CN106565673A - 5-fluoropyrimidine heterocyclic compound with Wnt signal path inhibitory activity and application of 5-fluoropyrimidine heterocyclic compound - Google Patents

5-fluoropyrimidine heterocyclic compound with Wnt signal path inhibitory activity and application of 5-fluoropyrimidine heterocyclic compound Download PDF

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CN106565673A
CN106565673A CN201610850360.XA CN201610850360A CN106565673A CN 106565673 A CN106565673 A CN 106565673A CN 201610850360 A CN201610850360 A CN 201610850360A CN 106565673 A CN106565673 A CN 106565673A
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heterocyclic compound
wnt signal
sodium sulfate
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CN106565673B (en
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张小虎
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SUZHOU YUNXUAN PHARMACEUTICAL Co Ltd
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SUZHOU YUNXUAN PHARMACEUTICAL Co Ltd
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Priority to US15/766,799 priority patent/US10450300B2/en
Priority to KR1020187013073A priority patent/KR20180061363A/en
Priority to EP16854369.2A priority patent/EP3359154B1/en
Priority to PCT/US2016/055851 priority patent/WO2017062688A1/en
Priority to JP2018518629A priority patent/JP6853819B2/en
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
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    • 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
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Abstract

The invention provides a 5-fluoropyrimidine heterocyclic compound with Wnt signal path inhibitory activity. The heterocyclic compound and the salt, isotope, isomer and crystal structure, which are medically acceptable, of the heterocyclic compound have the structure shown in the general formula I. The invention further provides application of the above 5-fluoropyrimidine heterocyclic compound with Wnt signal path inhibitory activity. The 5-fluoropyrimidine heterocyclic compound with Wnt signal path inhibitory activity serves as effective antagonist of a Wnt signal path and can be used for treating or preventing diseases caused by the abnormity of the Wnt signal path.

Description

5-FU heterocyclic compound with Wnt signal path inhibitory activity and its application
Technical field
The present invention relates to a kind of 5-FU heterocyclic compound with Wnt signal path inhibitory activity and its application, category In pharmaceutical technology field.
Background technology
The discovery of earliest Wnt signal paths is from the research to oncogenic viruss and fruit bat developmental mechanism.Wnt genes in Nineteen eighty-two finds, is initially certified as the site of mouse mammary tumor viruses preferential incorporation, and the gene can be in cell Between transmission propagation and break up information, be a kind of oncogene, be named as Int genes (mice Int-1 and Int-3) at that time.Subsequently It was found that it belongs to identical sources gene (orthologousgene) with the aptery gene (wingless) of fruit bat, so as to the two is tied Conjunction is named as Wnt genes.So far have found and clone 19 kinds of Wnt gene family members, by the people letter mediated by Wnt genes Number Signal Transduction Pathways are referred to as Wnt signal paths.Wnt paths are a very conservative signal transduction pathway.From unicellular lower eukaryote fruit bat Up to higher mammal, its member has the homology of height.Wnt signal transduction pathways take part in various biological process Regulation and control, including the growth and morphological development of embryo, the stable of tissue, the maintenance of the balance of energy metabolism and stem cell (Logan et al., Annu.Rev.Cell.Dev.Biol., 2004,20,781-810).People are being ground to stem cell in recent years Study carefully middle discovery, Wnt signal paths are for epidermal stem cells, intestinal stem cell, hematopoietic stem cell, neural stem cell, embryonic stem cell And the maintenance of tumor stem cell all plays important regulating and controlling effect (Reya et al., Nature, 2005,434,843-850).
Classical Wnt signal path is by the outer part Wnts albumen of after birth while Frizzled receptors with 7 cell transmembrane The conduction of rear unlatching Wnt/ β-catenin signal paths is combined with complementary receptor LRP5/6, and activates Dsh albumen in kytoplasm, The Dsh albumen of activation can suppress in the degraded complex formed by APC albumen, GSK-3 β, Axin, β-catenin etc. it is crucial into The activity of point GSK-3 β, makes β-catenin not by GSK-3 β phosphorylations so as to avoiding Ubiquitin-proteasome which being recognized and drop Solution, and then build up in kytoplasm (Boutros et al., Mech.Dev., 1999,83,27-37；Perrimon, Cell, 1994,76,781-784).Begin to when β-catenin accumulate to finite concentration in endochylema to cell nuclear transfer, and and born of the same parents Transcription factor TCF/LEFs in core combines the startup factor of the downstream target gene for causing β-cateninn and comes out and swashed Expression living, such as activates c-myc, cyclin-D1, survivin, gastrin, VEGF, ASEF etc. and causes abnormal cell proliferation. And in normal somatic cell, intracytoplasmic β-catenin are most of to be tied with after birth attachment proteinses E-cadherin and α-catenin Conjunction forms the regulation that complex participates in cytoskeleton, maintains homocellular adhesion, prevents cell from shifting, and the free β of small part- Catenin is degraded in endochylema after complex phosphorylation and is recognized and degraded by Ubiquitin-proteasome, keeps intracellular β-catenin Low-level state, so that Wnt signal paths are closed.
Research find when Wnt genes itself or path other any member factors change make its abnormal activation when, It is possible to cause the generation of tumor.For example, be widely present in colorectal cancer patients Wnt paths regulatory factor include APC, β- The isogenic mutation of catenin, Axin, TCF, so as to cause to grow related gene overexpression (Klaus et al., Nat.Rev.Cancer,2008,8,387-398).Lozzo etc. is swollen by and tumor tissues normal to more than 100 parts and 10 mankind The research of oncocyte system finds the excessive table that there is Wnt-5amRNA in breast carcinoma, pulmonary carcinoma, carcinoma of prostate and melanoma Reach, especially the abnormal expression in breast carcinoma substantially (Lozzo et al., Cancer Research, 1995,55,3495).
The abnormal activation of Wnt approach has important function during cell carcinogenesis, tumor generation and tumor invasiveness, and The abnormal Wnt signal paths of blocking can suppress tumor cell proliferation, inducing apoptosis of tumour cell.Therefore, Wnt signal paths tool There is preferable antineoplastic target effect.
Research shows that LRP5 overexpression causes in Wnt signal paths abnormal Wnt signals and certain cancers are associated (Hoang et al., Int.J.Cancer, 2004,109,106-111).Such as carcinoma of prostate, colorectal carcinoma, ovarian cancer, the esophageal carcinoma And gastric cancer.
β-catenin activation Wnt signal paths can increase the circulation and amplification of neural progenitor cell, and lacking to cause ancestral thin Intercellular every disappearance (Chenn et al., Science, 2002,297,365-369).The abnormal activation of Wnt signals is in nervous system In be tumorigenesis (Dahmen et al., Cancer Res., 2001,61,7039-7043).
Wnt signal paths can promote the renewal and maintenance of multipotential hemopoietic stem cell, and abnormal Wnt signals for by Caused by multipotential hemopoietic stem cell the various diseases cancer related to other blood it is responsible (Reya et al., Nature, 2005,434,843-850；Willert et al., Nature, 2003,423,448-452).
The imbalance of Wnt signal transductions also can cause sugar by induced retinal inflammation, vascular leakage and neovascularization The development of urine characteristic of disease retinopathy.
In recent years, immunotherapy of tumors becomes study hotspot.The main policies of immunotherapy of tumors are to utilize immunologic test Point inhibitor, monoclonal antibody of such as CTLA-4, PD-1 and PD-L1 etc., the activation of immunosuppressant receptor on blocking t cell.This strategy Effect is significant (the particularly tumor of T cell infiltration) in the patient of kinds of tumors (such as melanoma and pulmonary carcinoma), but do not having In having the tumor tissues of T cell infiltration, usually antineoplastic immune.Research show (Stefani Spranger et al., Nature, 2015,523,231-235), in T cell infiltration and the patient's sample of the melanoma without T cell infiltration, 49% soaks without T cell There is high-caliber active β-catenin in the melanoma of profit, and the patient of T cell infiltration only has 4%.The Wnt/ β of activation- Catenin signal paths make CD103+ dendritic cell (DC cells, the whistle of T cell immunity are defended) raise and be obstructed in tumor, thus T cell activation is obstructed and can not infiltrate tumor.Therefore, Wnt signal paths are suppressed to will be helpful to strengthen immunologic test point inhibitor Antitumous effect.Wnt signal path inhibitor has addition with the use in conjunction of immunologic test point inhibitor, better than the two Be used alone.
Therefore, improve because of the not normal disease for causing of above-mentioned Wnt signal paths, it is necessary to propose effective Wnt Signal path regulator.
The content of the invention
In view of the defect that above-mentioned prior art is present, the purpose of the present invention is to propose to a kind of suppress with Wnt signal paths The 5-FU heterocyclic compound of activity and its application, should the 5-FU heterocyclic compound with Wnt signal path inhibitory activity Thing can effective antagonism Wnt signal paths, can be used in treating or prevent because of the not normal disease for causing of Wnt signal paths
The purpose of the present invention is achieved by the following technical programs：
A kind of 5-FU heterocyclic compound with Wnt signal path inhibitory activity, and its pharmaceutically acceptable salt, Isotope, isomer and crystalline structure, with the structure shown in formula I：
Wherein, A is by 1-3 R41-4 is contained in substituent group or unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 units Individual heteroatomic hetero-aromatic ring, the hetero atom of the hetero-aromatic ring include one or more in N, O and S；
B is hydrogen atom, cyano group, halogen, hydroxyl, C1-8Alkyl, C3-8Cycloalkyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Alkoxyl, C2-8Ester group, by 1-3 R5Substituent group Or unsubstituted phenyl ring, by 1-3 R5Substituent group or unsubstituted 5-6 units containing 1-3 heteroatomic hetero-aromatic rings or By 1-3 R5Substituent group or unsubstituted 5-7 units are containing 1-2 heteroatomic saturated heterocyclic, the hetero-aromatic ring and heterocycle Hetero atom include in N, O and S one or more；
U is by 1-3 R6Substituent group or unsubstituted 6-12 units aromatic ring, 5-12 units hetero-aromatic ring, 5-7 circle heterocycles acenes Ring or 5-7 circle heterocycles 5-6 units hetero-aromatic ring, the heterocycle, hetero-aromatic ring contain the 1-4 hetero atom for being independently selected from N, O and S；
R1、R2、R3Separately selected from hydrogen atom, be substituted with a substituent or unsubstituted base replace C1-6Alkyl, institute Stating substituent group includes halogen, hydroxyl, cyano group, C1-3Alkyl, C3-5Cycloalkyl and C1-31-3 in alkoxyl；
R4、R5、R6Halogen, cyano group, hydroxyl, C are selected from separately1-8Alkyl, C3-8Cycloalkyl, C1-8Alkoxyl, C2-8Alkene Base, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Ester group, C2-8Contain 1-3 heteroatomic Heterocyclylalkyls, the hetero atom include one or more in N, O and S；
Or, R4、R5、R6Separately selected from by hydrogen, halogen, hydroxyl, cyano group, C1-3Alkyl, C1-3Alkoxyl and C3-8 The C of 1-3 substituent group in cycloalkyl1-8Alkyl, C3-8Cycloalkyl, C1-8Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Ester group, C2-8Containing 1-3 heteroatomic heterocycle alkane Base, the hetero atom include one or more in N, O and S；
R7Selected from hydrogen atom, D-atom, tritium atom, halogen, hydroxyl, cyano group, C1-8Alkyl, C3-8Cycloalkyl or C1-8Alcoxyl Base.
