CN105254613A - Heterocyclic compound with Wnt signal path inhibitory activity and application thereof - Google Patents

Heterocyclic compound with Wnt signal path inhibitory activity and application thereof Download PDF

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Publication number
CN105254613A
CN105254613A CN201510645986.2A CN201510645986A CN105254613A CN 105254613 A CN105254613 A CN 105254613A CN 201510645986 A CN201510645986 A CN 201510645986A CN 105254613 A CN105254613 A CN 105254613A
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signal path
sodium sulfate
wnt signal
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cancer
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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 CN201510645986.2A priority Critical patent/CN105254613A/en
Publication of CN105254613A publication Critical patent/CN105254613A/en
Priority to CN201610850360.XA priority patent/CN106565673B/en
Priority to CN201911060669.9A priority patent/CN111196803B/en
Priority to JP2018518629A priority patent/JP6853819B2/en
Priority to US15/766,799 priority patent/US10450300B2/en
Priority to PCT/US2016/055851 priority patent/WO2017062688A1/en
Priority to EP16854369.2A priority patent/EP3359154B1/en
Priority to KR1020187013073A priority patent/KR20180061363A/en
Priority to US16/653,217 priority patent/US20200048223A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides a heterocyclic compound with Wnt signal path inhibitory activity. The heterocyclic compound and chemically acceptable salt, isotope, isomer and a crystal structure thereof are provided with a structure shown as the general formula I (see the formula in the description). The invention further provides application of the heterocyclic compound with the Wnt signal path inhibitory activity. The heterocyclic compound with the 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 abnormity of the Wnt signal path.

Description

There is heterogeneous ring compound and the application thereof of Wnt signal path inhibit activities
Technical field
The present invention relates to a kind of heterogeneous ring compound and the application thereof with Wnt signal path inhibit activities, belong to medical art.
Background technology
The discovery of Wnt signal path is the earliest from the research to oncovirus and fruit bat developmental mechanism.Wnt gene found in nineteen eighty-two, be site as mouse mammary tumor virus preferential incorporation at first and certified, this gene in intercellular trafficking propagation and differentiation information, can be a kind of oncogene, was named as Int gene (mouse Int-1 and Int-3) at that time.Find that the aptery gene (wingless) of it and fruit bat belongs to identical sources gene (orthologousgene) subsequently, thus by the two in conjunction with called after Wnt gene.So far found and cloned 19 kinds of Wnt gene family members, the signal transduction pathway that Wnt gene mediates is called Wnt signal path by people.Wnt path is a very conservative signal transduction pathway.From unicellular lower eukaryote fruit bat until higher mammal, its member has the homology of height.Wnt signal transduction pathway take part in the regulation and control of regulate several biological processes, comprise maintenance (people such as Logan, Annu.Rev.Cell.Dev.Biol., 2004 of the growth of embryo and morphological development, the balance of stable, energy metabolism of tissue and stem cell, 20,781-810).People find in the research of stem cell in recent years, Wnt signal path all plays the important regulating and controlling effect (people such as Reya for the maintenance of epidermal stem cells, intestinal stem cell, hemopoietic stem cell, neural stem cell, embryonic stem cell and tumor stem cell, Nature, 2005,434,843-850).
The conduction of Wnt/ β-catenin signal path is opened after being combined with the Frizzled acceptor of 7 cell transmembrane and complementary acceptor LRP5/6 while that classical Wnt signal path being part Wnts albumen outer by after birth, and activate Dsh albumen in kytoplasm, the Dsh albumen of activation can suppress by APC albumen, GSK-3 β, Axin, the activity of key component GSK-3 β in the degraded complex body that β-catenin etc. are formed, make β-catenin not by GSK-3 β phosphorylation thus avoid Ubiquitin-proteasome to identify and degraded it, and then in kytoplasm, build up (the people such as Boutros, Mech.Dev., 1999, 83, 27-37, Perrimon, Cell, 1994,76,781-784).Just start when β-catenin accumulates to finite concentration in endochylema to shift to nucleus, and the transcription factor TCF/LEFs in karyon is combined and causes the startup factor of the downstream target gene of β-cateninn to come out and the expression that is activated, cause abnormal cell proliferation as activated c-myc, cyclin-D1, survivin, gastrin, VEGF, ASEF etc.And in normal somatic cell, intracytoplasmic β-catenin major part is combined with after birth attachment proteins E-cadherin and α-catenin and forms the adjustment that complex body participates in cytoskeleton, maintain homocellular adhesion, prevent cell from shifting, free β-the catenin of small part to be degraded after complex phosphorylates by Ubiquitin-proteasome identification and to degrade in endochylema, keep β-catenin low-level state in born of the same parents, thus make Wnt signal path be in closing condition.
Research find when Wnt gene itself or other arbitrary member's factors of path change make its abnormal activation time, all likely cause the generation of tumour.Such as, the regulatory factor that extensively there is Wnt path in colorectal cancer patients comprises APC, β-catenin, the isogenic sudden change of Axin, TCF, thus causes and the overexpression the growing relevant gene (people such as Klaus, Nat.Rev.Cancer, 2008,8,387-398).Lozzo etc. find by normal to more than 100 parts and tumor tissues and 10 human tumour cell lines research the overexpression that all there is Wnt-5amRNA in mammary cancer, lung cancer, prostate cancer and melanoma, especially the abnormal expression in mammary cancer is the (people such as Lozzo obviously, CancerResearch, 1995,55,3495).
The abnormal activation of Wnt approach occurs in cell carcinogenesis, tumour and has vital role in tumor invasiveness process, and the Wnt signal path blocking exception can be bred by inhibition tumor cell, inducing apoptosis of tumour cell.Therefore, Wnt signal path has good antineoplastic target effect.
Research shows that abnormal Wnt signal that in Wnt signal path, LRP5 process LAN causes and certain cancers are associated people such as (, Int.J.Cancer, 2004,109,106-111) Hoang.As prostate cancer, colorectal carcinoma, ovarian cancer, the esophageal carcinoma and cancer of the stomach.
β-catenin activates circulation and the amplification that Wnt signal path can increase neural progenitor cell, and disappearance can cause disappearance people such as (, Science, 2002,297,365-369) Chenn at progenitor cell interval.The abnormal activation of Wnt signal is tumorigenesis (people such as Dahmen, CancerRes., 2001,61,7039-7043) in neural system.
Wnt signal path can promote renewal and the maintenance of multipotential hemopoietic stem cell, and the Wnt signal of exception is for the cancer that the various disease caused by multipotential hemopoietic stem cell is relevant with other blood responsible (people such as Reya, Nature, 2005,434,843-850; The people such as Willert, Nature, 2003,423,448-452).
