alkane is for thiazolinyl, alkane is for alkynyl, and alkane is for amino, and alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, alkane is for sulfahydantoin, and alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring;
N is 0,1,2,3,4,5 or 6.
Preferably,
Pyridine-heterocyclic compound of the present invention, for thering is the structure shown in following general formula:
R9 is selected from any one in following group:
Wherein methylamine also can be replaced by lower class amine and their analogue:
R1 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl group, fat base, sulfuryl, sulfoxide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring;
Pyridine-heterocyclic compound of the present invention can also have the structure shown in following structural formula:
Pyridine-heterocyclic compound of the present invention can also have the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
Pyridine-heterocyclic compound of the present invention can also have the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
Pyridine-heterocyclic compound of the present invention can also have the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
Preferably,
This can be to have the compound shown in following any one structure for pyridine-heterocyclic compound of the present invention:
Being described as follows of above-mentioned each group:
Alkyl and alkane refer to the straight or branched of 1-10 carbon atom composition, ring-type, the hydrocarbon alkyl of double-ring and Spirocyclic for base.
Thiazolinyl and alkene refer to the straight or branched of 1-10 carbon atom composition for base, ring-type, and the hydrocarbon polymer of double-ring and Spirocyclic contains at least one carbon-carbon double bond.
Alkynyl and alkynes refer to the straight or branched of 1-10 carbon atom composition for base, ring-type, and the hydrocarbon polymer of double-ring and Spirocyclic contains at least one carbon carbon triple bond.
Halogen refers to fluorine, chlorine, bromine and iodine.
Heteroatoms refers to nitrogen, oxygen, and sulphur, comprises their various oxidation state, and the quaternary ammonium salt of nitrogen etc.
Aromatic nucleus refers to phenyl ring, and naphthalene nucleus and their substitutive derivative also refer to the derivative cyclic substituents of saturated rings and aromatic ring.
Heterocycle refers to nonaromatic monocycle, dicyclo, and three rings and volution contain 3-12 atom, comprising at least one nitrogen, the cyclic substituents of oxygen and sulphur and their various oxidation state forms.
Aromatic heterocycle refers to 5-12 former molecular ring, and comprising at least one nitrogen, the cyclic substituents of oxygen and sulphur and their various oxidation state forms, also refers to the derivative cyclic substituents of saturated rings and aromatic heterocycle.
The pyridine-heterocyclic compound that compound of the present invention has hedgehog path antagonistic activity has the purposes for the preparation of antitumor drug.
Compound of the present invention still comprises isotopic application, and common isotropic substance comprises but is not only limited to 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 32p, 35s, 36cl etc.
Compound of the present invention can be used for making pharmaceutically acceptable salt.
Compound of the present invention also comprises the various crystal formations of compound, the various isomer of various covering compounds, including, but not limited to, steric isomer, cis-trans-isomer, tautomer etc.
The pyridine-heterocyclic compound that compound of the present invention has hedgehog path antagonistic activity has the purposes for the preparation of antitumor drug, can be used for the Drug combination with one or more treatment tumours or other diseases.Wherein the medicine of one or more treatment tumours can be the medicines such as cis-platinum, taxol, Herceptin, imatinib mesylate.
Brief description of the drawings
Fig. 1 is the detected result graphic representation of test compound B1-5;
Fig. 2 is the detected result graphic representation of test compound B1;
Fig. 3 is the detected result graphic representation of test compound B3;
Fig. 4 is the detected result graphic representation of test compound B4;
Fig. 5 is the detected result graphic representation of test compound B5;
Fig. 6 is the detected result graphic representation of test compound B6;
Fig. 7 is the detected result graphic representation of test compound B2;
Fig. 8 is the detected result graphic representation of test compound B1-6.
Embodiment
In following examples, solvent for use and medicine are analytical pure or chemical pure; Solvent all passes through re-distillation before use; Anhydrous solvent is all processed 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 sherwood oil (60-90 DEG C)/ethyl acetate (v/v) as eluent; The ethanolic soln of iodine or phospho-molybdic acid for developer; All extraction solvent unexplained reference are all dry with anhydrous Na 2SO4.U.S. Varian unity INOVA400NB and Vnmrs high resolution NMR instrument record for 1HNMR, TMS is interior mark.Agilent company of the U.S. 1100 type HPLC-ESI-MSn combined instrument (LC-MSDTrap) records for LC-MS, diode-array detector (DAD), detect wavelength 214nM and 254nM, ion trap mass spectrometry (ESI source).HPLC post be Agela DurashellC18 (4.6 × 50mm, 3.5 μ m); Moving phase is the 0.1%TFA aqueous solution: acetonitrile (in 6 minutes from 5:95 to 95:5); Flow velocity is 1.2mL/min.