It is in the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity, described by 1-3 R4Group Replace or unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 unit is containing 1-4 heteroatomic hetero-aromatic ring, refer to by 1-3 R4 Substituent group or unsubstituted 6 yuan of aromatic rings, by 1-3 R4Substituent group or unsubstituted 10 yuan of aromatic rings or by 1-3 R4Base Group replaces or unsubstituted 5-10 units are containing 1-4 heteroatomic hetero-aromatic ring；
It is described by 1-3 R6Substituent group or unsubstituted 6-12 units aromatic ring, 5-12 units hetero-aromatic ring, 5-7 circle heterocycles are simultaneously Phenyl ring or 5-7 circle heterocycles 5-6 units hetero-aromatic ring, refer to by 1-3 R6Substituent group or unsubstituted 6-12 unit aromatic ring, by 1- 3 R6Substituent group or unsubstituted 5-12 unit hetero-aromatic ring, by 1-3 R6Substituent group or unsubstituted 5-7 circle heterocycles are simultaneously Phenyl ring or by 1-3 R6Substituent group or unsubstituted 5-7 circle heterocycles 5-6 units hetero-aromatic ring；
It is described by hydrogen, halogen, hydroxyl, cyano group, C1-3Alkyl, C1-3Alkoxyl and C3-81-3 substituent group in cycloalkyl C1-8Alkyl, C3-8Cycloalkyl, C1-8Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxygen For urea groups, C1-8Sulfoamido, C1-8Ester group, C2-8Containing 1-3 heteroatomic Heterocyclylalkyl, C is referred to1-8Alkyl, C3-8Cycloalkanes Base, C1-8Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfonamide Base, C1-8Ester group and C2-8Containing 1-3 heteroatomic Heterocyclylalkyl by hydrogen, halogen, hydroxyl, cyano group, C1-3Alkyl, C1-3Alkoxyl And C3-81-3 substituent group in cycloalkyl.
In the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity, it is preferred that U is by 1-3 R6Any one in substituent group or unsubstituted following groups：
In the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity, it is preferred that A is by 1-3 R4Any one in substituent group or unsubstituted following groups：
In the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity, it is preferred that B is following base Any one in group：
In the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity, it is preferred that the heterocyclic compound Thing includes：
The present invention also provides the joint of the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity should With compositionss, including by the described 5-FU heterocyclic compound with Wnt signal path inhibitory activity and its pharmaceutically may be used The salt of acceptance, isotope, isomer or crystal formation and antitumor drug, antibacterials, antiviral drugs, medicine for parasitic disease, The combination of one or more in central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament carries out joint should With the compositionss for obtaining.
The present invention also provides the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity and its pharmacy The upper application of acceptable salt, isotope, isomer or crystal formation in the medicine for preparing antagonism Wnt signal paths；
In above-mentioned application, it is preferred that the medicine of the antagonism Wnt signal paths includes breast carcinoma, pulmonary carcinoma, wing for treatment Guang cancer, cancer of pancreas, hepatocarcinoma, head and neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate Cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, gastric cancer, myeloma, lymphoma, lymphoma mantle cell, cutaneous T-cell Lymphoma, chronic and non-progressive anemia, spontaneity or primary thrombocytosiss, idiopathic myelofibrosis, lung fiber Change, renal fibrosiss, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute white blood Disease, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative disease, cerebroma, Astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, pituitary tumor and parasitic disease, schistosomicide A kind of medicine of the combination of disease or several diseases in disease and malaria.
The present invention also provides the joint of the above-mentioned 5-FU heterocyclic compound with Wnt signal path inhibitory activity should With application of the compositionss in the medicine for preparing antagonism Wnt signal paths.
In above-mentioned application, it is preferred that the medicine of the antagonism Wnt signal paths includes breast carcinoma, pulmonary carcinoma, wing for treatment Guang cancer, cancer of pancreas, hepatocarcinoma, head and neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate Cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, gastric cancer, myeloma, lymphoma, lymphoma mantle cell, cutaneous T-cell Lymphoma, chronic and non-progressive anemia, spontaneity or primary thrombocytosiss, idiopathic myelofibrosis, lung fiber Change, renal fibrosiss, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute white blood Disease, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative disease, cerebroma, Astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, pituitary tumor and parasitic disease, schistosomicide A kind of medicine of the combination of disease or several diseases in disease and malaria.
With according to specific embodiment, in the present invention, it is preferred that isotope includes but is not limited solely to2H,3H,11C,13C,14C ,15N,17O,18O,18F,32P,35S,36Cl etc..Various isomers, including but not limited to stereoisomer, cis-trans-isomer, mutually Tautomeric etc..
The present invention prominent effect be：
The 5-FU heterocyclic compound with Wnt signal path inhibitory activity of the present invention, as Wnt signal paths Effectively antagonist, can be used in treating or prevents because of the not normal disease for causing of Wnt signal paths.
Description of the drawings
Fig. 1 is the test result curve chart of heterocyclic compound A12 in embodiment 2；
Fig. 2 is the test result curve chart of heterocyclic compound A36 in embodiment 2.
Specific embodiment
In order to be more clearly understood to the technical characteristic of the present invention, purpose and beneficial effect, now to skill of the invention Art scheme carry out it is described further below, but it is not intended that to the present invention can practical range restriction.Institute in following embodiments Experimental technique is stated, if no special instructions, conventional method is；The reagent and material, if no special instructions, can be from business way Footpath obtains.
In following embodiments, solvent for use and medicine are and analyze pure or chemical pure；Solvent is being passed through using front Re-distillation；Anhydrous solvent is processed according to standard method or literature method.Column chromatography silica gel (100-200 mesh) and thin layer Chromatographic silica gel (GF254) is Haiyang Chemical Plant, Qingdao and Yantai chemical plant product；If not otherwise specified, using petroleum ether (60- 90 DEG C)/ethyl acetate (v/v) is used as eluant；The ethanol solution of developer iodine or phosphomolybdic acid；All extractants are without saying It is bright to use anhydrous Na2SO4It is dried.1HNMR is recorded with varian-400 types nuclear magnetic resonance analyser, and TMS is internal standard.The LC-MS U.S. Agilent companies 1100 type HPLC- ESI- MSn combined instrument (LC-MSDTrap) record, photodiode array detection Device (DAD), Detection wavelength 214nm and 254nm, ion trap mass spectrometry (ESI sources).HPLC column is AgelaDurashellC18 (4.6 × 50mm, 3.5 μm)；Mobile phase is 0.1%NH4HCO3 aqueous solutions：Acetonitrile is (from 5 in 5 minutes：95 to 95: 5)；Flow velocity is 1.8mL/min。
Embodiment 1
The present embodiment provides the 5-FU heterocyclic compound A1-A96 with Wnt signal path inhibitory activity and its synthesis Method.
(1) heterocyclic compound A1, which synthesizes by the following method：
1) synthesis of intermediate A 1-2:
Compound A1-1 (6.9g, 40mmol), duplex pinacol borate are added in the round-bottomed flask of 250mL (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd (dppf)2Cl2(1.63g, 2.0mmol) and tetrahydrofuran (100mL), Nitrogen displacement, is refluxed overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate be spin-dried for obtaining dark oil crude product (15.6g, Content:27%), it is directly used in next step.
2) synthesis of intermediate A 1-3：
Crude intermediate A1-2 (8g, 27%, 9.86mmol) is dissolved in into dioxane/water (100mL/20mL), it is right to add Bretylium tosylate (1.65g, 8.88mmol), potassium carbonate (2.72g, 19.73mmol), Pd (dba)2(567mg, 0.99mmol) and SPhos (810mg, 1.97mmol), nitrogen displacement, 80 DEG C of reactions are overnight.Room temperature is cooled to, with suction filtered through kieselguhr, filtrate addition 100mL water, ethyl acetate (150mL × 3) extraction merge organic faciess saturated aqueous common salt (300mL × 2) and wash, organic faciess nothing Aqueous sodium persulfate is dried, and filters sodium sulfate, is spin-dried for ethyl acetate, residue Jing column chromatography purification (dichloromethane:Methanol=50:1- 30:1 ammonification water), obtain brown solid (1.27g, 72%).
3) synthesis of intermediate A 1-4：
By intermediate A 1-3 (100mg, 0.51mmol), 4,6- bis- chloro- 5-FUs (101mg, 0.61mmol) are dissolved in four Hydrogen furan (10mL), adds diisopropyl ethyl amine (260mg, 2.02mmol), and 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain pale solid (140mg, 84%).1HNMR (400MHz, CDCl3) δ 8.54 (d, J=5.2Hz, 1H), 8.23 (s, 1H), 7.62 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 7.36 (s, 1H), 7.30 (d, J=5.2Hz, 1H), 5.60 (s, 1H), 4.79 (d, J=6.0Hz, 2H), 2.62 (s, 3H).
4) synthesis of product A1：
Intermediate A 1-4 (66mg, 0.20mmol), 2- naphthalene boronic acids (52mg, 0.30mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (116mg, 0.84mmol), four triphenyl phosphorus palladiums (12mg, 0.010mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, and with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate is done It is dry, sodium sulfate is filtered, solvent, residue Jing column chromatography purification (dichloromethane is spin-dried for:Methanol=200:1-50:1), obtain white Solid (45mg, 54%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A1
(2) heterocyclic compound A2, which synthesizes by the following method：
1) synthesis of intermediate A 2-2：
Compound A2-1 (100mg, 0.48mmol) is dissolved in into tetrahydrofuran (10mL), duplex pinacol borate is added (146mg, 0.58mmol), KOAc (141mg, 1.44mmol), Pd (dppf)2Cl2(39mg, 0.048mmol), nitrogen displacement are returned Night is flow through, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (250mg), be directly used in down One step.
2) synthesis of product A2：
By A1-4 (66mg, 0.20mmol), A2-2 (150mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C are stirred overnight, cooling To room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (64mg, 79%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A2
(3) heterocyclic compound A3, which synthesizes by the following method：
1) synthesis of intermediate A 3-2：
Compound A-13-1 (105mg, 0.51mmol) is dissolved in into dioxane (10mL), duplex pinacol borate is added (191mg, 0.75mmol), KOAc (147mg, 1.50mmol), Pd (dppf)2Cl2(20mg, 0.024mmol), nitrogen displacement, 90 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (360mg), directly use In next step.
2) synthesis of product A3：
By A1-4 (50mg, 0.15mmol), A3-2 (360mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cooling To room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain brown solid (40mg, 63%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A-13
(4) heterocyclic compound A4, which synthesizes by the following method：
1) synthesis of intermediate A 4-2：
Compound A4-1 (210mg, 1.01mmol) is dissolved in into tetrahydrofuran (10mL), duplex pinacol borate is added (760mg, 2.99mmol), KOAc (150mg, 1.53mmol), Pd (dppf)2Cl2(80mg, 0.10mmol), nitrogen displacement are returned Night is flow through, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, residue Jing column chromatography purification (petroleum ether:Ethyl acetate= 10:1), obtain colorless oil (240mg, 93%).
2) synthesis of product A4：
Intermediate A 1-4 (50mg, 0.15mmol), intermediate A 4-2 (57mg, 0.22mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (83mg, 0.60mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (53mg, 83%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A4
(5) heterocyclic compound A5, which synthesizes by the following method：
1) synthesis of intermediate A 5-2：
A5-1 (22mg, 0.099mmol) is dissolved in into dioxane (2mL), add duplex pinacol borate (30mg, 0.12mmol), KOAc (29mg, 0.30mmol), Pd (dppf)2Cl2(8mg, 0.01mmol), nitrogen displacement, 90 DEG C of stirrings 4 are little When, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (60mg), be directly used in next step.
2) synthesis of product A5：
A1-4 (20mg, 0.061mmol), A5-2 (60mg, crude product) are dissolved in into dioxane/water (2mL/0.4mL), are added Potassium carbonate (34mg, 0.24mmol), four triphenyl phosphorus palladiums (7mg, 0.006mmol), nitrogen displacement, 100 DEG C are stirred overnight, cooling To room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (10mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (15mg, 58%).Jing Nuclear magnetic spectrum parsing (spectrum data is shown in Table 1) is crossed, resulting solid is compound A-45
(6) heterocyclic compound A6, which synthesizes by the following method：
1) synthesis of intermediate A 6-2：
A6-1 (210mg, 1.01mmol) is dissolved in into tetrahydrofuran (10mL), add duplex pinacol borate (305mg, 1.20mmol), KOAc (294mg, 3.00mmol), Pd (dppf)2Cl2(80mg, 0.10mmol), nitrogen displacement flow back overnight, Room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, residue Jing column chromatography purification (petroleum ether:Ethyl acetate=4:1), obtain To yellow gummy solid (270mg, 106%).
2) synthesis of product A6：
By A1-4 (50mg, 0.15mmol), A6-2 (114mg, 0.45mmol) is dissolved in dioxane/water (5mL/1mL), plus Enter potassium carbonate (83mg, 0.60mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, Room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is revolved Dry solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (48mg, 75%). (spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A6
(7) heterocyclic compound A7, which synthesizes by the following method：
1) synthesis of intermediate A 7-2：
A7-1 (150mg, 0.72mmol) is dissolved in into dioxane (10mL), add duplex pinacol borate (220mg, 0.87mmol), KOAc (212mg, 2.16mmol), Pd (dppf)2Cl2(59mg, 0.072mmol), nitrogen displacement, 90 DEG C of stirrings Overnight, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (409mg), be directly used in next Step.