The imbalance of Wnt intracellular signaling also can pass through induced retinal inflammation, vascular leakage and neovascularization, causes the development of diabetic retinopathy.
Therefore, improve cause because above-mentioned Wnt signal path is not normal illness, just need to propose effective Wnt signal path conditioning agent.
Summary of the invention
In view of the defect that above-mentioned prior art exists, the object of the invention is to propose a kind of heterogeneous ring compound and application thereof with Wnt signal path inhibit activities, this heterogeneous ring compound with Wnt signal path inhibit activities can effective antagonism Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal
Object of the present invention is achieved by the following technical programs:
There is a heterogeneous ring compound for Wnt signal path inhibit activities, and pharmacy acceptable salt, isotropic substance, isomer and crystalline structure, there is the structure shown in general formula I:
Wherein, A is by 1-3 R 4group replace or unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 unit containing 1-4 heteroatomic hetero-aromatic ring, it is one or more that the heteroatoms of described hetero-aromatic ring comprises in N, O and S;
B is hydrogen atom, cyano group, halogen, hydroxyl, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8alkoxyl group, C 2-8ester group, by 1-3 R 5group replace or unsubstituted phenyl ring, by 1-3 R 5group replacement or unsubstituted 5-6 unit are containing 1-3 heteroatomic hetero-aromatic ring or by 1-3 R 5group replace or unsubstituted 5-7 unit containing 1-2 heteroatomic saturated heterocyclic, it is one or more that the heteroatoms of described hetero-aromatic ring and heterocycle comprises in N, O and S;
U is by 1-3 R 6group replace or unsubstituted 6-12 unit aromatic ring, 5-12 unit hetero-aromatic ring, 5-7 unit heterocycle and phenyl ring or 5-7 unit heterocycle and 5-6 unit hetero-aromatic ring, described heterocycle, hetero-aromatic ring contain the heteroatoms that 1-4 is independently selected from N, O and S;
R 1, R 2, R 3the C being separately selected from hydrogen atom, being substituted with a substituent or not being substituted with a substituent 1-6alkyl, described substituting group comprises halogen, hydroxyl, cyano group, C 1-3alkyl, C 3-5cycloalkyl and C 1-31-3 in alkoxyl group;
R 4, R 5, R 6separately be selected from halogen, cyano group, hydroxyl, C 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group, C 2-8containing 1-3 heteroatomic Heterocyclylalkyl, it is one or more that described heteroatoms comprises in N, O and S;
Or, R 4, R 5, R 6separately be selected from by hydrogen, halogen, hydroxyl, cyano group, C 1-3alkyl, C 1-3alkoxyl group and C 3-8the C that 1-3 group in cycloalkyl replaces 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group, C 2-8containing 1-3 heteroatomic Heterocyclylalkyl, it is one or more that described heteroatoms comprises in N, O and S.
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, described by 1-3 R 4group replaces or 1-4 heteroatomic hetero-aromatic ring is contained in unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 unit, refers to by 1-3 R 4group replace or unsubstituted 6 yuan of aromatic rings, by 1-3 R 4group replaces or unsubstituted 10 yuan of aromatic rings or by 1-3 R 4group replaces or 1-4 heteroatomic hetero-aromatic ring is contained in unsubstituted 5-10 unit;
Described by 1-3 R 6group replace or unsubstituted 6-12 unit aromatic ring, 5-12 unit hetero-aromatic ring, 5-7 unit heterocycle and phenyl ring or 5-7 unit heterocycle and 5-6 unit hetero-aromatic ring, refer to by 1-3 R 6group replace or unsubstituted 6-12 unit aromatic ring, by 1-3 R 6group replace or unsubstituted 5-12 unit hetero-aromatic ring, by 1-3 R 6group replaces or unsubstituted 5-7 unit's heterocycle phenyl ring or by 1-3 R 6group replace or unsubstituted 5-7 unit heterocycle and 5-6 unit hetero-aromatic ring;
Described by hydrogen, halogen, hydroxyl, cyano group, C 1-3alkyl, C 1-3alkoxyl group and C 3-8the C that 1-3 group in cycloalkyl replaces 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group, C 2-8containing 1-3 heteroatomic Heterocyclylalkyl, refer to C 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group and C 2-8containing 1-3 heteroatomic Heterocyclylalkyl by hydrogen, halogen, hydroxyl, cyano group, C 1-3alkyl, C 1-3alkoxyl group and C 3-81-3 group in cycloalkyl replaces.
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, U is by 1-3 R 6group replace or unsubstituted following groups in any one:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, A is by 1-3 R 4group replace or unsubstituted following groups in any one:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, B is any one in following groups:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, this heterogeneous ring compound comprises:
The present invention also provides the above-mentioned combined utilization composition with the heterogeneous ring compound of Wnt signal path inhibit activities, comprises the composition combination of one or more in the described heterogeneous ring compound with Wnt signal path inhibit activities and pharmacy acceptable salt, isotropic substance, isomer or crystal formation and antitumor drug, antibacterials, antiviral, medicine for parasitic disease, central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament being carried out combined utilization and obtain.
The present invention also provides the above-mentioned heterogeneous ring compound with Wnt signal path inhibit activities and the application in the medicine preparing antagonism Wnt signal path of pharmacy acceptable salt, isotropic substance, isomer or crystal formation thereof;
In above-mentioned application, preferably, the medicine of described antagonism Wnt signal path is that treatment comprises mammary cancer, lung cancer, bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, the medicine of a kind of illness in schistosomicide and malaria or the combination of several illness.
The present invention also provides the above-mentioned application of combined utilization composition in the medicine preparing antagonism Wnt signal path with the heterogeneous ring compound of Wnt signal path inhibit activities.
In above-mentioned application, preferably, the medicine of described antagonism Wnt signal path is that treatment comprises mammary cancer, lung cancer, bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, the medicine of a kind of illness in schistosomicide and malaria or the combination of several illness.
Follow according to specific embodiments, in the present invention, preferably, isotropic substance comprises but is not only limited to 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 32p, 35s, 36cl etc.Various isomer, including, but not limited to steric isomer, cis-trans-isomer, tautomer etc.
Outstanding effect of the present invention is:
The heterogeneous ring compound with Wnt signal path inhibit activities of the present invention, as effective antagonist of Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal.
Accompanying drawing explanation
Fig. 1 is the test result graphic representation of heterogeneous ring compound A12 in embodiment 2;
Fig. 2 is the test result graphic representation of heterogeneous ring compound A36 in embodiment 2.