Embodiment 1
Synthetic route is as follows:
1) intermediate B 1-2's is synthetic:
B1-1(10g, 10.5mmol) be dissolved in glycol dimethyl ether, (product is cooled to 0 DEG C for (23.6g, 13.0mmol), stirring at room temperature 2.5 hours, stirs and within 30 minutes, obtains brown precipitate to add alpha-brominated Pyruvic Acid Ethyl ester.To be precipitated and dissolved in ethanol, and reflux and become clarification to solution in 2 hours.Underpressure distillation, raffinate is dissolved in methylene dichloride, washs with saturated solution of sodium bicarbonate.Dichloromethane layer dried over sodium sulfate, filters, filter cake washing with alcohol, filtrate decompression distillation.Obtain yellow solid (0.546g, 27%) through column chromatography (methylene dichloride: methyl alcohol=99:1-97:3). 1HNMR(400MHz,CDCl 3)δ9.21(s,1H),8.26(s,1H),8.09(dd,J=4.7,1.6Hz,1H),7.96(d,J=4.7Hz,1H),4.49(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H)。
2) intermediate B 1-3's is synthetic:
B1-2 (1g, 5.2mmol) is dissolved in 50 milliliters of ethanol, adds BOC acid anhydrides, Pd/C (200mg), system hydrogen exchange three times, react under room temperature 24 hours.Product filters, and by washing with alcohol, filtrate is spin-dried for.Obtain yellow oil B1-3(0.973g, 63% through column chromatography (methylene dichloride: methyl alcohol=50:1)). 1HNMR(400MHz,CDCl 3)δ7.51（s，1H),4.68(s,2H),4.30(q,J=7.1Hz,2H),4.00(t,J=5.2Hz,2H),3.82(t,J=5.2Hz,2H),1.43(s,9H),1.21(t,J=7.1Hz,3H)。
3) intermediate B 1-4's is synthetic:
By B1-3(50mg, 0.17mmol) be dissolved in after a small amount of methylene dichloride, add the saturated ethyl acetate solution (3mL) of hydrogenchloride, stirring at normal temperature 3 hours, desolventizing is revolved in decompression, and solute joins saturated sodium bicarbonate aqueous solution and washes in (5mL) and methylene dichloride (20mL), and saturated aqueous common salt for organic phase (10mL) is washed, after filtering, anhydrous sodium sulfate drying obtains a white solid (27mg, 83%).
4) intermediate B 1-5's is synthetic:
B1-4(385mg, 4.0mmol), cesium fluoride (300mg, 4.0mmol) and A1-9(500mg, 1.98mmol) under agitation condition, be dissolved in methyl-sulphoxide (1mL) respectively, be heated to 120 DEG C, react 12 hours.Be cooled to room temperature, add ethyl acetate (50mL) and water (15mL), saturated aqueous common salt for organic phase (15mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains product (0.7g, 85%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:50). 1HNMR(400MHz,CDCl 3)δ8.37(s,1H),8.26(s,1H),7.58(s,1H),7.47(s,1H),6.65(s,1H),4.75(s,2H),4.36(q,J=7.2Hz,2H),4.34(brs,4H),2.62(s,3H),2.20(s,3H),1.39(t,J=7.1Hz,3H)；
ESI-MS(m/z):411.8[M+1] +。
5) intermediate B 1-6's is synthetic:
700 milligrams of B1-5(1.7mmol) be dissolved in the lithium hydroxide aqueous solution of tetrahydrofuran (THF) and 2M, stirred overnight at room temperature, regulating pH value with the hydrochloric acid of 1M is 7.0, with anti-phase (water: methyl alcohol=45:55) purifying, solution is spin-dried for and obtains white solid (450mg, 70%). 1HNMR(400MHz,CDCl 3):δ8.40(s,1H),8.21(s,1H),7.49(s,1H),7.44(s,1H),6.68(s,1H),4.69(s,2H),4.11(br,4H),2.37(s,3H),2.17(s,3H)；ESI-MS(m/z):383.8[M+1] +。
6) product B 1 is synthetic:
B1-6 (50mg, 0.131mmol), Pyrrolidine (10mg, 0.14mmol), N, N`-diisopropylethylamine (18.5mg, 0.14mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(55mg, 0.14mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (10mL), with saturated aqueous common salt (5mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains colourless oil liquid (15mg, 26%) through silicagel column (methylene dichloride: methyl alcohol=50:1) purifying. 1HNMR(400MHz,CDCl 3):δ8.36(s,1H),8.24(s,1H),7.53(s,1H),7.44(s,1H),6.68(s,1H),4.72(s,2H),4.15(br,4H),3.95(t,J=6.4Hz,2H),3.63(t,J=6.4Hz,2H),2.39(s,3H),2.18(s,3H)1.93-1.87(m,4H)；ESI-MS(m/z):436.8[M+1] +。
Embodiment 2
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 2.Synthetic route is as follows:
B1-6 (50mg, 0.131mmol), 4-hydroxy piperidine (14mg, 0.14mmol), N, N`-diisopropylethylamine (18.5mg, 0.14mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(55mg, 0.14mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (10mL), with saturated aqueous common salt (5mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains colourless oil liquid (20mg, 33%) through silicagel column (methylene dichloride: methyl alcohol=50:1) purifying. 1HNMR(400MHz,CDCl 3):δ8.34(s,1H),8.24(s,1H),7.52(s,1H),7.44(s,1H),6.63(s,1H),4.63(s,2H),4.14(br,4H),3.91(m,1H),3.60(br,1H),3.25(br,1H),2.38(s,3H),2.17(s,3H)1.93(m,2H),1.56(m,2H)；ESI-MS(m/z):466.8[M+1] +。
Embodiment 3
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 3.Synthetic route is as follows:
B1-6 (50mg, 0.131mmol), morpholine (22mg, 0.253mmol), N, N`-diisopropylethylamine (32mg, 0.246mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(60mg, 0.157mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid (32mg, 54%) through silicagel column (methylene dichloride: methyl alcohol=50:1 is to 20:1) purifying. 1HNMR(400MHz,CDCl 3):δ8.41(s,1H),8.30(s,1H),7.53(s,2H),6.76(s,1H),4.81(s,2H),4.21(s,4H),3.80(m,8H),2.46(s,3H),2.25(s,3H)；ESI-MS(m/z):452.8[M+1] +。
Embodiment 4
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 4.Synthetic route is as follows:
B1-6 (50mg, 0.131mmol), methylamine hydrochloride (18mg, 0.265mmol), N, N`-diisopropylethylamine (68mg, 0.524mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(60mg, 0.157mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid (32mg, 62%) through silicagel column (methylene dichloride: methyl alcohol=50:1 is to 20:1) purifying. 1HNMR(400MHz,CDCl 3):δ8.41(s,1H),8.28(s,1H),7.64(brs,1H),7.54(s,1H),6.74(s,1H),4.89-4.69(m,2H),4.20(s,4H),2.95(s,3H),2.45(s,3H),2.23(s,3H)；ESI-MS(m/z):396.8[M+1] +。
Embodiment 5
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 5.Synthetic route is as follows:
B1-6 (50mg, 0.131mmol), 2,6-dimethyl-piperizine (20mg, 0.175mmol), N, N`-diisopropylethylamine (23mg, 0.177mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(65mg, 0.171mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40ml), with saturated aqueous common salt (15mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid (45mg, 72%) through silicagel column (methylene dichloride: methyl alcohol=20:1 is to 10:1) purifying. 1HNMR(400MHz,CDCl 3):δ8.32(s,1H),8.30(s,1H),7.72(s,1H),7.60(s,1H),7.02(s,1H),4.77(s,2H),4.12(d,J=4.8Hz,2H),4.07(d,J=4.0Hz,2H),2.34(s,3H),2.09(s,3H),1.21(s,6H)；ESI-MS(m/z):479.8[M+1] +。
Embodiment 6
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 6.Synthetic route is as follows:
B1-6 (50mg, 0.131mmol), N-methyl amido ethanol (29mg, 0.387mmol), N, N`-diisopropylethylamine (36mg, 0.277mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(65mg, 0.171mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40ml), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid (40mg, 69%) through silicagel column (methylene dichloride: methyl alcohol=20:1 is to 10:1) purifying. 1HNMR(400MHz,CDCl 3)δ8.33-8.30(m,1H),8.29(s,1H),7.59(s,2H),7.07(s,1H),4.77(s,2H),4.14-4.03(m,4H),3.80(brs,1H),3.63-3.49(m,4H),2.99-2.87(m,2H),2.33(s,3H),2.09(s,3H)；ESI-MS(m/z):440.8[M+1] +。
Embodiment 7
Obtain intermediate B 1-6 according to the method in embodiment 1 is synthetic, then prepare product B 7.Synthetic route is as follows:
B1-6 (38mg, 0.099mmol), ethylamine hydrochloride (17mg, 0.21mmol), N, N`-diisopropylethylamine (61mg, 0.47mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(46mg, 0.12mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains colorless oil B7 (20mg, 49%) through silicagel column (methylene dichloride: methyl alcohol=40:1) purifying. 1HNMR(400MHz,CDCl 3)δ8.29(s,1H),8.18(s,1H),7.44(s,1H),7.39(s,1H),7.00(s,1H),6.60(s,1H),4.64(s,2H),4.07(s,4H),3.37(t,J=6.4Hz,2H),2.32(s,3H),2.10(s,3H),1.14(t,J=6.8Hz,3H)；ESI-MS(m/z):410.8[M+1] +。
Embodiment 8
Obtain intermediate B 1-3 according to the method in embodiment 1 is synthetic, then prepare product B 8.Synthetic route is as follows:
1) intermediate B 8-1's is synthetic
By B1-3 (50mg, 0.17mmol) be dissolved in anhydrous tetrahydro furan (2mL), under ice-water bath, slowly add Lithium Aluminium Hydride (13mg, 0.34mmol) in batches, this mixed solution is stirred 30 minutes at 0 DEG C, and some plate demonstration reaction is carried out complete.Under stirring, in reaction solution, slowly add 2mL ethyl acetate, then add saturated sodium bicarbonate aqueous solution, until generate without precipitation.Stop stirring, add anhydrous sodium sulphate, filter, filtrate is under reduced pressure revolved steaming, and except desolventizing, solute obtains white solid (30mg, 69.8%) through column chromatography (methylene dichloride: methyl alcohol=50:1). 1HNMR(400MHz,CDCl 3)δ6.81(s,1H),4.67(s,2H),4.57(s,2H),3.95(t,J=4.6Hz,2H),3.84(d,J=4.0Hz,2H),1.48(s,9H)。
2) intermediate B 8-2's is synthetic
B8-1 (200mg, 0.79mmol) is dissolved in 4mL ethyl acetate, adds ethyl acetate (4mL) solution of 3M hydrogenchloride.Under room temperature, react 2h, desolventizing is revolved in decompression, and solute obtains yellow oil (100mg, 82.6%) through column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=100:10:1). 1HNMR(400MHz,CDCl 3)δ6.77(s,1H),4.57(s,2H),4.09(s,2H),3.94(t,J=5.4Hz,2H),3.24(t,J=5.2Hz,2H)。
3) B8's is synthetic
B8-2(46mg, 0.3mmol), cesium fluoride (50mg, 0.329mmol) and A1-9(41mg, 0.162mmol) under agitation condition, be dissolved in methyl-sulphoxide (1mL) respectively, be heated to 120 DEG C, react 48 hours.Be cooled to room temperature, add ethyl acetate (10mL) and water (5mL), saturated aqueous common salt for organic phase (5mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains a green oily matter (20mg, 33.37%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:100). 1HNMR(400MHz,CDCl 3)δ8.35(s,1H),8.24(s,1H),7.44(s,1H),6.84(s,1H),6.65(s,1H),4.70(s,2H),4.58(s,2H),4.15(s,2H),4.09(d,J=4.0Hz,2H),2.38(s,3H),2.16(s,3H)；ESI-MS(m/z):370.1[M+1] +。
Embodiment 9
Obtain intermediate B 8-1 according to the method in embodiment 1 and 8 is synthetic, then prepare product B 9.Synthetic route is as follows:
1) intermediate B 9-1's is synthetic:
At B8-1 (400mg, in methylene dichloride (4mL) solution 1.579mmol), add triethylamine (320mg, 3.158mmol), then under agitation in ice-water bath, dropwise add methylsulfonyl chloride (199mg, 1.737mmol), this mixed solution at room temperature stirs 30 minutes.Point plate shows that reaction is complete.Be cooled to room temperature, add 10mL ethyl acetate, with 3mL water washing 2 times.Organic layer under reduced pressure revolves steaming, obtains crude product (440mg), directly throws the next step.