2) synthesis of product A7：
By A1-4 (66mg, 0.20mmol), A7-2 (409mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C are stirred overnight, cooling To room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (50mg, 59%).Jing Nuclear magnetic spectrum parsing (spectrum data is shown in Table 1) is crossed, resulting solid is compound A7
(8) heterocyclic compound A8, which synthesizes by the following method：
1) synthesis of intermediate A 8-2：
A8-1 (63mg, 0.30mmol) is dissolved in into dioxane (6mL), add duplex pinacol borate (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(25mg, 0.03mmol), nitrogen displacement, 90 DEG C of stirrings 2 are little When, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (160mg), be directly used in next step.
2) synthesis of product A8：
By A1-4 (66mg, 0.20mmol), A8-2 (160mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (110mg, 080mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to Room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (60mg, 71%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A-28
(9) heterocyclic compound A9, which synthesizes by the following method：
1) synthesis of intermediate A 9-2：
A9-1 (63mg, 0.30mmol) is dissolved in into dioxane (5mL), add duplex pinacol borate (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(25mg, 0.03mmol), nitrogen displacement, 90 DEG C of stirrings 4 are little When, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (183mg), be directly used in next step.
2) synthesis of product A9：
By A1-4 (50mg, 0.15mmol), A9-2 (183mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cooling To room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (35mg, 55%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A9
(10) heterocyclic compound A10, which synthesizes by the following method：
1) synthesis of intermediate A 10-2：
A10-1 (250mg, 0.84mmol) is dissolved in into dioxane (5mL), add duplex pinacol borate (257mg, 1.01mmol), KOAc (247mg, 2.53mmol), Pd (dppf)2Cl2(68mg, 0.084mmol), nitrogen displacement, 100 DEG C of stirrings Overnight, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (556mg), be directly used in next Step.
2) synthesis of product A10：
A1-4 (50mg, 0.15mmol), A10-2 (200mg, crude product) are dissolved in into dioxane/water (5mL/1mL), are added Potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cold But room temperature is arrived, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-20:1), obtain pale solid (31mg, 50%). (spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A10
(11) heterocyclic compound A11, which synthesizes by the following method：
1) synthesis of intermediate A 11-2：
A11-1 (60mg, 0.31mmol) is dissolved in into dioxane (5mL), add duplex pinacol borate (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf)2Cl2(25mg, 0.031mmol), nitrogen displacement, 90 DEG C of stirrings 4 Hour, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (190mg), be directly used in next Step.
2) synthesis of product A11：
A1-4 (50mg, 0.15mmol), A11-2 (190mg, crude product) are dissolved in into dioxane/water (5mL/1mL), are added Potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cold But room temperature is arrived, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30:1), obtain pale solid (22mg, 35%). (spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A11
(12) heterocyclic compound A12, which synthesizes by the following method：
1) synthesis of intermediate A 12-2：
A12-1 (43mg, 0.20mmol) is dissolved in into dioxane (4mL), add duplex pinacol borate (61mg, 0.24mmol), KOAc (59mg, 0.60mmol), Pd (dppf)2Cl2(16mg, 0.02mmol), nitrogen displacement, 90 DEG C of stirrings 4 are little When, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (126mg), be directly used in next step.
2) synthesis of product A12：
A1-4 (50mg, 0.15mmol), A12-2 (126mg, crude product) are dissolved in into dioxane/water (5mL/1mL), are added Potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cold But room temperature is arrived, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (28mg, 43%). (spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A12
(13) heterocyclic compound A13, which synthesizes by the following method：
1) synthesis of intermediate A 13-2：
A13-1 (300mg, 1.52mmol) is dissolved in into DMSO (10mL), add duplex pinacol borate (570mg, 2.24mmol), KOAc (440mg, 4.49mmol), Pd (dppf)2Cl2(60mg, 0.073mmol), nitrogen displacement, 90 DEG C of stirrings 24 hours, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (20mL), saturated aqueous common salt (20mL × 3) Wash, anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, (dichloromethane is to dichloromethane for residue Jing column chromatographies purification: Methanol=100:1), obtain brown oil (300mg, 81%).
2) synthesis of product A13：
A1-4 (66mg, 0.20mmol), A13-2 (146mg, 0.60mmol) are dissolved in into dioxane/water (5mL/1mL), Addition potassium carbonate (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C are stirred overnight, Room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-25:1), obtain white solid (40mg, 49%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A13
(14) heterocyclic compound A14, which synthesizes by the following method：
1) synthesis of intermediate A 14-2 and A14-3：
A14-1 (590mg, 2.99mmol) is dissolved in into tetrahydrofuran (10mL), NaH is added in the case where ice bath is stirred (180mg80%, 6.00mmol), stirring added CH after 30 minutes3I (468mg, 3.30mmol), continues stirring 3 hours, is raised to Room temperature, adds water (20mL), ethyl acetate (20mL × 3) extraction, organic faciess saturated aqueous common salt (50mL × 3) to wash, anhydrous sulfur Sour sodium is dried, and is spin-dried for solvent, residue Jing column chromatography purification (petroleum ether:Ethyl acetate=10：1-3：1), obtain A14-2 (230mg, 36%) and A14-3 (330mg, 52%).
A14-2：Pale solid.1HNMR (400MHz, DMSO) δ 8.33 (s, 1H), 7.96-7.95 (m, 1H), 7.57 (d, J=9.2Hz, 1H), 7.31-7.28 (m, 1H), 4.16 (s, 3H).
A14-3：White solid.1HNMR (400MHz, DMSO) δ 8.03 (s, 1H), 7.99 (d, J=1.6Hz, 1H), 7.64 (d, J=8.8Hz, 1H), 7.51-7.49 (m, 1H), 4.04 (s, 3H).
2) synthesis of intermediate A 14-4：
A14-2 (190mg, 0.90mmol) is dissolved in into DMSO (10mL), add duplex pinacol borate (274mg, 1.08mmol), KOAc (265mg, 2.70mmol), Pd (dppf)2Cl2(37mg, 0.045mmol), nitrogen displacement, 90 DEG C of stirrings Overnight, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (20mL), and saturated aqueous common salt (20mL × 3) is washed, Anhydrous sodium sulfate drying, filters sodium sulfate, is spin-dried for solvent and obtains dark oil thing (410mg), is directly used in next step.
3) synthesis of product A14：
By A1-4 (66mg, 0.20mmol), A14-4 (400mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds carbon Sour potassium (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to Room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, Residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain pale solid (50mg, 59%).Through core Magnetic spectrum analysis (spectrum data is shown in Table 1), resulting solid are compound A14
(15) heterocyclic compound A15, which synthesizes by the following method：
1) synthesis of intermediate A 15-1：
A14-3 (63mg, 0.30mmol) is dissolved in into DMSO (6mL), add duplex pinacol borate (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf)2Cl2(25mg, 0.03mmol), nitrogen displacement, 90 DEG C are stirred At night, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and saturated aqueous common salt (15mL × 3) is washed, nothing Aqueous sodium persulfate is dried, and filters sodium sulfate, is spin-dried for solvent and obtains dark oil thing (120mg), be directly used in next step.
2) synthesis of product A15：
A1-4 (50mg, 0.15mmol), A15-1 (120mg, crude product) are dissolved in into dioxane/water (5mL/1mL), are added Potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cold But room temperature is arrived, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (53mg, 82%).Jing Nuclear magnetic spectrum parsing (spectrum data is shown in Table 1) is crossed, resulting solid is compound A15
(16) heterocyclic compound A16, which synthesizes by the following method：
1) synthesis of intermediate A 16-2：
A16-1 (73mg, 0.32mmol) is dissolved in into dioxane (4mL), add duplex pinacol borate (98mg, 0.39mmol), KOAc (95mg, 0.97mmol), Pd (dppf)2Cl2(26mg, 0.032mmol), nitrogen displacement, 90 DEG C of stirrings 4 Hour, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is spin-dried for, obtains crude product dark oil thing (213mg), be directly used in next Step.
2) synthesis of product A16：
A1-4 (50mg, 0.15mmol), A16-2 (213mg, crude product) are dissolved in into dioxane/water (5mL/1mL), are added Potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, cold But room temperature is arrived, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain brown oil (48mg, 74%).Through Nuclear magnetic spectrum parses (spectrum data is shown in Table 1), and resulting solid is compound A16
(17) heterocyclic compound A17, which synthesizes by the following method：
A1-4 (50mg, 0.152mmol), phenylboric acid (28mg, 0.23mmol) are dissolved in into dioxane/water (5mL/1mL), Addition potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, Room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=150:1-100:1), obtain white solid (30mg, 54%).Jing Nuclear magnetic spectrum parsing (spectrum data is shown in Table 1) is crossed, resulting solid is compound A17
(18) heterocyclic compound A18, which synthesizes by the following method：
A1-4 (50mg, 0.15mmol), adjacent chlorophenylboronic acid (28mg, 0.18mmol) are dissolved in into dioxane/water (5mL/ 1mL), potassium phosphate (64mg, 0.30mmol), Pd (dppf) are added2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, with suction filtered through kieselguhr, filtrate ethyl acetate (15mL) dilute, anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:First Alcohol=100:1), obtain pale solid (15mg, 24%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, it is resulting Solid is compound A18
(19) heterocyclic compound A19, which synthesizes by the following method：
A1-4 (50mg, 0.15mmol), a chlorophenylboronic acid (28mg, 0.18mmol) are dissolved in dioxane/water (5mL/ 1mL), potassium phosphate (64mg, 0.304mmol), Pd (dppf) are added2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, with suction filtered through kieselguhr, filtrate ethyl acetate (15mL) dilute, anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:First Alcohol=100:1), obtain white solid, with n-hexane/ethyl acetate be recrystallized to give white solid (15mg, 24%).Through core Magnetic spectrum analysis (spectrum data is shown in Table 1), resulting solid are compound A19
(20) heterocyclic compound A20, which synthesizes by the following method：
A1-4 (50mg, 0.15mmol), is dissolved in dioxane/water (5mL/ to chlorophenylboronic acid (28mg, 0.18mmol) 1mL), potassium phosphate (64mg, 0.30mmol), Pd (dppf) are added2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, with suction filtered through kieselguhr, filtrate ethyl acetate (15mL) dilute, anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:First Alcohol=100:1), obtain white solid (40mg, 71%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting consolidates Body is compound A20
(21) heterocyclic compound A21, which synthesizes by the following method：
A1-4 (50mg, 0.15mmol), 3,4- dichloro phenylboric acids (28mg, 0.18mmol) are dissolved in dioxane/water (5mL/ 1mL), potassium phosphate (64mg, 0.30mmol), Pd (dppf) are added2Cl2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, with suction filtered through kieselguhr, filtrate ethyl acetate (15mL) dilute, anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:First Alcohol=100:1), obtain pale solid (14mg, 23%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, it is resulting Solid is compound A21
(22) heterocyclic compound A22, which synthesizes by the following method：
A1-4 (44mg, 0.13mmol) is dissolved in into N- N-methyl 2-pyrrolidone N -s (2mL) in tube sealing, adds 1,2,3,4- tetrahydrochysenes different Quinoline (178mg, 1.34mmol) and diisopropyl ethyl amine (86mg, 0.67mmol), 120 DEG C are stirred overnight, and are cooled to room temperature, Water (10mL), ethyl acetate (10mL × 3) extraction, organic faciess saturated aqueous common salt (20mL × 6) is added to wash, anhydrous sodium sulfate is done It is dry, sodium sulfate is filtered, solvent, residue Jing column chromatography purification (dichloromethane is spin-dried for:Methanol=100:1), obtain brown oil Thing (45mg, 79%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A22
(23) heterocyclic compound A23, which synthesizes by the following method：
1) synthesis of intermediate A 23-2：
A23-1 (300mg, 2.16mmol) is dissolved in into dichloromethane (6mL), 0 DEG C is cooled in nitrogen protection.By triethylamine (254mg, 2.37mmol) is added, and is subsequently adding trifluoroacetic anhydride (499mg, 2.37mmol), is warming up to and 0.5h is stirred at room temperature.Plus Enter frozen water to be extracted with ethyl acetate three times, merge organic faciess saturated nacl aqueous solution and wash three times, add anhydrous sodium sulfate drying, Spin off organic solvent obtain colorless oil compound (500mg, 98%).