Embodiment
In order to there be understanding clearly to technical characteristic of the present invention, object and beneficial effect, existing following detailed description is carried out to technical scheme of the present invention, but can not be interpreted as to of the present invention can the restriction of practical range.Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
In following embodiment, solvent for use and medicine are analytical pure or chemical pure; Solvent is before use all through re-distillation; Anhydrous solvent all processes according to standard method or literature method.Column chromatography silica gel (100-200 order) and tlc silica gel (GF254) are Haiyang Chemical Plant, Qingdao and chemical plant, Yantai product; If not otherwise specified, all adopt sherwood oil (60-90 DEG C)/ethyl acetate (v/v) as eluent; The ethanolic soln of developer iodine or phospho-molybdic acid; All extraction solvent unexplained reference all use anhydrous Na 2sO 4dry. 1hNMR varian-400 type nuclear magnetic resonance analyser record, TMS is interior mark.LC-MS Agilent company 1100 of U.S. type HPLC-ESI-MSn combined instrument (LC-MSDTrap) record, diode-array detector (DAD), determined wavelength 214nm and 254nm, ion trap mass spectrometry (ESI source).HPLC column is AgelaDurashellC18 (4.6 × 50mm, 3.5 μm); Moving phase is the 0.1%NH4HCO3 aqueous solution: acetonitrile (from 5: 95 to 95: 5 in 5 minutes); Flow velocity is 1.8mL/min.
Embodiment 1
The present embodiment provides the heterogeneous ring compound A1-A48 and synthetic method thereof with Wnt signal path inhibit activities.
(1) heterogeneous ring compound A1, it synthesizes by the following method:
1) synthesis of intermediate A 1-2:
Compd A 1-1 (6.9g, 40mmol) is added, duplex tetramethyl ethylene ketone boric acid ester (11.2g, 44mmol), KOAc (7.8g, 80mmol), Pd (dppf) in the round-bottomed flask of 250mL 2cl 2(1.63g, 2.0mmol) and tetrahydrofuran (THF) (100mL), nitrogen replacement, return stirring spends the night, and is cooled to normal temperature, with suction filtered through kieselguhr, filtrate being spin-dried for obtains dark oil crude product, and (15.6g, content: 27%), is directly used in next step.
2) synthesis of intermediate A 1-3:
Crude intermediate A1-2 (8g, 27%, 9.86mmol) is dissolved in dioxane/water (100mL/20mL), add bretylium (1.65g, 8.88mmol), salt of wormwood (2.72g, 19.73mmol), Pd (dba) 2(567mg, 0.99mmol) and SPhos (810mg, 1.97mmol), nitrogen replacement, 80 DEG C of reactions are spent the night.Be cooled to normal temperature, with suction filtered through kieselguhr, filtrate adds 100mL water, and ethyl acetate (150mL × 3) extracts, and merges organic phase saturated aqueous common salt (300mL × 2) and washes, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for ethyl acetate, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1 adds ammoniacal liquor), obtain brown solid (1.27g, 72%).
3) synthesis of intermediate A 1-4:
By intermediate A 1-3 (100mg, 0.51mmol), 4, the chloro-5-FU (101mg, 0.61mmol) of 6-bis-, is dissolved in tetrahydrofuran (THF) (10mL), add diisopropyl ethyl amine (260mg, 2.02mmol), 50 DEG C of stirrings are spent the night, and are cooled to normal temperature, be spin-dried for solvent, residuum, through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtains pale solid (140mg, 84%). 1HNMR(400MHz，CDCl 3)δ8.54(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 A 1:
By intermediate A 1-4 (66mg, 0.20mmol), 2-naphthalene boronic acids (52mg, 0.30mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (116mg, 0.84mmol), four triphenyl phosphorus palladium (12mg, 0.010mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=200:1-50:1), obtain white solid (45mg, 54%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(2) heterogeneous ring compound A2, it synthesizes by the following method:
1) synthesis of intermediate A 2-2:
Compd A 2-1 (100mg, 0.48mmol) is dissolved in tetrahydrofuran (THF) (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (146mg, 0.58mmol), KOAc (141mg, 1.44mmol), Pd (dppf) 2cl 2(39mg, 0.048mmol), nitrogen replacement, backflow is spent the night, and is cooled to normal temperature, and with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (250mg), is directly used in next step.
2) synthesis of product A 2:
By A1-4 (66mg, 0.20mmol), A2-2 (150mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (64mg, 79%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(3) heterogeneous ring compound A3, it synthesizes by the following method:
1) synthesis of intermediate A 3-2:
Compound A-13-1 (105mg, 0.51mmol) is dissolved in dioxane (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (191mg, 0.75mmol), KOAc (147mg, 1.50mmol), Pd (dppf) 2cl 2(20mg, 0.024mmol), nitrogen replacement, 90 DEG C of stirrings are spent the night, and are cooled to normal temperature, and with suction filtered through kieselguhr, filtrate is spin-dried for, and obtain crude product dark oil thing (360mg), are directly used in next step.
2) synthesis of product A 3:
By A1-4 (50mg, 0.15mmol), A3-2 (360mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain brown solid (40mg, 63%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(4) heterogeneous ring compound A4, it synthesizes by the following method:
1) synthesis of intermediate A 4-2:
Compd A 4-1 (210mg, 1.01mmol) is dissolved in tetrahydrofuran (THF) (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (760mg, 2.99mmol), KOAc (150mg, 1.53mmol), Pd (dppf) 2cl 2(80mg, 0.10mmol), nitrogen replacement, backflow is spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, residuum, through column chromatography purification (sherwood oil: ethyl acetate=10:1), obtains colorless oil (240mg, 93%).
2) synthesis of product A 4:
By intermediate A 1-4 (50mg, 0.15mmol), intermediate A 4-2 (57mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (83mg, 0.60mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (53mg, 83%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(5) heterogeneous ring compound A5, it synthesizes by the following method:
1) synthesis of intermediate A 5-2:
A5-1 (22mg, 0.099mmol) is dissolved in dioxane (2mL), adds duplex tetramethyl ethylene ketone boric acid ester (30mg, 0.12mmol), KOAc (29mg, 0.30mmol), Pd (dppf) 2cl 2(8mg, 0.01mmol), nitrogen replacement, 90 DEG C are stirred 4 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (60mg), is directly used in next step.
2) synthesis of product A 5:
By A1-4 (20mg, 0.061mmol), A5-2 (60mg, crude product) is dissolved in dioxane/water (2mL/0.4mL), adds salt of wormwood (34mg, 0.24mmol), four triphenyl phosphorus palladiums (7mg, 0.006mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (10mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (15mg, 58%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(6) heterogeneous ring compound A6, it synthesizes by the following method:
1) synthesis of intermediate A 6-2:
A6-1 (210mg, 1.01mmol) is dissolved in tetrahydrofuran (THF) (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (305mg, 1.20mmol), KOAc (294mg, 3.00mmol), Pd (dppf) 2cl 2(80mg, 0.10mmol), nitrogen replacement, backflow is spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, residuum, through column chromatography purification (sherwood oil: ethyl acetate=4:1), obtains yellow gummy solid (270mg, 106%).