2) intermediate B 9-2's is synthetic
B9-1 (440mg, 1.33mmol) and salt of wormwood (395mg, 3.98mmol) are dissolved in 8mLDMF, under normal temperature, add morpholine (347mg, 3.98mmol), at 100 DEG C, stir 2h.Point plate shows that reaction is complete, adds ethyl acetate 20mL and water 5mL, with 5mL salt water washing three times.Organic layer under reduced pressure revolves steaming, and solute obtains brown oil (220mg, 51.43%) through column chromatography (methylene dichloride: methyl alcohol=50:1). 1HNMR(400MHz,CDCl 3)δ6.75(s,1H),4.67(s,2H),3.95(t,J=5.0Hz,2H),3.83(t,J=5.4Hz,2H),3.74-3.72(m,4H),3.45(s,2H),2.53(s,4H),1.48(s,9H)。
3) intermediate B 9-3's is synthetic
B9-2 (170mg, 0.527mmol) is added to the ethyl acetate solution of 3M hydrogenchloride.Under room temperature, react 3h, desolventizing is revolved in decompression, and solute obtains yellow oil (110mg, 94.87%) through column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=100:10:1). 1HNMR(400MHz,CDCl 3)δ6.71(s,1H),4.08(s,2H),3.92(t,J=5.4Hz,2H),3.72(t,J=4.6Hz,4H),3.44(s,2H),3.23(t,J=5.6Hz,2H),2.52(s,4H)。
4) B9's is synthetic:
B9-3 (46mg, 0.3mmol), cesium fluoride (150mg, 0.987mmol) and A1-9 (40mg, 0.158mmol) are dissolved in methyl-sulphoxide (1mL) respectively under agitation condition, are heated to 120 DEG C, react 48 hours.Be cooled to room temperature, add ethyl acetate (10mL) and water (5mL), saturated aqueous common salt for organic phase (5mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains a green oily matter (11mg, 15.82%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:100). 1HNMR(400MHz,CDCl 3)δ8.34(s,1H),8.24(s,1H),7.43(s,1H),7.00(s,1H),6.63(s,1H),4.68(s,2H),4.14(s,2H),4.08(s,2H),3.83(s,4H),3.66(s,2H),2.73(s,4H),2.38(s,3H),2.16(s,3H)；ESI-MS(m/z):438.8[M+1] +。
Embodiment 10
Synthetic route is as follows:
1) intermediate B 10-1's is synthetic
B1-1(10g, 10.5mmol) be dissolved in 80mL pyridine, add Tosyl chloride (22g, 115.4mmol).Stirring at room temperature 80 minutes, decompression steams pyridine, in solute, adds 1L water, and mixture stirring at room temperature, after one hour, is filtered, and gained solid with the ether washing of 100mL water and 200mL, is dried and obtains yellow solid (19g, 72.4%) successively. 1HNMR(400MHz,CDCl 3)δ8.74(s,1H),8.29(d,J=5.6Hz,2H),7.80(d,J=7.6Hz,2H),7.29(s,1H),2.40(s,3H)。
2) intermediate B 10-2's is synthetic
B10-1 (8.6g, 34.5mmol) is dissolved in 60mLDMF, adds iodo-acetamide (7g, 37.8mmol) and N, N-di-isopropyl ethanamide (6.6mL, 37.9mmol), and stirring at normal temperature 28 hours, reacts complete.In reaction solution, add 40mL water, stirring at normal temperature 100 minutes, leaves standstill, and filters, and the water of 200mL and the washing of the ether of 100mL for gained solid, obtain gray solid (7g, 64.3%).