2) synthesis of intermediate A 23-3：
A23-2 (500mg, 2.13mmol) and paraformaldehyde (109mg, 3.40mmol) are dissolved in into glacial acetic acid (2.9mL), Slowly Deca concentrated sulphuric acid (1.88mL) under ice bath, is then stirred at room temperature 8h.The frozen water of 10mL is poured in reactant liquor, uses acetic acid Ethyl ester is extracted three times, is merged organic faciess saturated sodium bicarbonate aqueous solution and is washed till bubble-free generation, then water-soluble with saturated sodium-chloride Liquid is washed once, anhydrous sodium sulfate drying, and solvent, Jing column chromatography purification (petroleum ether is evaporated off:Ethyl acetate=1:0-200:1), obtain To colorless oil compound (260mg, 49%).
3) synthesis of intermediate A 23-4：
By A23-3 (200mg, 0.81mmol), saturated aqueous sodium carbonate (0.8mL) and methanol (0.8mL) addition flask In, 1h is stirred at 60 DEG C, spin off methanol, added water 15mL, be extracted with ethyl acetate three times, merge organic faciess, saturation chlorination Sodium water solution is washed once, anhydrous sodium sulfate drying, be spin-dried for colorless oil compound (58mg, 47%).
4) synthesis of product A23：
A1-4 (56mg, 0.17mmol), A23-4 (130mg, 0.86mmol), diisopropyl ethyl amine are added in reaction bulb (119mg, 0.86mmol) and N-Methyl pyrrolidone (1.5mL).8h is reacted at 120 DEG C, be cooled to room temperature and add water, use second Acetoacetic ester is extracted three times, is merged organic faciess saturated sodium-chloride water solution and is washed, and anhydrous sodium sulfate drying is evaporated off solvent, Jing column chromatographies Purification (petroleum ether:Ethyl acetate=5:1-3:1), obtain oily compound (50mg, 60%).(collection of illustrative plates is parsed through nuclear magnetic spectrum 1) data are shown in Table, and resulting solid is compound A23
(24) heterocyclic compound A24, which synthesizes by the following method：
1) synthesis of intermediate A 24-2：
A24-1 (300mg, 2.16mmol) is dissolved in into dichloromethane (6mL), 0 DEG C is cooled in nitrogen protection.By triethylamine (254mg, 2.37mmol) is added, and is subsequently adding trifluoroacetic anhydride (499mg, 2.37mmol), is warming up to and 0.5h is stirred at room temperature.Plus Enter frozen water to be extracted with ethyl acetate three times, merge organic faciess saturated nacl aqueous solution and wash three times, add anhydrous sodium sulfate drying, Spin off organic solvent obtain colorless oil compound (500mg, 98%).
2) synthesis of intermediate A 24-3：
A24-2 (500mg, 2.13mmol) and paraformaldehyde (109mg, 3.40mmol) are dissolved in into glacial acetic acid (2.9mL), Slowly Deca concentrated sulphuric acid (1.88mL) under ice bath, is then stirred at room temperature 8h.The frozen water of 10mL is poured in reactant liquor, uses acetic acid Ethyl ester is extracted three times, is merged organic faciess saturated sodium bicarbonate aqueous solution and is washed till bubble-free generation, then water-soluble with saturated sodium-chloride Liquid is washed once, anhydrous sodium sulfate drying, and solvent, Jing column chromatography purification (petroleum ether is evaporated off:Ethyl acetate=1:0-200:1), obtain To colorless oil compound (260mg, 49%).
3) synthesis of intermediate A 24-4：
By A24-3 (260mg, 0.89mmol), saturated aqueous sodium carbonate (0.8mL) and methanol (0.8mL) addition flask In, 1h is stirred at 60 DEG C, spin off methanol, added water 15mL, be extracted with ethyl acetate three times, merge organic faciess, saturation chlorination Sodium water solution is washed once, anhydrous sodium sulfate drying, be spin-dried for colorless oil compound (130mg, 69%).
4) synthesis of product A24：
A1-4 (50mg, 0.15mmol), A23-4 (116mg, 0.76mmol), diisopropyl ethyl amine are added in reaction bulb (100mg, 0.77mmol) and N-Methyl pyrrolidone (1.5mL).8h is reacted at 120 DEG C, be cooled to room temperature and add water, use second Acetoacetic ester is extracted three times, is merged organic faciess saturated sodium-chloride water solution and is washed, and anhydrous sodium sulfate drying is evaporated off solvent, Jing column chromatographies Purification (petroleum ether:Ethyl acetate=5:1-3:1), obtain oily compound (40mg, 59%).(collection of illustrative plates is parsed through nuclear magnetic spectrum 1) data are shown in Table, and resulting solid is compound A24
(25) heterocyclic compound A25, which synthesizes by the following method：
1) synthesis of intermediate A 25-2：
A25-1 (1.0g, 5.0mmol) is dissolved in into dichloromethane (20mL), 0 DEG C is cooled in nitrogen protection.By triethylamine (556mg, 5.5mmol) is added, and is subsequently adding trifluoroacetic anhydride (1.16g, 5.5mmol), is warming up to and 0.5h is stirred at room temperature.Add Frozen water is extracted with ethyl acetate three times, merges organic faciess saturated nacl aqueous solution and washes three times, adds anhydrous sodium sulfate drying, rotation Fall organic solvent and obtain colorless oil compound (1.5g, quantitative).
2) synthesis of intermediate A 25-3：
A25-2 (1.5g, 5.0mmol) and paraformaldehyde (291mg, 9.1mmol) are dissolved in into glacial acetic acid (5.9mL), in ice Slowly Deca concentrated sulphuric acid (3.76mL) under bath, is then stirred at room temperature 8h.The frozen water of 20mL is poured in reactant liquor, uses acetic acid second Ester is extracted three times, is merged organic faciess saturated sodium bicarbonate aqueous solution and is washed till bubble-free generation, then uses saturated sodium-chloride water solution Wash once, anhydrous sodium sulfate drying, solvent, Jing column chromatography purification (petroleum ether is evaporated off:Ethyl acetate=1:0-200:1), obtain Colorless oil compound (1.26g, 82%).
3) synthesis of intermediate A 25-4：
By A25-3 (590mg, 1.92mmol), saturated aqueous sodium carbonate (2.4mL) and methanol (2.4mL) addition flask In, 1h is stirred at 60 DEG C, spin off methanol, added water 15mL, be extracted with ethyl acetate three times, merge organic faciess, saturation chlorination Sodium water solution is washed once, anhydrous sodium sulfate drying, be spin-dried for colorless oil compound (200mg, 49%).
4) synthesis of product A25：
A1-4 (60mg, 0.18mmol), A25-4 (194mg, 0.92mmol), diisopropyl ethyl amine are added in reaction bulb (119mg, 0.92mmol) and N-Methyl pyrrolidone (1.5mL).8h is reacted at 120 DEG C, be cooled to room temperature and add water, use second Acetoacetic ester is extracted three times, is merged organic faciess saturated sodium-chloride water solution and is washed, and anhydrous sodium sulfate drying is evaporated off solvent, Jing column chromatographies Purification (petroleum ether:Ethyl acetate=5:1-3:1), obtain oily compound (40mg, 44%).(collection of illustrative plates is parsed through nuclear magnetic spectrum 1) data are shown in Table, and resulting solid is compound A25
(26) heterocyclic compound A26, which synthesizes by the following method：
1) synthesis of intermediate A 26-2：
A28-1 (5.25g, 27.8mmol) and propargyl amine (3.05g, 55.5mmol) are dissolved in into dehydrated alcohol (50mL) In, sodium chloraurate (252mg, 0.70mmol) is subsequently added, backflow is overnight.Room temperature is cooled to, concentrating under reduced pressure adds water (30mL), extracted with dichloromethane (30mL × 3), merge organic faciess, anhydrous sodium sulfate drying, Jing column chromatographies after concentrating under reduced pressure (ethyl acetate:Petroleum ether=1:1) yellow oil (3.08g, 50%).1HNMR (400MHz, CDCl3) δ 8.39 (d, J= 4.4Hz, 1H), 7.41-7.32 (m, 4H), 7.30 (d, J=6.4Hz, 2H), 7.06-7.03 (m, 1H), 3.71 (s, 2H), 3.62 (s, 2H), 3.06 (t, J=5.8Hz, 2H), 2.86 (t, J=6.0Hz, 2H).
2) synthesis of intermediate A 26-3：
Intermediate A 26-2 (2.8g, 12.5mmol) is dissolved in acetic acid (10mL), 10%Pd/C (560mg) is added, in hydrogen Under the conditions of gas, 60 DEG C are heated to, are reacted 2 hours.Room temperature is cooled to, is filtered, filtrate is spin-dried for obtaining brown oil (3.4g, thick product Product, content：56%).1HNMR (400MHz, CDCl3) δ 8.48 (d, J=4.4Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 7.20-7.16 (m, 1H), 4.23 (s, 2H), 3.42 (t, J=6.2Hz, 2H), 3.17 (t, J=6.2Hz, 2H).
3) synthesis of product A26：
Intermediate A 1-4 (50mg, 0.15mmol) is dissolved in into N- N-methyl 2-pyrrolidone N -s (2mL) in tube sealing, A26-3 is added (102mg, 0.76mmol) and diisopropyl ethyl amine (98mg, 0.76mmol), 120 DEG C are stirred overnight, and are cooled to room temperature, add Water (10mL), ethyl acetate (10mL × 3) extraction, organic faciess saturated aqueous common salt (20mL × 6) are washed, anhydrous sodium sulfate drying, Sodium sulfate is filtered, solvent, residue Jing column chromatography purification (dichloromethane is spin-dried for:Methanol=50:1), obtain white solid (23mg, 35%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A26
(27) heterocyclic compound A27, which synthesizes by the following method：
Compound A1 (30mg, 0.07mmol) is dissolved in into tetrahydrofuran (3mL), ice bath stirring add NaH (6mg80%, 0.20mmol), CH is added after continuing stirring 30 minutes3I (20mg, 0.14mmol), continues reaction 6 hours, is spin-dried for solvent, remaining Thing Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain light yellow oil (30mg, 97%).Through nuclear magnetic spectrum Parsing (spectrum data is shown in Table 1), resulting solid are compound A27
(28) heterocyclic compound A28, which synthesizes by the following method：
1) synthesis of intermediate A 28-2：
Crude intermediate A1-2 (1.57g, 27%, 2.75mmol) is dissolved in into dioxane/water (20mL/4mL), additionization Compound A28-1 (500mg, 2.50mmol), potassium carbonate (690mg, 5.00mmol), Pd (dba) 2 (144mg, 0.25mmol) and SPhos (206mg, 0.50mmol), nitrogen displacement, 80 DEG C of reactions overnight, are cooled to room temperature, with suction filtered through kieselguhr, filtrate addition 50mL water, ethyl acetate (60mL × 3) extraction merge organic faciess saturated aqueous common salt (150mL × 2) and wash, and organic faciess are with anhydrous Sodium sulfate is dried, and filters sodium sulfate, is spin-dried for ethyl acetate, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30: 1 ammonification water), obtain brown solid (340mg, 64%).
2) synthesis of intermediate A 28-3：
Intermediate A 28-2 (100mg, 0.47mmol) is dissolved in into tetrahydrofuran (5mL), 4,6-, bis- chloro- 5-FUs are added (79mg, 0.47mmol), diisopropyl ethyl amine (180mg, 1.40mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1) obtain colorless oil (110mg, 68%).1HNMR (400MHz, CDCl3) δ 8.54 (d, J=4.8Hz, 1H), 8.16 (s, 1H), 7.62 (d, J=8.0Hz, 2H), 7.48 (d, J= 8.0Hz, 2H), 7.37 (s, 1H), 7.32 (d, J=4.8Hz, 1H), 5.39 (s, 2H), 2.64 (s, 3H), 1.66 (d, J= 6.0Hz, 3H).