2) synthesis of product A 6:
By A1-4 (50mg, 0.15mmol), A6-2 (114mg, 0.45mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (83mg, 0.60mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (48mg, 75%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(7) heterogeneous ring compound A7, it synthesizes by the following method:
1) synthesis of intermediate A 7-2:
A7-1 (150mg, 0.72mmol) is dissolved in dioxane (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (220mg, 0.87mmol), KOAc (212mg, 2.16mmol), Pd (dppf) 2cl 2(59mg, 0.072mmol), nitrogen replacement, 90 DEG C of stirrings are spent the night, and are cooled to normal temperature, and with suction filtered through kieselguhr, filtrate is spin-dried for, and obtain crude product dark oil thing (409mg), are directly used in next step.
2) synthesis of product A 7:
By A1-4 (66mg, 0.20mmol), A7-2 (409mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (50mg, 59%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(8) heterogeneous ring compound A8, it synthesizes by the following method:
1) synthesis of intermediate A 8-2:
A8-1 (63mg, 0.30mmol) is dissolved in dioxane (6mL), adds duplex tetramethyl ethylene ketone boric acid ester (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf) 2cl 2(25mg, 0.03mmol), nitrogen replacement, 90 DEG C are stirred 2 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (160mg), is directly used in next step.
2) synthesis of product A 8:
By A1-4 (66mg, 0.20mmol), A8-2 (160mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (110mg, 080mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (60mg, 71%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(9) heterogeneous ring compound A9, it synthesizes by the following method:
1) synthesis of intermediate A 9-2:
A9-1 (63mg, 0.30mmol) is dissolved in dioxane (5mL), adds duplex tetramethyl ethylene ketone boric acid ester (91mg, 0.36mmol), KOAc (59mg, 0.60mmol), Pd (dppf) 2cl 2(25mg, 0.03mmol), nitrogen replacement, 90 DEG C are stirred 4 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (183mg), is directly used in next step.
2) synthesis of product A 9:
By A1-4 (50mg, 0.15mmol), A9-2 (183mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (35mg, 55%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(10) heterogeneous ring compound A10, it synthesizes by the following method:
1) synthesis of intermediate A 10-2:
A10-1 (250mg, 0.84mmol) is dissolved in dioxane (5mL), adds duplex tetramethyl ethylene ketone boric acid ester (257mg, 1.01mmol), KOAc (247mg, 2.53mmol), Pd (dppf) 2cl 2(68mg, 0.084mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, and are cooled to normal temperature, and with suction filtered through kieselguhr, filtrate is spin-dried for, and obtain crude product dark oil thing (556mg), are directly used in next step.
2) synthesis of product A 10:
By A1-4 (50mg, 0.15mmol), A10-2 (200mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-20:1), obtain pale solid (31mg, 50%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(11) heterogeneous ring compound A11, it synthesizes by the following method:
1) synthesis of intermediate A 11-2:
A11-1 (60mg, 0.31mmol) is dissolved in dioxane (5mL), adds duplex tetramethyl ethylene ketone boric acid ester (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf) 2cl 2(25mg, 0.031mmol), nitrogen replacement, 90 DEG C are stirred 4 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (190mg), is directly used in next step.
2) synthesis of product A 11:
By A1-4 (50mg, 0.15mmol), A11-2 (190mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain pale solid (22mg, 35%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(12) heterogeneous ring compound A12, it synthesizes by the following method:
1) synthesis of intermediate A 12-2:
A12-1 (43mg, 0.20mmol) is dissolved in dioxane (4mL), adds duplex tetramethyl ethylene ketone boric acid ester (61mg, 0.24mmol), KOAc (59mg, 0.60mmol), Pd (dppf) 2cl 2(16mg, 0.02mmol), nitrogen replacement, 90 DEG C are stirred 4 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (126mg), is directly used in next step.
2) synthesis of product A 12:
By A1-4 (50mg, 0.15mmol), A12-2 (126mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (28mg, 43%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(13) heterogeneous ring compound A13, it synthesizes by the following method:
1) synthesis of intermediate A 13-2:
A13-1 (300mg, 1.52mmol) is dissolved in DMSO (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (570mg, 2.24mmol), KOAc (440mg, 4.49mmol), Pd (dppf) 2cl 2(60mg, 0.073mmol), nitrogen replacement, 90 DEG C are stirred 24 hours, are cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (20mL), saturated aqueous common salt (20mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum, through column chromatography purification (methylene dichloride is to methylene dichloride: methyl alcohol=100:1), obtains brown oil (300mg, 81%).
2) synthesis of product A 13:
By A1-4 (66mg, 0.20mmol), A13-2 (146mg, 0.60mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (110mg, 0.80mmol), four triphenyl phosphorus palladium (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-25:1), obtain white solid (40mg, 49%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(14) heterogeneous ring compound A14, it synthesizes by the following method:
1) synthesis of intermediate A 14-2 and A14-3:
A14-1 (590mg, 2.99mmol) is dissolved in tetrahydrofuran (THF) (10mL), adds NaH (180mg80%, 6.00mmol) when ice bath stirs, stir and add CH after 30 minutes 3i (468mg, 3.30mmol), continues stirring 3 hours, be raised to normal temperature, add water (20mL), ethyl acetate (20mL × 3) extracts, and organic phase saturated aqueous common salt (50mL × 3) is washed, anhydrous sodium sulfate drying, be spin-dried for solvent, through column chromatography purification, (sherwood oil: ethyl acetate=10: 1-3: 1), obtains A14-2 (230mg to residuum, 36%) and A14-3 (330mg, 52%).
A14-2: pale solid. 1HNMR(400MHz，DMSO)δ8.33(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)δ8.03(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 DMSO (10mL), adds duplex tetramethyl ethylene ketone boric acid ester (274mg, 1.08mmol), KOAc (265mg, 2.70mmol), Pd (dppf) 2cl 2(37mg, 0.045mmol), nitrogen replacement, 90 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (20mL), and saturated aqueous common salt (20mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent and obtains dark oil thing (410mg), be directly used in next step.