3) intermediate B 10-3's is synthetic
B10-2 (7.14g, 23.3mmol) is dissolved in 110mL methylene dichloride, adds 43mL trifluoro-acetic anhydride, back flow reaction 2 hours at 50 DEG C.Revolve and steam solvent, in raffinate, add 220mL ethyl acetate, the sedimentation and filtration of generation, gained solid washs by ethyl acetate, obtains gray solid (5.2g, 96.9%). 1HNMR(400MHz,DMSO-d6)δ12.71(s,1H),8.98(s,1H),8.63(d,J=4.8Hz,1H),8.40(s,1H),7.93(d,J=4.4Hz,1H)。
4) intermediate B 10-4's is synthetic
B10-3 (5.2g, 22.61mmol) is dissolved in 130mL methyl alcohol, adds 780 milligrams of Pd/C (humidity 50%), reacts 10h passing under hydrogen.Reaction product is through diatomite filtration, and by methanol wash, filtrate is under reduced pressure revolved and steamed except desolventizing.Solute obtains white solid (1.3g, 24.6%) through column chromatography (methylene dichloride: methyl alcohol=30:1). 1HNMR(400MHz,CDCl 3)δ9.74(s,1H),7.29(s,1H),4.02(s,2H),3.96(t,J=5.4Hz,2H),3.27(t,J=5.4Hz,2H)。
5) B10's is synthetic
B10-4 (800mg, 3.1mmol), cesium fluoride (2g, 12.8mmol) and A1-9 (500mg, 2.1mmol) are dissolved in methyl-sulphoxide (6mL) respectively under agitation condition, are heated to 120 DEG C, react 48 hours.Be cooled to room temperature, add ethyl acetate (100mL) and water (50mL), saturated aqueous common salt for organic phase (50mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains yellow solid (250mg, 26%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:50). 1HNMR(400MHz,CDCl 3)δ10.76(s,1H),8.34(s,1H),8.25(d,J=2.8Hz,1H),7.43(s,1H),7.36(d,J=2.4Hz,1H),6.64(s,1H),4.63(s,2H),4.11(s,4H),2.37(s,3H),2.16(s,3H)；ESI-MS(m/z):450.7[M+1] +。
Embodiment 11
Obtain intermediate B 10-3 according to the method in embodiment 10 is synthetic, then prepare product B 11.Synthetic route is as follows:
1) intermediate B 11-1's is synthetic
By B10-3(4.2g, 18.26mmol) be dissolved in 50mL methyl alcohol, under normal temperature, add 20mL ammoniacal liquor, this mixed solution return stirring 6 hours at 70 DEG C.Cooling, vacuum rotary steam, removes methyl alcohol.Solute obtains yellow solid (1.2g, 44%) through column chromatography (methylene dichloride: methyl alcohol=30:1). 1HNMR(400MHz,CDCl 3)δ8.74(s,1H),7.88(d,J=4.8Hz,1H),7.79(d,J=4.4Hz,1H),7.01(s,1H),4.20(s,2H)。
2) intermediate B 11-2's is synthetic
By B11-1 (300mg, 2.238mmol), propionic acid (216mg, 2.91mmol), HATU(1.1g, 2.91mmol), N, N`-diisopropylethylamine (432mg, 3.36mmol) be dissolved in N, in N`-dimethyl formamide (5mL), mixture at room temperature stirs 24 hours.Add ethyl acetate (150mL) and water (40mL), saturated aqueous common salt for organic phase (40mL) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains product (200mg, 47%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:60). 1HNMR(400MHz,CDCl 3)δ8.90(s,1H),8.57(s,1H),8.21(s,1H),8.05(d,J=4.8Hz,1H),7.91(d,J=4.4Hz,1H),2.50(q,J=7.6Hz,2H),1.28(t,J=7.6Hz,3H)。
3) intermediate B 11-3's is synthetic
B11-2 (150mg, 0.79mmol) is dissolved in 10mL methyl alcohol, adds 15mg platinum dioxide, system hydrogen exchange three times, react 48h under room temperature.Product filters, and by methanol wash, filtrate is spin-dried for.Obtain white solid (110mg, 73%) through column chromatography (methylene dichloride: methyl alcohol=30:1).
4) B11's is synthetic
B11-3 (40mg, 0.206mmol), cesium fluoride (188mg, 1.236mmol) and A1-9 (104mg, 0.412mmol) are dissolved in respectively in methyl-sulphoxide (1.5mL) under agitation condition, be heated to 120 DEG C, react 48 hours.Be cooled to room temperature, add ethyl acetate (30mL) and water (5mL), saturated aqueous common salt for organic phase (5mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains green solid (20mg, 23.6%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:60). 1HNMR(400MHz,CDCl 3)δ8.35(s,1H),8.25(s,1H),8.22(s,1H),7.44(s,1H),7.25(s,1H),6.65(s,1H),4.63(s,2H),4.12(s,2H),4.07(d,J=4.0Hz,2H),2.38-2.35(m,5H),2.17(s,3H),1.22(t,J=7.8Hz,3H)；ESI-MS(m/z):410.9[M+1] +。
Embodiment 12
Obtain intermediate B 11-1 according to the method in embodiment 10 and 11 is synthetic, then prepare product B 12.Synthetic route is as follows:
1) intermediate B 12-1's is synthetic
By B11-1 (200mg, 1.5mmol), methoxyacetic acid (175.5mg, 1.95mmol), HATU(741mg, 1.95mmol), N, N`-diisopropylethylamine (290mg, 2.25mmol) be dissolved in N, in N`-dimethyl formamide (3mL), mixture at room temperature stirs 24 hours.Add ethyl acetate (150mL) and water (40mL), saturated aqueous common salt for organic phase (40mL) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains product (160mg, 51.8%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:60). 1HNMR(400MHz,CDCl 3)δ9.43(s,1H),8.95(s,1H),8.25(s,1H),8.05(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),4.11(s,2H),3.53(s,3H)。
2) intermediate B 12-2's is synthetic