3) synthesis of product A25：
Intermediate A 28-3 (50mg, 0.15mmol), 2- naphthalene boronic acids (38mg, 0.22mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (80mg, 0.60mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C stirred At night, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is revolved Dry solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain white solid (27mg, 43%).Through core Magnetic spectrum analysis (spectrum data is shown in Table 1), resulting solid are compound A28
(29) heterocyclic compound A29, which synthesizes by the following method：
1) synthesis of intermediate A 29-2：
Compound A29-1 (1.42g, 7.43mmol) is dissolved in into acetonitrile (30mL), add t-butyl carbamate (1.22g, 10.4mmol), triethyl silicane (2.61g, 22.3mmol), trifluoroacetic acid (2.54g, 22.3mmol), stirring at normal temperature 24 hours, Saturated aqueous sodium carbonate is slowly added under stirring to not having bubble to produce, ethyl acetate (100mL × 3) is extracted, organic faciess Washed with saturated aqueous common salt (150mL × 2), anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, residue Jing column chromatographies are pure Change (petroleum ether:Ethyl acetate=40:1-20:1), obtain colorless oil (1.19g, 55%).1HNMR (400MHz, CDCl3)δ 6.87 (s, 1H), 6.69 (s, 1H), 4.90 (s, 1H), 4.37 (s, 2H), 1.46 (s, 9H).
2) synthesis of intermediate A 29-3：
Intermediate A 29-2 (1.16g, 3.97mmol) is dissolved in into dichloromethane/trifluoroacetic acid (10mL/10mL), room temperature is stirred Mixing 3 hours, saturated aqueous sodium carbonate being slowly added to not having bubble to produce, dichloromethane (30mL × 3) is extracted, anhydrous sulfur Sour sodium is dried, and filters sodium sulfate, is spin-dried for solvent, obtain yellow oil (660mg, 87%).
3) synthesis of intermediate A 29-4：
Intermediate A 29-3 (580mg, 3.02mmol) is dissolved in into dioxane/water (20mL/4mL), crude intermediate is added A1-2 (1.17g, 27%, 3.32mmol), potassium carbonate (1.67g, 12.1mmol), four triphenyl phosphorus palladiums (175mg, 0.15mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, add water (30mL), dichloromethane (30mL × 6) extraction Take, organic faciess anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:First Alcohol=50:1), obtain dark oil thing (360mg, 58%).
4) synthesis of intermediate A 29-5：
Intermediate A 29-4 (180mg, 0.88mmol) is dissolved in into tetrahydrofuran (10mL), 4,6-, bis- chloro- 5-FUs are added (147mg, 0.88mmol), diisopropyl ethyl amine (341mg, 2.64mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1) obtain light yellow solid (190mg, 64%).1HNMR (400MHz, CDCl3) δ 8.46 (d, J=5.2Hz, 1H), 8.27 (s, 1H), 7.34 (d, J=3.6Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=5.2Hz, 1H), 7.06 (d, J=3.2Hz, 1H), 5.62 (s, 1H), 4.92 (d, J=6.0Hz, 2H), 2.58 (s, 3H).
5) synthesis of product A29：
A29-5 (50mg, 0.15mmol), 2- naphthalene boronic acids (39mg, 0.23mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (82mg, 0.59mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred Mix overnight, be cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sulfur Sour sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain white solid (50mg, 78%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A29
(30) heterocyclic compound A30, which synthesizes by the following method：
1) synthesis of intermediate A 30-2：
Compound A-13 0-1 (500mg, 3.50mmol) is dissolved in into dioxane/water (20mL/4mL), crude intermediate is added A1-2 (1.51g, 27%, 3.85mmol), potassium carbonate (1.93g, 14.0mmol), four triphenyl phosphorus palladiums (202mg, 0.175mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, add water (30mL), dichloromethane (50mL × 6) extraction Take, organic faciess anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, obtain brown oil (620mg, 89%).
2) synthesis of intermediate A 30-3：
A30-2 (200mg, 1.01mmol) is dissolved in into tetrahydrofuran (10mL), 4,6-, bis- chloro- 5-FUs are added (168mg, 1.01mmol), diisopropyl ethyl amine (389mg, 3.02mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain pale solid (230mg, 69%).1HNMR (400MHz, CDCl3) δ 8.74 (s, 1H), 8.59 (d, J=5.2Hz, 1H), 8.23 (s, 1H), 7.84-7.75 (m, 3H), 7.65 (d, J=5.2Hz, 1H), 5.76 (s, 1H), 4.82 (d, J=6.0Hz, 2H), 2.65 (s, 3H).
3) synthesis of product A30：
Intermediate A 30-3 (50mg, 0.15mmol), 2- naphthalene boronic acids (39mg, 0.23mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain white solid (52mg, 81%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 0
(31) heterocyclic compound A31, which synthesizes by the following method：
Intermediate A 30-3 (50mg, 0.15mmol), intermediate A 4-2 (58mg, 0.23mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (18mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30:1), obtain white solid (44mg, 69%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 1
(32) heterocyclic compound A32, which synthesizes by the following method：
Intermediate A 30-3 (50mg, 0.15mmol) is dissolved in into N- N-methyl 2-pyrrolidone N -s (2mL) in tube sealing, A26-3 is added (102mg, 0.76mmol) and diisopropyl ethyl amine (98mg, 0.76mmol), 120 DEG C are stirred overnight, and are cooled to room temperature, add Water (10mL), ethyl acetate (10mL × 3) extraction, organic faciess saturated aqueous common salt (20mL × 6) are washed, anhydrous sodium sulfate drying, Sodium sulfate is filtered, solvent, residue Jing column chromatography purification (dichloromethane is spin-dried for:Methanol=50:1-30:1), obtain brown solid (25mg, 39%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 2
(33) heterocyclic compound A33, which synthesizes by the following method：
1) synthesis of intermediate A 33-2：
POCl3 (18.3mL, 200mmol), 100 DEG C of stirrings, by compound A-13 3-1 are added in the two-neck bottle of 100mL (10.43g, 70%, 90mmol) is dissolved in DMF (15.4mL, 200mmol) and is slowly dropped in above-mentioned solution, and drop finishes 110 DEG C of stirrings 24 hours, room temperature is cooled to, dichloromethane (100mL) dilution is poured slowly in frozen water, dichloromethane (100mL × 3) extraction Take, organic faciess saturated aqueous common salt (200mL × 3) is washed, and anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, residue Jing Column chromatography purification (petroleum ether:Ethyl acetate=10:1), obtain white solid (2.9g, 21%).1HNMR (400MHz, CDCl3)δ 10.08 (s, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 2.48 (s, 3H).
2) synthesis of intermediate A 33-3：
Compound A-13 3-2 (1.00g, 6.41mmol) is dissolved in into acetonitrile (50mL), add t-butyl carbamate (1.50g, 12.8mmol), Et3SiH (7.40g, 63.8mmol), trifluoroacetic acid (2.20g, 19.3mmol), stirring at normal temperature 24 hours, stirring Under be slowly added to saturated aqueous sodium carbonate to not there is bubble to produce, ethyl acetate (100mL × 3) extraction, organic faciess are with full Wash with saline solution (150mL × 2), anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, residue Jing column chromatography purification (stones Oily ether:Ethyl acetate=5:1), obtain colorless oil (1.60g, 97%).
3) synthesis of intermediate A 33-4：
Intermediate A 33-3 (1.60g, 6.23mmol) is dissolved in into dichloromethane/trifluoroacetic acid (10mL/10mL), room temperature is stirred Mixing 3 hours, saturated aqueous sodium carbonate being slowly added to not having bubble to produce, dichloromethane (30mL × 6) is extracted, anhydrous sulfur Sour sodium is dried, and filters sodium sulfate, is spin-dried for solvent, obtain yellow oil (810mg, 83%).
4) synthesis of intermediate A 33-5：
Intermediate A 33-4 (780mg, 4.97mmol) is dissolved in into dioxane/water (20mL/4mL), crude intermediate is added A1-2 (1.92g, 27%, 5.46mmol), potassium carbonate (2.74g, 19.8mmol), four triphenyl phosphorus palladiums (287mg, 0.248mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, add water (30mL), dichloromethane (50mL × 6) extraction Take, organic faciess anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, obtain brown oil (1.07g, 100%).
5) synthesis of intermediate A 33-6：
Intermediate A 33-5 (200mg, 0.94mmol) is dissolved in into tetrahydrofuran (10mL), 4,6-, bis- chloro- 5-FUs are added (160mg, 0.96mmol), diisopropyl ethyl amine (360mg, 2.79mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain white solid (220mg, 68%).1HNMR (400MHz, CDCl3) δ 8.57 (d, J=5.2Hz, 1H), 8.55 (s, 1H), 8.23 (s, 1H), 7.62 (s, 1H), 7.32 (s, 1H), 7.24 (d, J=4.8Hz, 1H), 5.86 (s, 1H), 4.78 (d, J=6.0Hz, 3H), 2.63 (s, 3H), 2.37 (s, 3H).
6) synthesis of product A33：
Intermediate A 33-6 (50mg, 0.15mmol), 2- naphthalene boronic acids (37mg, 0.22mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (80mg, 0.58mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C stirred At night, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, It is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain white solid (40mg, 63%).Through core Magnetic spectrum analysis (spectrum data is shown in Table 1), resulting solid are compound A-13 3
(34) heterocyclic compound A34, which synthesizes by the following method：
Intermediate A 33-6 (50mg, 0.15mmol), intermediate A 4-2 (56mg, 0.22mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (80mg, 0.58mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30:1), obtain pale solid (30mg, 48%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 4
(35) heterocyclic compound A35, which synthesizes by the following method：
1) synthesis of intermediate A 35-2：
Compound A-13 5-1 (5g, 34.3mmol) is dissolved in into acetonitrile (100mL), NBS (18.3g, 103mmol) and mistake is added BP (829mg, 3.43mmol), backflow overnight, are cooled to room temperature, add water (200mL), ethyl acetate (200mL × 3) extract, organic faciess saturated aqueous common salt (300mL × 3) is washed, and anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, it is remaining Thing Jing column chromatography purification (petroleum ether:Ethyl acetate=100:1), obtain yellow oil (7.45g, 97%).1HNMR (400MHz, CDCl3) δ 8.23 (d, J=1.2Hz, 1H), 7.56-7.53 (m, 1H), 4.45 (s, 2H).
2) synthesis of intermediate A 35-3：
Intermediate A 35-2 (7.45g, 33.1mmol) is dissolved in into DMF (50mL), NaN is added under ice bath3(8.61g, 132mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, add water (100mL), ethyl acetate (100mL × 3) extraction, organic faciess Washed with saturated aqueous common salt (200mL × 3), anhydrous sodium sulfate drying filters sodium sulfate, be spin-dried for solvent, residue Jing column chromatographies are pure Change (petroleum ether:Ethyl acetate=50:1), obtain colorless oil (5.6g, 90%).1HNMR (400MHz, CDCl3)δ8.19 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 4.45 (s, 2H).
3) synthesis of intermediate A 35-4：
Intermediate A 35-3 (5.6g, 29.9mmol) is dissolved in into tetrahydrofuran (50mL), under ice bath stirring, PPh3 is dividedly in some parts (8.6g, 32.9mmol), is heated to reflux, and is slowly added dropwise water (10mL), is refluxed 8 hours, is cooled to room temperature, ethyl acetate (100mL) dilute, extracted with the hydrochloric acid (100mL × 2) of 0.2M, water is mutually washed once with ethyl acetate (100mL), and then water is mutually used The NaOH aqueous solutions of 2M are adjusted to 9 PH, and ethyl acetate (200mL × 3) extraction, the organic faciess for obtaining are dry with anhydrous sodium sulfate It is dry, sodium sulfate is filtered, solvent, residue Jing column chromatography purification (dichloromethane is spin-dried for:Methanol=50:1), obtain brown oil (2.57g, 53%).1HNMR (400MHz, DMSO) δ 8.23 (s, 1H), 7.89 (d, J=9.6Hz, 1H), 3.75 (s, 2H).
4) synthesis of intermediate A 35-5：
Intermediate A 35-4 (2.36g, 14.6mmol) is dissolved in into dioxane/water (50mL/10mL), is added in the middle of crude product Body A1-2 (6.31g, 27%, 16.1mmol), potassium carbonate (8.09g, 58.6mmol), four triphenyl phosphorus palladiums (847mg, 0.73mmol), nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, add water (100mL), dichloromethane (100mL × 6) Extraction, organic faciess anhydrous sodium sulfate drying filter sodium sulfate, are spin-dried for solvent, residue Jing column chromatography purification (dichloromethane: Methanol=50:1-20:1 ammonification water), obtain brown solid (2.5g, 79%).1HNMR (400MHz, CDCl3) δ 8.61 (d, J= 4.8Hz, 1H), 8.50 (s, 1H), 7.77 (s, 1H), 7.69 (d, J=4.0Hz, 1H), 7.58 (d, J=12.0Hz, 1H), 4.01 (s, 2H), 2.65 (s, 3H).