3) synthesis of product A 14:
By A1-4 (66mg, 0.20mmol), A14-4 (400mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (110mg, 0.80mmol), four triphenyl phosphorus palladiums (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain pale solid (50mg, 59%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(15) heterogeneous ring compound A15, it synthesizes by the following method:
1) synthesis of intermediate A 15-1:
A14-3 (63mg, 0.30mmol) is dissolved in DMSO (6mL), adds duplex tetramethyl ethylene ketone boric acid ester (91mg, 0.36mmol), KOAc (88mg, 0.90mmol), Pd (dppf) 2cl 2(25mg, 0.03mmol), nitrogen replacement, 90 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), and saturated aqueous common salt (15mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent and obtains dark oil thing (120mg), be directly used in next step.
2) synthesis of product A 15:
By A1-4 (50mg, 0.15mmol), A15-1 (120mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (53mg, 82%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(16) heterogeneous ring compound A16, it synthesizes by the following method:
1) synthesis of intermediate A 16-2:
A16-1 (73mg, 0.32mmol) is dissolved in dioxane (4mL), adds duplex tetramethyl ethylene ketone boric acid ester (98mg, 0.39mmol), KOAc (95mg, 0.97mmol), Pd (dppf) 2cl 2(26mg, 0.032mmol), nitrogen replacement, 90 DEG C are stirred 4 hours, and be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is spin-dried for, and obtains crude product dark oil thing (213mg), is directly used in next step.
2) synthesis of product A 16:
By A1-4 (50mg, 0.15mmol), A16-2 (213mg, crude product) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain brown oil (48mg, 74%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(17) heterogeneous ring compound A17, it synthesizes by the following method:
By A1-4 (50mg, 0.152mmol), phenylo boric acid (28mg, 0.23mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=150:1-100:1), obtain white solid (30mg, 54%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(18) heterogeneous ring compound A18, it synthesizes by the following method:
By A1-4 (50mg, 0.15mmol), adjacent chlorophenylboronic acid (28mg, 0.18mmol) is dissolved in dioxane/water (5mL/1mL), adds potassiumphosphate (64mg, 0.30mmol), Pd (dppf) 2cl 2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain pale solid (15mg, 24%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(19) heterogeneous ring compound A19, it synthesizes by the following method:
A1-4 (50mg, 0.15mmol), a chlorophenylboronic acid (28mg, 0.18mmol) is dissolved in dioxane/water (5mL/1mL), adds potassiumphosphate (64mg, 0.304mmol), Pd (dppf) 2cl 2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain white solid, obtain white solid (15mg, 24%) with n-hexane/ethyl acetate recrystallization.Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(20) heterogeneous ring compound A20, it synthesizes by the following method:
A1-4 (50mg, 0.15mmol), is dissolved in dioxane/water (5mL/1mL) to chlorophenylboronic acid (28mg, 0.18mmol), adds potassiumphosphate (64mg, 0.30mmol), Pd (dppf) 2cl 2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain white solid (40mg, 71%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(21) heterogeneous ring compound A21, it synthesizes by the following method:
A1-4 (50mg, 0.15mmol), 3,4-dichlorobenzene boric acid (28mg, 0.18mmol) are dissolved in dioxane/water (5mL/1mL), add potassiumphosphate (64mg, 0.30mmol), Pd (dppf) 2cl 2(12mg, 0.015mmol), dppf (8mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain pale solid (14mg, 23%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(22) heterogeneous ring compound A22, it synthesizes by the following method:
By A1-4 (44mg in tube sealing, 0.13mmol) be dissolved in N-N-methyl 2-pyrrolidone N-(2mL), add 1, 2, 3, 4-tetrahydroisoquinoline (178mg, 1.34mmol) with diisopropyl ethyl amine (86mg, 0.67mmol), 120 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (10mL), ethyl acetate (10mL × 3) extracts, organic phase saturated aqueous common salt (20mL × 6) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain brown oil (45mg, 79%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(23) heterogeneous ring compound A23, it synthesizes by the following method:
1) synthesis of intermediate A 23-2:
A23-1 (300mg, 2.16mmol) is dissolved in methylene dichloride (6mL), is cooled to 0 DEG C in nitrogen protection.Triethylamine (254mg, 2.37mmol) is added, then adds trifluoroacetic anhydride (499mg, 2.37mmol), be warming up to stirring at room temperature 0.5h.Add frozen water and be extracted with ethyl acetate three times, merge organic phase saturated nacl aqueous solution and wash three times, add anhydrous sodium sulfate drying, spin off organic solvent and 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 glacial acetic acid (2.9mL), under ice bath, slowly drip the vitriol oil (1.88mL), then at room temperature stir 8h.The frozen water of 10mL is poured in reaction solution, be extracted with ethyl acetate three times, merge organic phase saturated sodium bicarbonate aqueous solution and be washed till bubble-free generation, wash once with saturated sodium-chloride water solution again, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: ethyl acetate=1:0-200:1), obtain 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 methyl alcohol (0.8mL) add in flask, at 60 DEG C, stir 1h, spin off methyl alcohol, add water 15mL, be extracted with ethyl acetate three times, merge organic phase, saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, is spin-dried for obtain colorless oil compound (58mg, 47%).
4) synthesis of product A 23:
A1-4 (56mg, 0.17mmol) is added, A23-4 (130mg, 0.86mmol), diisopropyl ethyl amine (119mg, 0.86mmol) and N-Methyl pyrrolidone (1.5mL) in reaction flask.8h is reacted at 120 DEG C, be cooled to room temperature and add water, be extracted with ethyl acetate three times, merge organic phase saturated sodium-chloride water solution to wash, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1), obtain oily compound (50mg, 60%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(24) heterogeneous ring compound A24, it synthesizes by the following method:
1) synthesis of intermediate A 24-2:
A24-1 (300mg, 2.16mmol) is dissolved in methylene dichloride (6mL), is cooled to 0 DEG C in nitrogen protection.Triethylamine (254mg, 2.37mmol) is added, then adds trifluoroacetic anhydride (499mg, 2.37mmol), be warming up to stirring at room temperature 0.5h.Add frozen water and be extracted with ethyl acetate three times, merge organic phase saturated nacl aqueous solution and wash three times, add anhydrous sodium sulfate drying, spin off organic solvent and 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 glacial acetic acid (2.9mL), under ice bath, slowly drip the vitriol oil (1.88mL), then at room temperature stir 8h.The frozen water of 10mL is poured in reaction solution, be extracted with ethyl acetate three times, merge organic phase saturated sodium bicarbonate aqueous solution and be washed till bubble-free generation, wash once with saturated sodium-chloride water solution again, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: ethyl acetate=1:0-200:1), obtain 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 methyl alcohol (0.8mL) add in flask, at 60 DEG C, stir 1h, spin off methyl alcohol, add water 15mL, be extracted with ethyl acetate three times, merge organic phase, saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, is spin-dried for obtain colorless oil compound (130mg, 69%).