B12-1 (120mg, 0.79mmol) is dissolved in 10mL methyl alcohol, adds 15mg platinum dioxide, system hydrogen exchange three times, react 48h under room temperature.Product filters, and by methanol wash, filtrate is spin-dried for.Obtain B11-3 (80mg, 73%) through column chromatography (methylene dichloride: methyl alcohol=30:1). 1HNMR(400MHz,CDCl 3)δ8.64(s,1H),7.21(s,1H),4.02(s,2H),4.00(s,2H),3.92(t,J=5.2Hz,2H),3.46(s,3H),3.24(t,J=5.4Hz,2H)。
3) B12's is synthetic
B12-2 (55mg, 0.262mmol), cesium fluoride (239mg, 1.57mmol) and A1-9 (165.6mg, 0.655mmol) are dissolved in respectively in methyl-sulphoxide (1.5mL) under agitation condition, be heated to 120 DEG C, react 48 hours.Be cooled to room temperature, add ethyl acetate (30mL) and water (5mL), saturated aqueous common salt for organic phase (5mL) is washed, after anhydrous sodium sulfate drying filters, revolve desolventizing, solute obtains green solid (20mg, 18%) through column chromatography refining (moving phase is methyl alcohol: methylene dichloride=1:60). 1HNMR(400MHz,CDCl 3)δ8.65(s,1H),8.36(s,1H),8.26(s,1H),7.44(s,1H),7.29(s,1H),6.65(s,1H),4.64(s,2H),4.15-4.07(m,4H),4.02(s,2H),3.47(s,3H),2.39(s,3H),2.18(s,3H)；ESI-MS(m/z):426.8[M+1] +。
Embodiment 13
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 13.Synthetic route is as follows:
B1-6(20mg, 0.052mmol) be dissolved in 2mL Virahol, under ice bath, add thionyl chloride (12mg, 0.11mmol), mixture refluxes at 84 DEG C.Vacuum rotary steam, removes Virahol, drips 4M aqueous sodium hydroxide solution to PH7, adds ethyl acetate (20mL), and water (10mL × 3) is washed, then uses saturated aqueous common salt (10mL × 3) to wash.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B13 (10mg, 45.2%) through silicagel column (methylene dichloride: methyl alcohol=80:1) purifying. 1HNMR(300MHz,CDCl 3)δ8.34(s,1H),8.24(s,1H),7.56(s,1H),7.43(s,1H),6.62(s,1H),5.34-5.18(m,1H),4.74(s,2H),4.16(s,4H),2.38(s,3H),2.16(s,3H),1.37(s,3H),1.35(s,3H)；ESI-MS(m/z):425.8[M+1] +。
Embodiment 14
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 14.Synthetic route is as follows:
B1-6(20mg, 0.052mmol) be dissolved in 2mL cyclopropyl-carbinol, under ice bath, add thionyl chloride (12mg, 0.11mmol), mixture refluxes at 84 DEG C.Vacuum rotary steam, removes Virahol, drips 4M aqueous sodium hydroxide solution to PH7, adds ethyl acetate (20mL), and water (10mL × 3) is washed, then uses saturated aqueous common salt (10mL × 3) to wash.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B14 (8mg, 36.3%) through silicagel column (methylene dichloride: methyl alcohol=80:1) purifying. 1HNMR(300MHz,CDCl 3)δ8.35(s,1H),8.25(s,1H),7.59(s,1H),7.44(s,1H),6.63(s,1H),4.74(s,2H),4.23-4.10(m,6H),2.39(s,3H),2.16(s,3H),1.32-1.19(m,1H),0.62-0.54(m,2H),0.38-0.30(m,2H)；ESI-MS(m/z):437.8[M+1] +。
Embodiment 15
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 15.Synthetic route is as follows:
B1-6(30mg, 0.078mmol), cyclopentanol (13mg, 0.16mmol) and DMAP (14mg, 0.12mmol) be dissolved in methylene dichloride, ice bath adds I-hydroxybenzotriazole (17mg under stirring, 0.13mmol) and dicyclohexylcarbodiimide (24mg, 0.12mmol), mixture at room temperature stirs 2 days.Add ethyl acetate (20mL) and water (10mL), saturated aqueous common salt for organic phase (10mL × 3) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains white solid B15 (10mg, 28.4%) through column chromatography refining (methylene dichloride: methyl alcohol=80:1). 1HNMR(300MHz,CDCl 3)δ8.35(s,1H),8.24(s,1H),7.53(s,1H),7.44(s,1H),6.63(s,1H),5.38(s,1H),4.73(s,2H),4.16(s,4H),2.38(s,3H),2.16(s,3H),2.08-1.92(m,2H),1.89-1.73(m,4H),1.59-1.56(m,2H)；ESI-MS(m/z):451.8[M+1] +。
Embodiment 16
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 16.Synthetic route is as follows:
B1-6(20mg, 0.026mmol), phenol (10mg, 0.10mmol) and DMAP (10mg, 0.078mmol) be dissolved in methylene dichloride, ice bath adds I-hydroxybenzotriazole (10.6mg under stirring, 0.078mmol) and dicyclohexylcarbodiimide (16mg, 0.078mmol), mixture at room temperature stirs 6 hours.Add ethyl acetate (20mL) and water (10mL), saturated aqueous common salt for organic phase (10mL × 3) is washed, and anhydrous sodium sulfate drying revolves desolventizing after filtering, solute obtains white solid B16 (16mg, 66.9%) through column chromatography refining (methylene dichloride: methyl alcohol=80:1). 1HNMR(300MHz,CDCl 3)δ8.35(s,1H),8.26(s,1H),7.74(s,1H),7.47-7.33(m,3H),7.30-7.15(m,3H),6.66(s,1H),4.78(s,2H),4.21(s,4H),2.38(s,3H),2.17(s,3H)；ESI-MS(m/z):459.8[M+1] +。
Embodiment 17
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 17.Synthetic route is as follows:
B1-6 (20mg, 0.052mmol), aniline (5.3mg, 0.057mmol), N, N`-diisopropylethylamine (7.4mg, 0.057mmol) is dissolved in N, N`-dimethyl formamide (1mL).HATU(22mg, 0.057mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (20mL), with saturated aqueous common salt (10mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B17 (14mg, 58.7%) through silicagel column (methylene dichloride: methyl alcohol=80:1) purifying. 1HNMR(300MHz,CDCl 3)δ8.87(s,1H),8.36(s,1H),8.27(s,1H),7.70(s,1H),7.68(s,1H),7.59(s,1H),7.45(s,1H),7.38-7.29(m,2H),7.14-7.06(m,1H),6.69(s,1H),4.75(s,2H),4.18(s,4H),2.39(s,3H),2.18(s,3H)；ESI-MS(m/z):458.8[M+1] +。