5) synthesis of intermediate A 35-6：
Intermediate A 35-5 (200mg, 0.92mmol) is dissolved in into tetrahydrofuran (10mL), 4,6-, bis- chloro- 5-FUs are added (154mg, 0.92mmol), diisopropyl ethyl amine (357mg, 2.77mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1) obtain pale solid (200mg, 62%).1HNMR (400MHz, CDCl3) δ 8.61 (d, J=4.8Hz, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.55 (d, J=11.6Hz, 1H), 5.78 (s, 1H), 4.84 (d, J=6.0Hz, 2H), 2.65 (s, 3H).
6) synthesis of product A35：
Intermediate A 35-6 (50mg, 0.15mmol), 2- naphthalene boronic acids (37mg, 0.22mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (79mg, 0.57mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (68mg, 100%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 5
(36) heterocyclic compound A36, which synthesizes by the following method：
Intermediate A 35-6 (50mg, 0.15mmol), intermediate A 4-2 (55mg, 0.22mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (80mg, 0.58mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30:1), obtain pale solid (28mg, 44%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 6
(37) heterocyclic compound A37, which synthesizes by the following method：
1) synthesis of intermediate A 37-2：
A37-1 (800mg, 4.28mmol) is dissolved in into dioxane/water (20mL/4mL), crude intermediate A1-2 is added (1.84g, 27%, 4.71mmol), potassium carbonate (1.77g, 12.8mmol), four triphenyl phosphorus palladiums (247mg, 0.21mmol), nitrogen Gas is replaced, and 100 DEG C are stirred overnight, and are cooled to room temperature, and with suction filtered through kieselguhr, filtrate adds water (30mL), dichloromethane (50mL × 6) extract, organic faciess anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethanes Alkane:Methanol=50:1-20:1) obtain brown solid (300mg, 35%).
2) synthesis of intermediate A 37-3：
Intermediate A 37-2 (150mg, 0.75mmol) is dissolved in into tetrahydrofuran (5mL), 4,6-, bis- chloro- 5-FUs are added (126mg, 0.75mmol), diisopropyl ethyl amine (292mg, 2.26mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain pale solid (136mg, 55%).1HNMR (400MHz, CDCl3) δ 8.85 (s, 1H), 8.61 (d, J=5.2Hz, 1H), 8.22 (s, 1H), 7.93 (d, J=8.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.37 (s, 1H), 7.31 (d, J=5.2Hz, 1H), 6.65 (s, 1H), 4.87 (d, J= 4.8Hz, 2H), 2.65 (s, 3H).
3) synthesis of product A37：
A37-3 (50mg, 0.15mmol), compound 12 (39mg, 0.23mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen displacement, 100 DEG C are stirred Mix overnight, be cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sulfur Sour sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain white solid (47mg, 74%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 7
(38) heterocyclic compound A38, which synthesizes by the following method：
1) synthesis of intermediate A 38-2：
4- pyridine boronic acids (397mg, 3.23mmol) are dissolved in into dioxane/water (20mL/4mL), are added to bretylium tosylate (500mg, 2.69mmol), potassium carbonate (742mg, 5.38mmol), Pd (dba) 2 (155mg, 0.27mmol) and SPhos (220mg, 0.54mmol), nitrogen displacement, 80 DEG C of reactions overnight, are cooled to room temperature, with suction filtered through kieselguhr, filtrate addition 50mL Water, ethyl acetate (60mL × 3) extraction merge organic faciess saturated aqueous common salt (150mL × 2) and wash, organic faciess anhydrous slufuric acid Sodium is dried, and filters sodium sulfate, is spin-dried for ethyl acetate, residue Jing column chromatography purification (dichloromethane:Methanol=50:1-30:1 adds Ammonia), obtain brown solid (240mg, 48%).
2) synthesis of intermediate A 38-3：
Intermediate A 38-2 (100mg, 0.54mmol) is dissolved in into tetrahydrofuran (5mL), 4,6-, bis- chloro- 5-FUs are added (90mg, 0.54mmol), diisopropyl ethyl amine (210mg, 1.63mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for molten Agent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1) obtain yellow solid (80mg, 47%).1HNMR (400MHz, CDCl3) δ 8.69 (brs, 2H), 8.23 (s, 1H), 7.64 (d, J=6.8Hz, 2H), 7.58-7.39 (m, 4H), 5.60 (s, 1H), 4.80 (d, J=5.2Hz, 2H).
3) synthesis of product A38：
Intermediate A 38-3 (63mg, 0.20mmol), 2- naphthalene boronic acids (52mg, 0.30mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen displacement, 100 DEG C stirred At night, room temperature is cooled to, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sodium sulfate, is revolved Dry solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1), obtain white solid (46mg, 57%).Through core Magnetic spectrum analysis (spectrum data is shown in Table 1), resulting solid are compound A-13 8
(39) heterocyclic compound A39, which synthesizes by the following method：
1) synthesis of intermediate A 39-2：
Dioxane/water will be dissolved in bretylium tosylate (800mg, 4.30mmol), A39-1 (1.52g, 12.1mmol) will be added, Add potassium phosphate (1.82g, 8.58mmol), Pd (dppf)2Cl2(176mg, 0.22mmol), dppf (119mg, 0.22mmol), Nitrogen displacement, 100 DEG C are stirred overnight, and are cooled to room temperature, with suction filtered through kieselguhr, filtrate addition water (30mL), dichloromethane (50mL × 6) extract, organic faciess anhydrous sodium sulfate drying filters sodium sulfate, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethanes Alkane:Methanol=50:1-20:1 ammonification water) obtain brown oil (410mg, 51%).
2) synthesis of intermediate A 38-3：
Intermediate A 39-2 (200mg, 1.07mmol) is dissolved in into tetrahydrofuran (5mL), 4,6-, bis- chloro- 5-FUs are added (179mg, 1.07mmol), diisopropyl ethyl amine (414mg, 3.21mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=150:1), obtain colorless oil (240mg, 71%).1HNMR (400MHz, CDCl3) δ 8.23 (s, 1H), 7.51 (s, 1H), 7.45-7.40 (m, 4H), 6.30 (s, 1H), 5.55 (s, 1H), 4.79 (d, J=6.0Hz, 2H), 3.89 (s, 3H).
3) synthesis of product A38：
Intermediate A 39-3 (50mg, 0.16mmol), 2- naphthalene boronic acids (41mg, 0.24mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (87mg, 0.63mmol), four triphenyl phosphorus palladiums (18mg, 0.016mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=150:1), obtain white solid (37mg, 58%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A-13 9
(40) heterocyclic compound A40, which synthesizes by the following method：
1) synthesis of intermediate A 40-2：
In 50mL two-neck bottles, add LiAlH4 (450mg, 11.8mmol), nitrogen displacement to add tetrahydrochysene furan with syringe Mutter (10mL), and A40-1 (500mg, 2.96mmol) is dissolved in tetrahydrofuran (10mL), above-mentioned solution is slowly added into syringe In, it is stirred at reflux 2 hours.Room temperature is cooled to, saturated aqueous sodium sulfate is slowly added dropwise under ice bath and is produced to there is no longer bubble, Stirring 1 hour, sucking filtration, filtrate anhydrous sodium sulfate drying filter sodium sulfate, be spin-dried for solvent obtain brown oil (570mg, 100%).
2) synthesis of intermediate A 40-3：
Intermediate A 40-2 (200mg, 1.16mmol) is dissolved in into tetrahydrofuran (5mL), 4,6-, bis- chloro- 5-FUs are added (193mg, 1.16mmol), diisopropyl ethyl amine (447mg, 3.46mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for Solvent, residue Jing column chromatography purification (dichloromethane:Methanol=50:1), obtain pale solid (150mg, 43%).1HNMR (400MHz, CDCl3) δ 8.22 (s, 1H), 7.84 (s, 1H), 7.47 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 7.27 (s, 1H), 7.21 (s, 1H), 5.69 (s, 1H), 4.79 (d, J=5.6Hz, 2H).
3) synthesis of product A40：
Intermediate A 40-3 (50mg, 0.16mmol), 2- naphthalene boronic acids (42mg, 0.24mmol) are dissolved in into dioxane/water (5mL/1mL), addition potassium carbonate (91mg, 0.66mmol), four triphenyl phosphorus palladiums (19mg, 0.016mmol), nitrogen displacement, 100 DEG C it is stirred overnight, is cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), anhydrous sodium sulfate drying, filter Sulfuric acid sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (36mg, 55%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A40
(41) heterocyclic compound A41, which synthesizes by the following method：
1) synthesis of intermediate A 41-2：
A41-1 (200mg, 1.26mmol) is dissolved in into tetrahydrofuran (5mL), add 4,6-, bis- chloro- 5-FUs (211mg, 1.26mmol), diisopropyl ethyl amine (490mg, 3.80mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for solvent, remain Excess Jing column chromatography purification (dichloromethane:Methanol=150:1), obtain yellow solid (120mg, 33%).1HNMR (400MHz, CDCl3) δ 9.24 (s, 1H), 8.54 (d, J=5.6Hz, 1H), 8.23 (s, 1H), 7.98 (d, J=8.4Hz, 1H), 7.76 (s, 1H), 7.63 (d, J=5.6Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 5.70 (s, 1H), 4.95 (d, J=6.0Hz, 2H).
2) synthesis of product A41：
Intermediate A 41-2 (50mg, 0.17mmol), A4-2 (66mg, 0.26mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (96mg, 0.69mmol), four triphenyl phosphorus palladiums (20mg, 0.017mmol), nitrogen displacement, 100 DEG C are stirred Mix overnight, be cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sulfur Sour sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain white solid (43mg, 65%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A41
(42) heterocyclic compound A42, which synthesizes by the following method：
1) synthesis of intermediate A 42-2：
A42-1 (1.0g, 5.92mmol) is dissolved in into dichloromethane (30mL), sequentially add triethylamine (896mg, 8.88mmol), Trifluoromethanesulfonic anhydride (2.5g, 8.88mmol), overnight, water is added and is quenched stirring at normal temperature, ethyl acetate extraction Three times, organic faciess are washed with saturated common salt, and anhydrous sodium sulfate drying is evaporated off solvent, residue Jing column chromatography purification (petroleum ether: Ethyl acetate=30:1), obtain white solid (1.65g, 93%).
2) synthesis of intermediate A 42-3：
A42-2 (1.35g, 4.49mmol), potassium phosphate (1.27g, 5.99mmol), Pd (dba) 2 are added in reaction bulb (114mg, 0.20mmol), XPhos (143mg, 0.30mmol), evacuation replace nitrogen, add nitromethane (4mL), dioxy Six rings (25mL), are heated to 80 DEG C and stir 18 hours, are cooled to room temperature, and acetic acid (8mL) is added, and zinc powder (2.93g, 45mmol) adds Enter, 35 DEG C are reacted 3 hours, be filtered to remove the zinc powder not reacted, water (30mL) is added, and ethyl acetate is extracted twice, and water is mutually used 1MNaOH adjusts PH=10, ethyl acetate to extract three times, and organic faciess are washed with saturated common salt, and anhydrous sodium sulfate drying is evaporated off solvent, Residue Jing column chromatography purification (petroleum ether:Ethyl acetate=3:1-0:1), obtain faint yellow solid (280mg, 34%).
3) synthesis of intermediate A 42-4：
A42-3 (182mg, 1.0mmol) is dissolved in into tetrahydrofuran (1mL), add 4,6-, bis- chloro- 5-FUs (167mg, 1.0mmol), diisopropyl ethyl amine (260mg, 2.0mmol), 50 DEG C are stirred overnight, and are cooled to room temperature, are spin-dried for solvent, remaining Thing Jing column chromatography purification (petroleum ether:Ethyl acetate=5:1-3:1), obtain faint yellow solid (120mg, 38%).