4) synthesis of product A 24:
A1-4 (50mg, 0.15mmol) is added, A23-4 (116mg, 0.76mmol), diisopropyl ethyl amine (100mg, 0.77mmol) and N-Methyl pyrrolidone (1.5mL) in reaction flask.8h is reacted at 120 DEG C, be cooled to room temperature and add water, be extracted with ethyl acetate three times, merge organic phase saturated sodium-chloride water solution to wash, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1), obtain oily compound (40mg, 59%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(25) heterogeneous ring compound A25, it synthesizes by the following method:
1) synthesis of intermediate A 25-2:
A25-1 (1.0g, 5.0mmol) is dissolved in methylene dichloride (20mL), is cooled to 0 DEG C in nitrogen protection.Triethylamine (556mg, 5.5mmol) is added, then adds trifluoroacetic anhydride (1.16g, 5.5mmol), be warming up to stirring at room temperature 0.5h.Add frozen water and be extracted with ethyl acetate three times, merge organic phase saturated nacl aqueous solution and wash three times, add anhydrous sodium sulfate drying, spin off 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 glacial acetic acid (5.9mL), under ice bath, slowly drip the vitriol oil (3.76mL), then at room temperature stir 8h.The frozen water of 20mL is poured in reaction solution, be extracted with ethyl acetate three times, merge organic phase saturated sodium bicarbonate aqueous solution and be washed till bubble-free generation, wash once with saturated sodium-chloride water solution again, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: 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 methyl alcohol (2.4mL) add in flask, at 60 DEG C, stir 1h, spin off methyl alcohol, add water 15mL, be extracted with ethyl acetate three times, merge organic phase, saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, is spin-dried for obtain colorless oil compound (200mg, 49%).
4) synthesis of product A 25:
A1-4 (60mg, 0.18mmol) is added, A25-4 (194mg, 0.92mmol), diisopropyl ethyl amine (119mg, 0.92mmol) and N-Methyl pyrrolidone (1.5mL) in reaction flask.8h is reacted at 120 DEG C, be cooled to room temperature and add water, be extracted with ethyl acetate three times, merge organic phase saturated sodium-chloride water solution to wash, anhydrous sodium sulfate drying, steaming desolventizes, through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1), obtain oily compound (40mg, 44%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(26) heterogeneous ring compound A26, it 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 dehydrated alcohol (50mL), add sodium chloraurate (252mg, 0.70mmol) subsequently, backflow is spent the night.Be cooled to room temperature, concentrating under reduced pressure, add water (30mL), extract with methylene dichloride (30mL × 3), merge organic phase, anhydrous sodium sulfate drying, obtains yellow oil (3.08g, 50%) through column chromatography (ethyl acetate: sherwood oil=1:1) after concentrating under reduced pressure. 1HNMR(400MHz，CDCl 3)δ8.39(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), adds 10%Pd/C (560mg), under hydrogen atmosphere, be heated to 60 DEG C, react 2 hours.Be cooled to room temperature, filter, filtrate is spin-dried for obtain brown oil (3.4g, thick product, content: 56%). 1HNMR(400MHz，CDCl3)δ8.48(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 A 26:
By intermediate A 1-4 (50mg in tube sealing, 0.15mmol) be dissolved in N-N-methyl 2-pyrrolidone N-(2mL), add A26-3 (102mg, 0.76mmol) with diisopropyl ethyl amine (98mg, 0.76mmol), 120 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (10mL), ethyl acetate (10mL × 3) extracts, organic phase saturated aqueous common salt (20mL × 6) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain white solid (23mg, 35%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(27) heterogeneous ring compound A27, it synthesizes by the following method:
Compd A 1 (30mg, 0.07mmol) is dissolved in tetrahydrofuran (THF) (3mL), ice bath stirs and adds NaH (6mg80%, 0.20mmol), continues stirring and adds CH after 30 minutes 3i (20mg, 0.14mmol), continue reaction 6 hours, be spin-dried for solvent, residuum, through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtains light yellow oil (30mg, 97%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(28) heterogeneous ring compound A28, it synthesizes by the following method:
1) synthesis of intermediate A 28-2:
By crude intermediate A1-2 (1.57g, 27%, 2.75mmol) be dissolved in dioxane/water (20mL/4mL), add compd A 28-1 (500mg, 2.50mmol), salt of wormwood (690mg, 5.00mmol), Pd (dba) 2 (144mg, 0.25mmol) with SPhos (206mg, 0.50mmol), nitrogen replacement, 80 DEG C of reactions are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate adds 50mL water, ethyl acetate (60mL × 3) extracts, merge organic phase saturated aqueous common salt (150mL × 2) to wash, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for ethyl acetate, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1 adds ammoniacal liquor), obtain brown solid (340mg, 64%).
2) synthesis of intermediate A 28-3:
By intermediate A 28-2 (100mg, 0.47mmol) be dissolved in tetrahydrofuran (THF) (5mL), add the chloro-5-FU (79mg of 4,6-bis-, 0.47mmol), diisopropyl ethyl amine (180mg, 1.40mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum obtains colorless oil (110mg, 68%) through column chromatography purification (methylene dichloride: methyl alcohol=100:1). 1hNMR (400MHz, CDCl 3) 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 A 25:
By intermediate A 28-3 (50mg, 0.15mmol), 2-naphthalene boronic acids (38mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (80mg, 0.60mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain white solid (27mg, 43%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(29) heterogeneous ring compound A29, it synthesizes by the following method:
1) synthesis of intermediate A 29-2:
By compd A 29-1 (1.42g, 7.43mmol) be dissolved in 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 to not having bubble to produce under stirring, ethyl acetate (100mL × 3) extracts, organic phase saturated aqueous common salt (150mL × 2) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (sherwood oil: ethyl acetate=40:1-20:1), obtain colorless oil (1.19g, 55%). 1hNMR (400MHz, CDCl 3) 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:
By intermediate A 29-2 (1.16g, 3.97mmol) be dissolved in methylene dichloride/trifluoroacetic acid (10mL/10mL), stirring at normal temperature 3 hours, slowly add saturated aqueous sodium carbonate to not having bubble to produce, methylene dichloride (30mL × 3) extracts, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, obtain yellow oil (660mg, 87%).
3) synthesis of intermediate A 29-4:
By intermediate A 29-3 (580mg, 3.02mmol) be dissolved in dioxane/water (20mL/4mL), add crude intermediate A1-2 (1.17g, 27%, 3.32mmol), salt of wormwood (1.67g, 12.1mmol), four triphenyl phosphorus palladium (175mg, 0.15mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (30mL), methylene dichloride (30mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain dark oil thing (360mg, 58%).