Embodiment 18
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 18.Synthetic route is as follows:
B1-6 (20mg, 0.052mmol), 2-fluoroaniline (6.4mg, 0.057mmol), N, N`-diisopropylethylamine (7.4mg, 0.057mmol) is dissolved in N, N`-dimethyl formamide (1mL).HATU(22mg, 0.057mmol) add in solution, under room temperature, stir 2 days.Reaction solution adds in ethyl acetate (20mL), with saturated aqueous common salt (10mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B18 (5mg, 20.2%) through silicagel column (methylene dichloride: methyl alcohol=80:1) purifying. 1HNMR(300MHz,CDCl 3)δ9.16(s,1H),8.53-8.45(m,1H),8.36(s,1H),8.27(s,1H),7.60(s,1H),7.44(s,1H),7.18-6.98(m,3H),6.70(s,1H),4.75(s,2H),4.19(s,4H),2.39(s,3H),2.18(s,3H)；ESI-MS(m/z):476.8[M+1] +。
Embodiment 19
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 19.Synthetic route is as follows:
B1-6 (20mg, 0.052mmol), 4-fluoroaniline (6.4mg, 0.057mmol), N, N`-diisopropylethylamine (7.4mg, 0.057mmol) is dissolved in N, N`-dimethyl formamide (1mL).HATU(22mg, 0.057mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (20mL), with saturated aqueous common salt (10mL × 3) washing.Organic phase is with filtering after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B18 (18mg, 72.6%) through silicagel column (methylene dichloride: methyl alcohol=80:1) purifying. 1HNMR(300MHz,CDCl 3)δ8.85(s,1H),8.36(s,1H),8.27(s,1H),7.69-7.61(m,2H),7.59(s,1H),7.44(s,1H),7.08-6.96(m,2H),6.69(s,1H),4.74(s,2H),4.18(s,4H),2.39(s,3H),2.17(s,3H)；ESI-MS(m/z):476.8[M+1] +。
Embodiment 20
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 20.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), cyclopropyl methylamine (12mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B20(12mg, 21% through silicagel column (methylene dichloride: methyl alcohol=40:1) purifying). 1HNMR(400MHz,CDCl 3)δ8.35(s,1H),8.26(s,1H),7.50(s,1H),7.44(s,1H),7.12(s,1H),6.67(s,1H),4.72(s,2H),4.15(s,4H),3.26(t,J=6.4Hz,2H),2.39(s,3H),2.17(s,3H),1.48(m,1H),0.55-0.50(m,2H),0.27-0.23(m,2H);ESI-MS(m/z):437.4[M+1]+.
Embodiment 21
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 21.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), 3-hydroxy azetidine hydrochloride (19mg, 0.17mmol), N, N`-diisopropylethylamine (52mg, 0.40mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B21(10mg, 17% through silicagel column (methylene dichloride: methyl alcohol=30:1) purifying). 1HNMR(400MHz,DMSO-d6)δ8.32(s,1H),8.30(s,1H),7.75(s,1H),7.60(s,1H),7.00(s,1H),4.78(s,2H),4.66(m,1H),4.53(s,1H),4.25(s,2H),4.15(s,2H),4.06(s,2H),3.78(s,2H),2.34(s,3H),2.09(s,3H);ESI-MS(m/z):439.3[M+1]+.
Embodiment 22
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 22.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), 3-hydroxyl pyrrolidine (15mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B22(12mg, 20% through silicagel column (methylene dichloride: methyl alcohol=30:1) purifying). 1HNMR(400MHz,DMSO-d6)δ8.32(s,1H),8.30(s,1H),7.64(s,1H),7.60(s,1H),7.02(s,1H),4.94(s,1H),4.78(s,2H),4.29(d,J=18.8Hz,1H),4.13-4.07(m,4H),3.87(s,2H),3.54-3.47(m,2H),2.34(s,3H),2.10(s,3H),1.94-1.80(m,2H);ESI-MS(m/z):453.3[M+1]+.
Embodiment 23
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 23.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), (R)-2-(methoxyl methyl)-tetramethyleneimine (20mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B23(11mg, 17% through silicagel column (methylene dichloride: methyl alcohol=40:1) purifying). 1HNMR(400MHz,CDCl 3)δ8.36(s,1H),8.23(s,1H),7.59(s,1H),7.46(s,1H),6.71(s,1H),5.08(m,2H),4.64(s,1H),4.29(s,2H),4.09(s,2H),3.74(s,3H),3.38(m,1H),3.35(s,1H),3.21(s,1H),3.19(s,1H),2.39(s,3H),2.18(s,3H),2.07(s,2H),1.94(s,2H);ESI-MS(m/z):481.4[M+1]+.
Embodiment 24
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 24.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), m-fluoroaniline (19mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B24(28mg, 45% through silicagel column (sherwood oil: ethyl acetate=3:1) purifying). 1HNMR(400MHz,CDCl 3)δ8.92(s,1H),8.36(s,1H),8.27(s,1H),7.67(d,J=11.2Hz,1H),7.60(s,1H),7.45(s,1H),7.30(t,J=7.2Hz,2H),6.80(t,J=7.8Hz,1H),6.69(s,1H),4.75(s,2H),4.19(s,4H),2.39(s,3H),2.18(s,3H);ESI-MS(m/z):477.3[M+1]+.
Embodiment 25
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 25.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), 3,4-difluoroaniline (22mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B25(30mg, 46% through silicagel column (sherwood oil: ethyl acetate=3:1) purifying). 1HNMR(400MHz,CDCl 3)δ8.86(s,1H),8.36(s,1H),8.27(s,1H),7.80(m,1H),7.59(s,1H),7.44(s,1H),7.21(m,1H),7.12(q,J=9.2Hz,1H),6.69(s,1H),4.74(s,2H),4.18(s,4H),2.39(s,3H),2.17(s,3H);ESI-MS(m/z):495.3[M+1]+.