4) synthesis of product A42：
Intermediate A 42-4 (53mg, 0.17mmol), A4-2 (66mg, 0.26mmol) are dissolved in into dioxane/water (5mL/ 1mL), addition potassium carbonate (96mg, 0.69mmol), four triphenyl phosphorus palladiums (20mg, 0.017mmol), nitrogen displacement, 100 DEG C are stirred Mix overnight, be cooled to room temperature, with suction filtered through kieselguhr, filtrate is diluted with ethyl acetate (15mL), and anhydrous sodium sulfate drying filters sulfur Sour sodium, is spin-dried for solvent, residue Jing column chromatography purification (dichloromethane:Methanol=100:1-50:1), obtain faint yellow solid (35mg, 66%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A42
(43) heterocyclic compound A43, which synthesizes by the following method：
By A42 (17mg, 0.04mmol), potassium carbonate (2.8mg, 0.02mmol) is dissolved in DMSO (1mL), adds 30%H2O2 (6mg, 0.05mmol), stirring at normal temperature 3 hours, is poured into water, sucking filtration, and washing, normal hexane are washed, and is vacuum dried, obtains faint yellow Solid (14mg, 83%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A43
(44) heterocyclic compound A44, which synthesizes by the following method：
A42-4 (40mg, 0.13mmol), A26-3 (51mg, 0.39mmol), DIPEA (83mg, 0.64mmol) are dissolved in In NMP (1.5mL), 130 DEG C of reaction 12h are heated to, room temperature are cooled to, are added water, be extracted with ethyl acetate three times, merge organic Phase, is washed once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, removes solvent, Jing column chromatography purification (petroleum ether under reduced pressure: Ethyl acetate=5:1-3:1) (20mg, 38%) parses (spectrum data is shown in Table 1) through nuclear magnetic spectrum, resulting to obtain brown solid Solid be compound A44
(45) heterocyclic compound A45, which synthesizes by the following method：
A35-6 (50mg, 0.15mmol), A26-3 (97mg, 0.72mmol), DIPEA (93mg, 0.72mmol) are dissolved in In NMP (1.5mL), 130 DEG C of reaction 8h are heated to, room temperature are cooled to, are added water, be extracted with ethyl acetate three times, merge organic Phase, is washed once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, removes solvent, Jing column chromatography purification (petroleum ether under reduced pressure: Ethyl acetate=5:1-3:1) brown solid (25mg, 39%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, gained The solid for arriving is compound A45
(46) heterocyclic compound A46, which synthesizes by the following method：
A33-6 (50mg, 0.15mmol) is dissolved in into NMP (2mL) in tube sealing, add A26-3 (97mg, 0.73mmol) and DIPEA (94mg, 0.73mmol), 120 DEG C are stirred overnight, and are cooled to room temperature, add water (10mL), ethyl acetate (10mL*3) extraction Take, organic faciess saturated aqueous common salt (20mL*6) is washed, and anhydrous sodium sulfate drying filters sodium sulfate, remove solvent, Jing posts under reduced pressure Chromatography purification (dichloromethane:Methanol=50:1-30:1), obtain brown oil (50mg, 78%).Parse through nuclear magnetic spectrum (spectrum data is shown in Table 1), resulting solid are compound A46
(47) heterocyclic compound A47, which synthesizes by the following method：
1) synthesis of intermediate A 47-2：
Addition A47-1 (10g, 50mmol) in the flask of 100mL, sulfur (3.22g, 100mmol), cyanamide (4.36g, 100mmol) with pyridine (40mL), it is heated to 130 DEG C and reacts 90 minutes.Room temperature is cooled to, solid is leached, use ethyl acetate Wash, and dry dark brown solid (9.7g, 76%).1H NMR(400MHz,DMSO)δ6.86(s,2H),4.29(s,2H),3.56 (m,2H),2.43(s,2H),1.41(s,9H).
2) synthesis of intermediate A 47-3：
By A47-2 (9.7g, 38mmol), amyl nitrite (11g, 95mmol) is dissolved in tetrahydrofuran 150mL, at 80 DEG C Reaction 2h, is cooled to room temperature and adds water, be extracted with ethyl acetate three times, merge organic faciess, wash one with saturated sodium-chloride water solution Secondary, anhydrous sodium sulfate drying removes solvent, Jing column chromatography purification (petroleum ether under reduced pressure:Ethyl acetate=10:1-5:1) obtain Huang Color solid (3.3g, 36%).1H NMR(400MHz,CDCl3)δ8.67(s,1H),4.67(s,2H),3.76(s,2H),2.93 (s,2H),1.49(s,9H).
3) synthesis of intermediate A 47-4：
A47-4 (800mg, 3.3mmol) is dissolved in into the ethyl acetate solution (3M, 5mL) of hydrogen chloride, is stirred at room temperature 2h.Remove solvent under reduced pressure, obtain yellow solid (580mg, 100%).1H NMR(400MHz,DMSO)δ9.76(s,2H),9.08 (s, 1H), 4.41 (s, 2H), 3.43 (s, 2H), 3.04 (t, J=5.8Hz, 2H).
3) synthesis of product A47：
A1-4 (50mg, 0.15mmol), A47-4 (107mg, 0.77mmol), DIPEA (198mg, 1.53mmol) are dissolved in NMP (2mL), is heated to reacting 8h at 120 DEG C.Room temperature is cooled to, water is added, is extracted with ethyl acetate three times, merge organic faciess, Washed once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, remove solvent, Jing column chromatography purification (petroleum ether under reduced pressure:Acetic acid Ethyl ester=5:1-3:1) brown solid compound (30mg, 45%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, institute The solid for obtaining is compound A47
(48) heterocyclic compound A48, which synthesizes by the following method：
1) synthesis of intermediate A 48-2：
By A48-1 (180mg, 0.91mmol), duplex pinacol borate (348mg, 1.37mmol), bis- (hexichol of 1,1'- Phosphino-) ferrocene palladium chloride (II) (37mg, 0.045mmol), potassium acetate (180mg, 1.83mmol) is dissolved in tetrahydrofuran (10mL).8h being reacted at 80 DEG C under nitrogen protection, being cooled to room temperature, Jing kieselguhr is filtered, and removes solvent under reduced pressure, obtains black solid Body (300mg, content：74%).
2) synthesis of product A48：
By A1-4 (50mg, 0.15mmol), A48-2 (54mg, 0.23mmol), four triphenyl phosphorus palladiums (18mg, 0.015mmol), potassium carbonate (74mg, 0.53mmol) is dissolved in dioxane (5mL) and water (1mL).At 100 DEG C under nitrogen protection Lower reaction 8h.Room temperature is cooled to, kieselguhr is filtered, and is added water, is extracted with ethyl acetate three times, is merged organic faciess, is used saturation chlorine Change sodium water solution to wash once, anhydrous sodium sulfate removes solvent, Jing column chromatography purification (petroleum ether under reduced pressure:Ethyl acetate=2:1-1: 1) obtain white solid (24mg, 39%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is chemical combination Thing A48
(49) heterocyclic compound A64, which synthesizes by the following method：
1) synthesis of intermediate A 64-2：
Intermediate A 1-4 (133mg, 0.404mmol) is dissolved in into dichloromethane (5mL), under stirring at normal temperature, m-chloro is slowly added to Benzoyl hydroperoxide (174mg, 1.01mmol), stirring at normal temperature overnight, add dichloromethane (15mL) dilution, add unsaturated carbonate hydrogen Sodium solution, stirs 30 minutes, separates organic faciess and use anhydrous sodium sulfate drying, filter sodium sulfate, be spin-dried for solvent, residue post layer Analysis (dichloromethane：Methanol=100:1 to 50:1) obtain white solid (130mg, 96%).1H NMR(400MHz,CDCl3)δ 8.25 (d, J=6.8Hz, 1H), 8.22 (s, 1H), 7.54 (d, J=8.0Hz, 2H), 7.43 (d, J=8.0Hz, 3H), 7.35- 7.29 (m, 1H), 5.91 (s, 1H), 4.79 (d, J=6.0Hz, 2H), 2.57 (s, 3H).
2) synthesis of product A64：
Intermediate A 4-2 (67mg, 0.194mmol) is dissolved in into dioxane/water (5mL/1mL), intermediate 2 is added (74mg, 0.291mmol), potassium carbonate (107mg, 0.777mmol), tetra-triphenylphosphine palladium (22mg, 0.019mmol), use nitrogen Displacement, back flow reaction is overnight.Room temperature is cooled to, with suction filtered through kieselguhr, filtrate is with diluted ethyl acetate (15mL), anhydrous sodium sulfate It is dried, filters sodium sulfate, be spin-dried for solvent, residue column chromatography (dichloromethane：Methanol=50:1 to 30:1) obtain white solid (65mg, 77%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A64
(50) heterocyclic compound A69, which synthesizes by the following method：
By A33-6 (100mg, 0.29mmol), and 3- ethynyl pyridines (92mg, 0.87mmol), two triphenyl phosphorus palladium of dichloro (9mg, 0.012mmol), triphenyl phosphorus (6.1m g, 0.023mmol), Hydro-Giene (Water Science). (0.55mg, 0,023mmol) are added to two In isopropyl ammonia 2mL and N-Methyl pyrrolidone 2mL.Nitrogen is protected, and at 100 DEG C reacts 24h.It is cooled to room temperature, Jing kieselguhr Filter.Filtrate adds water dilution, extracts (10mL × 3) with ethyl acetate.Merge organic faciess, washed with saturated sodium-chloride water solution, Jing anhydrous sodium sulfate dryings, concentrating under reduced pressure.Residue Jing column chromatography purification (petroleum ether：Ethyl acetate=2:1—1:1) obtain white Color solid (17mg, 14%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A69
(51) heterocyclic compound A85, which synthesizes by the following method：
1) synthesis of intermediate A 85-2：
By A85-1 (45.6g, 200mmol), formamidine acetate (20.8g, 200mmol) and Sodium ethylate (13.6g, 200mmol) It is dissolved in 200mL dehydrated alcohol successively.After backflow 12h, solvent is spin-dried for.It is added thereto to 2N HCl (100mL).Water mutually uses acetic acid Ethyl ester is extracted.Organic faciess merge drying, and rotation is removed solvent, obtains a brown solid (22g), are directly used in next step reaction.
2) synthesis of intermediate A 85-3：
A85-2 (21.0g, 112.9mmol) and 0.5mL DMF are dissolved in after 200mL dichloromethane, under ice bath, thereto Deca oxalyl chloride (43.0g, 338.7mmol).Drop finishes, and reaction backflow is overnight.After being cooled to room temperature, solvent is spin-dried for.Solute acetic acid Ethyl ester dissolves, and organic faciess use saturated sodium bicarbonate, saturated common salt washing successively.Organic faciess are dried after being spin-dried for, solute column chromatography It is refined that (mobile phase is petroleum ether：Ethyl acetate=10: 1) a colorless oil (17.8g, 77%).1HNMR(400MHz, CDCl3) δ 8.90 (s, 1H), 4.52 (q, J=7.1Hz, 2H), 1.44 (t, J=7.2Hz, 3H).
3) synthesis of intermediate A 85-4：
A85-3 (6.14g, 30.0mmol) is dissolved in 50mL methanol, under room temperature thereto Deca triethylamine (3.03g, 30.0mmol).Normal-temperature reaction overnight after, be spin-dried for solvent.Solute column chromatography is refined, and (mobile phase is petroleum ether：Ethyl acetate= 10: 1), obtain a white solid (4.14g, 74%)1H NMR(400MHz,CDCl3)δ8.59(s,1H),4.11(s,3H),4.01 (s,3H).
4) synthesis of intermediate A 85-5：
3- methyl -2- pyridine carboxylic acid the tert-butyl esters (2.69g, 14.0mmol) is dissolved in 50mL anhydrous tetrahydro furans, -40 At DEG C, Deca LDA (2M, 28mL, 56.0mmol) thereto.After -40 DEG C of reaction 30min, it is cooled to -60 DEG C.It is quick thereto to add Enter A85-4 (2.60g, 14.0mmol).After continuing reaction 1h, 10mL saturations NH4Cl are added to be quenched.It is extracted with ethyl acetate, has Machine mutually merges drying, is spin-dried for solvent, and solute column chromatography is refined, and (mobile phase is petroleum ether：Ethyl acetate=3: 1) obtain a yellow Solid (1.36g, 28%)1H NMR (400MHz, CDCl3) δ 8.61 (s, 1H), 8.48 (d, J=4.4Hz, 1H), 8.08 (s, 1H), 7.60 (d, J=7.6Hz, 1H), 7.41-7.37 (m, 1H), 4.86 (s, 2H), 4.13 (s, 3H), 1.40 (s, 9H).