4) synthesis of intermediate A 29-5:
By intermediate A 29-4 (180mg, 0.88mmol) be dissolved in tetrahydrofuran (THF) (10mL), add the chloro-5-FU (147mg of 4,6-bis-, 0.88mmol), diisopropyl ethyl amine (341mg, 2.64mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum obtains light yellow solid (190mg, 64%) through column chromatography purification (methylene dichloride: methyl alcohol=100:1). 1HNMR(400MHz，CDCl 3)δ8.46(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 A 29:
By A29-5 (50mg, 0.15mmol), 2-naphthalene boronic acids (39mg, 0.23mmol) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (82mg, 0.59mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain white solid (50mg, 78%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(30) heterogeneous ring compound A30, it synthesizes by the following method:
1) synthesis of intermediate A 30-2:
By compound A-13 0-1 (500mg, 3.50mmol) be dissolved in dioxane/water (20mL/4mL), add crude intermediate A1-2 (1.51g, 27%, 3.85mmol), salt of wormwood (1.93g, 14.0mmol), four triphenyl phosphorus palladiums (202mg, 0.175mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, and are cooled to normal temperature, add water (30mL), methylene dichloride (50mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering 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 tetrahydrofuran (THF) (10mL), adds 4, chloro-5-FU (the 168mg of 6-bis-, 1.01mmol), diisopropyl ethyl amine (389mg, 3.02mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain pale solid (230mg, 69%). 1HNMR(400MHz，CDCl 3)δ8.74(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 A 30:
By intermediate A 30-3 (50mg, 0.15mmol), 2-naphthalene boronic acids (39mg, 0.23mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain white solid (52mg, 81%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(31) heterogeneous ring compound A31, it synthesizes by the following method:
By intermediate A 30-3 (50mg, 0.15mmol), intermediate A 4-2 (58mg, 0.23mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladium (18mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain white solid (44mg, 69%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(32) heterogeneous ring compound A32, it synthesizes by the following method:
By intermediate A 30-3 (50mg in tube sealing, 0.15mmol) be dissolved in N-N-methyl 2-pyrrolidone N-(2mL), add A26-3 (102mg, 0.76mmol) with diisopropyl ethyl amine (98mg, 0.76mmol), 120 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (10mL), ethyl acetate (10mL × 3) extracts, organic phase saturated aqueous common salt (20mL × 6) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain brown solid (25mg, 39%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(33) heterogeneous ring compound A33, it synthesizes by the following method:
1) synthesis of intermediate A 33-2:
POCl3 (18.3mL is added in the two-neck bottle of 100mL, 200mmol), 100 DEG C of stirrings, by compound A-13 3-1 (10.43g, 70%, 90mmol) be dissolved in DMF (15.4mL, 200mmol) be slowly added drop-wise in above-mentioned solution, drip and finish 110 DEG C of stirrings 24 hours, be cooled to normal temperature, methylene dichloride (100mL) dilutes, slowly be poured in frozen water, methylene dichloride (100mL × 3) extracts, organic phase saturated aqueous common salt (200mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (sherwood oil: ethyl acetate=10:1), obtain white solid (2.9g, 21%). 1HNMR(400MHz，CDCl 3)δ10.08(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 acetonitrile (50mL), adds t-butyl carbamate (1.50g, 12.8mmol), Et 3siH (7.40g, 63.8mmol), trifluoroacetic acid (2.20g, 19.3mmol), stirring at normal temperature 24 hours, saturated aqueous sodium carbonate is slowly added to not having bubble to produce under stirring, ethyl acetate (100mL × 3) extracts, organic phase saturated aqueous common salt (150mL × 2) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum, through column chromatography purification (sherwood oil: ethyl acetate=5:1), obtains colorless oil (1.60g, 97%).
3) synthesis of intermediate A 33-4:
By intermediate A 33-3 (1.60g, 6.23mmol) be dissolved in methylene dichloride/trifluoroacetic acid (10mL/10mL), stirring at normal temperature 3 hours, slowly add saturated aqueous sodium carbonate to not having bubble to produce, methylene dichloride (30mL × 6) extracts, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, obtain yellow oil (810mg, 83%).
4) synthesis of intermediate A 33-5:
By intermediate A 33-4 (780mg, 4.97mmol) be dissolved in dioxane/water (20mL/4mL), add crude intermediate A1-2 (1.92g, 27%, 5.46mmol), salt of wormwood (2.74g, 19.8mmol), four triphenyl phosphorus palladiums (287mg, 0.248mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, and are cooled to normal temperature, add water (30mL), methylene dichloride (50mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering 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 tetrahydrofuran (THF) (10mL), adds 4, chloro-5-FU (the 160mg of 6-bis-, 0.96mmol), diisopropyl ethyl amine (360mg, 2.79mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain white solid (220mg, 68%). 1HNMR(400MHz，CDCl 3)δ8.57(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 A 33:
By intermediate A 33-6 (50mg, 0.15mmol), 2-naphthalene boronic acids (37mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (80mg, 0.58mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain white solid (40mg, 63%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(34) heterogeneous ring compound A34, it synthesizes by the following method:
By intermediate A 33-6 (50mg, 0.15mmol), intermediate A 4-2 (56mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (80mg, 0.58mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain pale solid (30mg, 48%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(35) heterogeneous ring compound A35, it synthesizes by the following method:
1) synthesis of intermediate A 35-2:
By compound A-13 5-1 (5g, 34.3mmol) be dissolved in acetonitrile (100mL), add NBS (18.3g, 103mmol) with benzoyl peroxide (829mg, 3.43mmol), backflow is spent the night, and is cooled to normal temperature, adds water (200mL), ethyl acetate (200mL × 3) extracts, organic phase saturated aqueous common salt (300mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum, through column chromatography purification (sherwood oil: ethyl acetate=100:1), obtains yellow oil (7.45g, 97%). 1hNMR (400MHz, CDCl 3) 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 DMF (50mL), under ice bath, adds NaN 3(8.61g, 132mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (100mL), ethyl acetate (100mL × 3) extracts, and organic phase saturated aqueous common salt (200mL × 3) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (sherwood oil: ethyl acetate=50:1), obtain colorless oil (5.6g, 90%). 1HNMR(400MHz，CDCl 3)δ8.19(s，1H)，7.50(d，J＝8.0Hz，1H)，4.45(s，2H).