Embodiment 26
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 26.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), PA (16mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B26(26mg, 43% through silicagel column (methylene dichloride: methyl alcohol=30:1) purifying). 1HNMR(400MHz,CDCl 3)δ9.47(s,1H),8.35(d,J=6.4Hz,1H),8.31(m,1H),8.26(s,1H),7.70(m,1H),7.61(s,1H),7.44(s,1H),7.01(m,1H),6.68(s,1H),4.70(s,2H),4.18(s,4H),2.38(s,3H),2.17(s,3H);ESI-MS(m/z):460.3[M+1]+.
Embodiment 27
Obtain intermediate B 6-1 according to the method in embodiment 1 is synthetic, then prepare product B 27.Synthetic route is as follows:
B1-6 (50mg, 0.13mmol), 3-aminopyridine (16mg, 0.17mmol), N, N`-diisopropylethylamine (26mg, 0.20mmol) is dissolved in N, N`-dimethyl formamide (1.5mL).HATU(64mg, 0.17mmol) add in solution, under room temperature, stir and spend the night.Reaction solution adds in ethyl acetate (40mL), with saturated aqueous common salt (15mL × 3) washing.Organic phase is filtered after anhydrous sodium sulfate drying, and filtrate decompression is concentrated, obtains white solid B27(31mg, 51% through silicagel column (methylene dichloride: methyl alcohol=30:1) purifying). 1HNMR(400MHz,CDCl 3)δ8.91(s,1H),8.72(d,J=2.4Hz,1H),8.35(s,1H),8.34(d,J=4.8Hz,1H),8.31(d,J=8.8Hz,1H),8.27(s,1H),7.61(s,1H),7.44(s,1H),7.29(m,1H),6.69(s,1H),4.75(s,2H),4.19(s,4H),2.39(s,3H),2.18(s,3H);ESI-MS(m/z):460.3[M+1]+.
Embodiment 28 bioassays
1, NIH3T3-GRE-Luc luciferase reporter gene test experience
NIH3T3 cell is to cultivate in the DMEM that contains 10%FBS (Hyclone) (11965, Gibico).GRE-firefly luciferin plasmid is to implant in MCS and obtain via the cell transcription factor GLI-1 response element that amplifies octuple.Mono-clonal is that the small molecules agonist SAG being shown below through recombinate Su Nike hedgehog path albumen and structural formula verifies.The selected clone who is verified is for detection of hedgehog path signal.
The NIH3T3 cell of expressing GRE-Lampyridea element is to maintain in complete nutrient solution.In the time that needs do analyzing and testing, cell is added in 96 orifice plates, and final every hole is containing cell approximately 15,000.96 orifice plates are being cultivated 48 hours.Detected compound is by DMSO and detect damping fluid by serial dilution.10nMSAG is as hedgehog path agonist.The analysis buffer that 100 microlitres include test compound and agonist subsequently carefully joins and contains in cell in 96 orifice plates, and cultivates 48 hours at 37 degrees Celsius.
Cultivating after 48 hours, 40 microlitre Photinus pyralis LUCs are added in each hole.At room temperature jog 5 minutes of 96 orifice plates.Luminous signal is by reading plate device record.The activity of compound is calculated by its blocking-up to luminous signal, and the compound of synthesized is tested, and result is as following table:
The above results demonstration, 12 in 21 compounds having surveyed have activity, wherein B1-5, B1, B6, B17 has reached 300 nmoles, has good hedgehog path antagonistic effect.
The antagonist relation of hedgehog path signal intensity in compound concentration and cell has been set up in above-mentioned experiment.The vismodegib going on the market taking success in 2012 is as standard substance.This test highly sensitive, favorable reproducibility, is suitable for the screening of the hedgehog path antagonist to cell.

Claims (7)

1. a class has the pyridine-heterocyclic compound of hedgehog path antagonistic activity, it is characterized in that, it has the structure as shown in formula I:
Wherein,
A is nitrogen-atoms or C-R9;
R1, R2, R3, R4, R5, R6, R7, R8, R9 is selected from hydrogen atom, halogen, alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl group, fat base, sulfuryl, sulfoxide group, sulfahydantoin, azido-, alkane is for thiazolinyl, alkane is for alkynyl, and alkane is for amino, and alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, alkane is for sulfahydantoin, and alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring;
N is 0,1,2,3,4,5 or 6.
2. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, has the structure shown in following general formula:
R9 is selected from any one in following group:
Wherein methylamine also can be replaced by lower class amine and their analogue:
R1 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, sulfydryl, alkoxyl group, fat base, sulfuryl, sulfoxide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
3. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, has the structure shown in following structural formula:
4. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, has the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
5. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, has the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
6. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, has the structure shown in following arbitrary general formula:
Wherein, R9 is selected from hydrogen atom, halogen, and alkane is for halogen, cyano group, alkane is for cyano group, trifluoromethyl, alkyl, thiazolinyl, alkynyl, amino, hydroxyl, alkoxyl group, fat base, sulfuryl, sulfoxide group, amide group, sulfahydantoin, azido-, alkane is for thiazolinyl, and alkane is for alkynyl, and alkane is for amino, alkane is for hydroxyl, and alkane is for fat base, and alkane is for sulfuryl, and alkane is for sulfoxide group, and alkane is for sulfahydantoin, alkane is for azido-, cyclic alkyl, ring-type thiazolinyl, 3-12 heterocycle, aromatic nucleus or 5-12 hetero-aromatic ring.
7. the pyridine-heterocyclic compound with hedgehog path antagonistic activity according to claim 1, is characterized in that, described compound is to have the compound shown in following any one structural formula:
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