5) synthesis of intermediate A 85-6：
A85-5 (1.36g, 3.93mmol) and ammonium acetate (3.03g, 39.3mmol) are dissolved in 20mL acetic acid.108 DEG C anti- After answering overnight, solvent is spin-dried for.After solute is with ethyl acetate dissolving, saturation NaHCO is used3Wash.Organic faciess are dried to obtain a yellow Solid (880mg) is directly used in next step reaction.
6) synthesis of intermediate A 85-7：
A85-6 (440mg, 1.62mmol) and triethylamine (327mg, 3.24mmol) are dissolved in into 10mL (POCl3:Toluene=3 : in 1).After 100 DEG C of reaction 1h, solvent is spin-dried for.After solute diluted ethyl acetate, organic faciess saturation NaHCO3 is washed.Organic faciess Drying is spin-dried for.Solute column chromatography is refined, and (mobile phase is petroleum ether：Ethyl acetate=2: 1) a white solid (440mg, 100%).
7) synthesis of intermediate A 85-8：
By A85-7 (440mg, 1.62mmol), formic acid (253mg, 5.50mmol), triethylamine (924mg, 9.15mmol) and Pd (PPh3) 4 (200mg, 0.173mmol) is dissolved in 10mL DMSO.Under nitrogen protection, after 100 DEG C of reaction 1h, filter.Filtrate Use diluted ethyl acetate.Organic faciess are washed three times with saturated common salt.Organic faciess are dried and are spin-dried for, the solute refined (flowing of column chromatography It is mutually petroleum ether：Ethyl acetate=3: 1) a white solid (400mg, 96%).1H NMR(400MHz,CDCl3)δ9.70(s, 1H), 9.12 (d, J=3.6Hz, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 8.30 (d, J=8.4Hz, 1H), 7.56-7.53 (m,1H),4.16(s,3H).
8) synthesis of intermediate A 85-9：
A85-8 (400mg, 1.56mmol) is dissolved in 10mL hydrobromic acids (37%) solution.After 100 DEG C of reaction 1h, it is spin-dried for Solvent.Solute adds 10mL isopropanols, and the solid for being separated out is filtered, and solid ether drip washing obtains a yellow solid (400mg) It is directly used in next step reaction.
9) synthesis of product A85：
A85-9 (25mg, 0.1mmol), A35-5 (22mg, 0.1mmol) and DIPEA (26mg, 0.2mmol) are dissolved in into 1mL In DMF.After being dividedly in some parts PyBOP (78mg, 0.15mmol) thereto, stirring at normal temperature 12h.With diluted ethyl acetate, organic faciess Washed three times with saturated common salt.Organic faciess are dried and are spin-dried for, and solute column chromatography is refined, and (mobile phase is dichloromethane：Methanol=100 : 4) a white solid (30mg, 68%).(spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is chemical combination Thing A85
(52) heterocyclic compound A92, which synthesizes by the following method：
1) synthesis of intermediate A 92-2：
By A92-1 (100mg, 0.8mmol), 4,6- bis- chloro- 5-FUs (134mg, 0.8mmol), N, N- diisopropyl second Amine (310mg, 2.4mmol) is dissolved in tetrahydrofuran 3mL, at 50 DEG C reacts 12h.Concentrating under reduced pressure, Jing column chromatography purification (oil Ether：Ethyl acetate=1:1—0:1) obtain gray solid (180mg, 88%).1H NMR(400MHz,CDCl3)δ8.27(s, 1H),7.61(s,1H),5.10(s,2H),4.60(m,2H),4.29(m,2H).
2) synthesis of product A92：
A92-2 (80mg, 0.32mmol) and A92-3 (123mg, 0.47mmol) are dissolved in into N-Methyl pyrrolidone (2mL), Diisopropyl second ammonia (408mg, 3.16mmol) is added, 135 DEG C of reaction 24h are heated to.Room temperature is cooled to, 5mL water is added, is used Ethyl acetate (10mL × 3) is extracted.Merge organic faciess, use saturated common salt water washing, anhydrous sodium sulfate drying to filter sodium sulfate, Concentrating under reduced pressure.Residue Jing column chromatography purification (petroleum ether:Ethyl acetate=2:1-1:1), obtain yellow solid (50mg, 36%). (spectrum data is shown in Table 1) is parsed through nuclear magnetic spectrum, resulting solid is compound A92
Using above-mentioned synthetic method, with the initiation material being similar to, synthesize compound A1-A96, its structure and wave spectrum number According to as shown in table 1.
The analytic structure and spectral data of 1 heterocyclic compound A1-A96 of table
Embodiment 2
The 5-FU heterocyclic compound with Wnt signal path inhibitory activity that the present embodiment is prepared to embodiment 1 Thing A1-A96 is measured to the rejection ability of Wnt signal paths.
LWnt3A cells (CRL-2647, ATCC) culture is in the DMEM culture medium containing 10% hyclone (Hyclone) (Gibico) in.(transfection has " Super-TopFlash " TCF fluorescence report plasmids to HEK293STF stable clone cells HEK293 cells) cultivate in complete medium (containing 4mML- glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucoses, 6 μ The DMEM culture medium of g/mL blasticidin Ss and 10% hyclone) in.When LWnt3A cells and HEK293STF stable clones it is thin Born of the same parents are cultivated to degree of converging to be harvested when being 90% respectively, and with 1:1 ratio mixing.The mixed cell culture liquid in 100 μ L/ holes is added To in 96 orifice plates, make final cell concentration be 12000 cells/wells, be then further cultured for 24h.Test compound with DMSO by Level dilution, is then diluted to wanted concentration with DMEM culture medium again.Take 20 μ L compound solutions be added to it is aforesaid equipped with cell In 96 orifice plates of culture fluid, then hatch 48h in 37 DEG C.It is last per hole in add 50 μ L luciferase solution (Brigh-Glo, Promega), shake 5 minutes under room temperature.Luminous signal is determined with microplate reader (PHERAstarFS, BMG), then dense according to difference Degree compound calculates the IC of compound to the histamine result of luminous signal50Value (potency).As a result such as 2 (heterocyclic compound A1- of table Results of the A96 to the rejection ability determination experiment of Wnt signal paths) shown in.IC50Value is lower, represents the work of the heterocyclic compound Property is higher.
Results of the 2 heterocyclic compound A1-A96 of table to the rejection ability determination experiment of Wnt signal paths
From upper table 2, the heterocyclic compound in the present invention can be used as effective antagonist of Wnt signal paths, can Effectively blocking Wnt signal paths, can be used in treating or prevent because of the not normal disease for causing of Wnt signal paths.

Claims (10)

1. it is a kind of 5-FU heterocyclic compound with Wnt signal path inhibitory activity, and its pharmaceutically acceptable salt, same Position element, isomer and crystalline structure, with the structure shown in formula I：
Wherein, A is by 1-3 R4Substituent group or unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 unit are containing 1-4 miscellaneous original The hetero-aromatic ring of son, the hetero atom of the hetero-aromatic ring include one or more in N, O and S；
B is hydrogen atom, cyano group, halogen, hydroxyl, C1-8Alkyl, C3-8Cycloalkyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Acyl Amido, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Alkoxyl, C2-8Ester group, by 1-3 R5Substituent group or not Substituted phenyl ring, by 1-3 R5Substituent group or unsubstituted 5-6 units are containing 1-3 heteroatomic hetero-aromatic ring or by 1-3 Individual R5The miscellaneous original of substituent group or unsubstituted 5-7 units containing 1-2 heteroatomic saturated heterocyclic, the hetero-aromatic ring and heterocycle Attached bag includes one or more in N, O and S；
U is by 1-3 R6Substituent group or unsubstituted 6-12 units aromatic ring, 5-12 units hetero-aromatic ring, 5-7 circle heterocycles phenyl ring or 5-7 circle heterocycles 5-6 units hetero-aromatic ring, the heterocycle, hetero-aromatic ring contain the 1-4 hetero atom for being independently selected from N, O and S；
R1、R2、R3Separately selected from hydrogen atom, be substituted with a substituent or unsubstituted base replace C1-6Alkyl, it is described to take Dai Ji includes halogen, hydroxyl, cyano group, C1-3Alkyl, C3-5Cycloalkyl and C1-31-3 in alkoxyl；
R4、R5、R6Halogen, cyano group, hydroxyl, C are selected from separately1-8Alkyl, C3-8Cycloalkyl, C1-8Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Ester group, C2-8Containing 1-3 Individual heteroatomic Heterocyclylalkyl, the hetero atom include one or more in N, O and S；
Or, R4、R5、R6Separately selected from by hydrogen, halogen, hydroxyl, cyano group, C1-3Alkyl, C1-3Alkoxyl and C3-8Cycloalkanes The C of 1-3 substituent group in base1-8Alkyl, C3-8Cycloalkyl, C1-8Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-8Sulfuryl, C1-8 Amide groups, C1-8Urea groups, C1-8Oxo urea groups, C1-8Sulfoamido, C1-8Ester group, C2-8Containing 1-3 heteroatomic Heterocyclylalkyl, The hetero atom includes one or more in N, O and S；
R7Selected from hydrogen atom, D-atom, tritium atom, halogen, hydroxyl, cyano group, C1-8Alkyl, C3-8Cycloalkyl or C1-8Alkoxyl.
2. the 5-FU heterocyclic compound with Wnt signal path inhibitory activity according to claim 1, its feature exist In U be by 1-3 R6Any one in substituent group or unsubstituted following groups：
3. the 5-FU heterocyclic compound with Wnt signal path inhibitory activity according to claim 1, its feature exist In A be by 1-3 R4Any one in substituent group or unsubstituted following groups：
4. the 5-FU heterocyclic compound with Wnt signal path inhibitory activity according to claim 1, its feature exist Any one in B is following groups：
5. the 5-FU heterocyclic compound with Wnt signal path inhibitory activity according to claim 1, its feature exist Include in the heterocyclic compound：
6. the connection of the 5-FU heterocyclic compound with Wnt signal path inhibitory activity described in any one of claim 1-5 Application combination thing is closed, including by the described 5-FU heterocyclic compound with Wnt signal path inhibitory activity and its pharmacy Upper acceptable salt, isotope, isomer or crystal formation and antitumor drug, antibacterials, antiviral drugs, parasiticide disease medicine The combination of one or more in thing, central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament is combined Using the compositionss for obtaining.
7. the 5-FU heterocyclic compound with Wnt signal path inhibitory activity described in any one of claim 1-5 and its The application of pharmaceutically acceptable salt, isotope, isomer or crystal formation in the medicine for preparing antagonism Wnt signal paths.
8. application according to claim 7, it is characterised in that：The medicine of the antagonism Wnt signal paths includes for treatment Breast carcinoma, pulmonary carcinoma, bladder cancer, cancer of pancreas, hepatocarcinoma, head and neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, Melanoma, carcinoma of prostate, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, gastric cancer, myeloma, lymphoma, jacket cell drench Bar tumor, cutaneous T cell lymphoma, chronic and non-progressive anemia, spontaneity or primary thrombocytosiss, agnogenic myeloid Fibrosiss, pulmonary fibrosiss, renal fibrosiss, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, white blood Disease, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferation Sexually transmitted disease (STD) disease, cerebroma, astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, pituitary tumor and parasitism A kind of medicine of the combination of disease or several diseases in parasitosis, schistosomicide and malaria.
9. the use in conjunction group of the 5-FU heterocyclic compound with Wnt signal path inhibitory activity described in claim 6 Application of the compound in the medicine for preparing antagonism Wnt signal paths.
10. application according to claim 9, it is characterised in that：The medicine of the antagonism Wnt signal paths includes for treatment Breast carcinoma, pulmonary carcinoma, bladder cancer, cancer of pancreas, hepatocarcinoma, head and neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, Melanoma, carcinoma of prostate, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, gastric cancer, myeloma, lymphoma, jacket cell drench Bar tumor, cutaneous T cell lymphoma, chronic and non-progressive anemia, spontaneity or primary thrombocytosiss, agnogenic myeloid Fibrosiss, pulmonary fibrosiss, renal fibrosiss, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, white blood Disease, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferation Sexually transmitted disease (STD) disease, cerebroma, astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, pituitary tumor and parasitism A kind of medicine of the combination of disease or several diseases in parasitosis, schistosomicide and malaria.
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