3) synthesis of intermediate A 35-4:
By intermediate A 35-3 (5.6g, 29.9mmol) be dissolved in tetrahydrofuran (THF) (50mL), ice bath adds PPh3 (8.6g under stirring in batches, 32.9mmol), reflux, slow dropping water (10mL), return stirring 8 hours, be cooled to normal temperature, ethyl acetate (100mL) is diluted, extract with the hydrochloric acid (100mL × 2) of 0.2M, aqueous phase ethyl acetate (100mL) is washed once, then the NaOH aqueous solution of aqueous phase 2M is adjusted to 9 PH, ethyl acetate (200mL × 3) extracts, the organic phase anhydrous sodium sulfate drying obtained, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain brown oil (2.57g, 53%). 1HNMR(400MHz，DMSO)δ8.23(s，1H)，7.89(d，J＝9.6Hz，1H)，3.75(s，2H).
4) synthesis of intermediate A 35-5:
By intermediate A 35-4 (2.36g, 14.6mmol) be dissolved in dioxane/water (50mL/10mL), add crude intermediate A1-2 (6.31g, 27%, 16.1mmol), salt of wormwood (8.09g, 58.6mmol), four triphenyl phosphorus palladium (847mg, 0.73mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, add water (100mL), methylene dichloride (100mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-20:1 adds ammoniacal liquor), obtain brown solid (2.5g, 79%). 1HNMR(400MHz，CDCl 3)δ8.61(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:
By intermediate A 35-5 (200mg, 0.92mmol) be dissolved in tetrahydrofuran (THF) (10mL), add the chloro-5-FU (154mg of 4,6-bis-, 0.92mmol), diisopropyl ethyl amine (357mg, 2.77mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum obtains pale solid (200mg, 62%) through column chromatography purification (methylene dichloride: methyl alcohol=50:1). 1HNMR(400MHz，CDCl 3)δ8.61(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 A 35:
By intermediate A 35-6 (50mg, 0.15mmol), 2-naphthalene boronic acids (37mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (79mg, 0.57mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (68mg, 100%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(36) heterogeneous ring compound A36, it synthesizes by the following method:
By intermediate A 35-6 (50mg, 0.15mmol), intermediate A 4-2 (55mg, 0.22mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (80mg, 0.58mmol), four triphenyl phosphorus palladium (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain pale solid (28mg, 44%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(37) heterogeneous ring compound A37, it synthesizes by the following method:
1) synthesis of intermediate A 37-2:
By A37-1 (800mg, 4.28mmol) be dissolved in dioxane/water (20mL/4mL), add crude intermediate A1-2 (1.84g, 27%, 4.71mmol), salt of wormwood (1.77g, 12.8mmol), four triphenyl phosphorus palladium (247mg, 0.21mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate adds water (30mL), methylene dichloride (50mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum obtains brown solid (300mg through column chromatography purification (methylene dichloride: methyl alcohol=50:1-20:1), 35%).
2) synthesis of intermediate A 37-3:
Intermediate A 37-2 (150mg, 0.75mmol) is dissolved in tetrahydrofuran (THF) (5mL), adds 4, chloro-5-FU (the 126mg of 6-bis-, 0.75mmol), diisopropyl ethyl amine (292mg, 2.26mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain pale solid (136mg, 55%). 1HNMR(400MHz，CDCl 3)δ8.85(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 A 37:
By A37-3 (50mg, 0.15mmol), compound 12 (39mg, 0.23mmol) is dissolved in dioxane/water (5mL/1mL), adds salt of wormwood (84mg, 0.61mmol), four triphenyl phosphorus palladiums (17mg, 0.015mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, and residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain white solid (47mg, 74%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(38) heterogeneous ring compound A38, it synthesizes by the following method:
1) synthesis of intermediate A 38-2:
By 4-pyridine boronic acid (397mg, 3.23mmol) be dissolved in dioxane/water (20mL/4mL), add bretylium (500mg, 2.69mmol), salt of wormwood (742mg, 5.38mmol), Pd (dba) 2 (155mg, 0.27mmol) with SPhos (220mg, 0.54mmol), nitrogen replacement, 80 DEG C of reactions are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate adds 50mL water, ethyl acetate (60mL × 3) extracts, merge organic phase saturated aqueous common salt (150mL × 2) to wash, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for ethyl acetate, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1 adds ammoniacal liquor), obtain brown solid (240mg, 48%).
2) synthesis of intermediate A 38-3:
By intermediate A 38-2 (100mg, 0.54mmol) be dissolved in tetrahydrofuran (THF) (5mL), add the chloro-5-FU (90mg of 4,6-bis-, 0.54mmol), diisopropyl ethyl amine (210mg, 1.63mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum obtains yellow solid (80mg, 47%) through column chromatography purification (methylene dichloride: methyl alcohol=100:1). 1HNMR(400MHz，CDCl 3)δ8.69(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 A 38:
By intermediate A 38-3 (63mg, 0.20mmol), 2-naphthalene boronic acids (52mg, 0.30mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (110mg, 0.80mmol), four triphenyl phosphorus palladium (23mg, 0.02mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1), obtain white solid (46mg, 57%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(39) heterogeneous ring compound A39, it synthesizes by the following method:
1) synthesis of intermediate A 39-2:
Dioxane/water will be dissolved in bretylium (800mg, 4.30mmol), add A39-1 (1.52g, 12.1mmol), add potassiumphosphate (1.82g, 8.58mmol), Pd (dppf) 2cl 2(176mg, 0.22mmol), dppf (119mg, 0.22mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate adds water (30mL), methylene dichloride (50mL × 6) extracts, organic phase anhydrous sodium sulfate drying, filtering sodium sulfate, is spin-dried for solvent, residuum obtains brown oil (410mg, 51%) through column chromatography purification (methylene dichloride: methyl alcohol=50:1-20:1 adds ammoniacal liquor).
2) synthesis of intermediate A 38-3:
Intermediate A 39-2 (200mg, 1.07mmol) is dissolved in tetrahydrofuran (THF) (5mL), adds 4, chloro-5-FU (the 179mg of 6-bis-, 1.07mmol), diisopropyl ethyl amine (414mg, 3.21mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=150:1), obtain colorless oil (240mg, 71%). 1HNMR(400MHz，CDCl 3)δ8.23(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 A 38:
By intermediate A 39-3 (50mg, 0.16mmol), 2-naphthalene boronic acids (41mg, 0.24mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (87mg, 0.63mmol), four triphenyl phosphorus palladium (18mg, 0.016mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=150:1), obtain white solid (37mg, 58%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(40) heterogeneous ring compound A40, it synthesizes by the following method:
1) synthesis of intermediate A 40-2:
LiAlH4 (450mg is added in 50mL two-neck bottle, 11.8mmol), nitrogen replacement, tetrahydrofuran (THF) (10mL) is added with syringe, by A40-1 (500mg, 2.96mmol) be dissolved in tetrahydrofuran (THF) (10mL), slowly join in above-mentioned solution with syringe, stirring and refluxing 2 hours.Be cooled to normal temperature, under ice bath, slowly drip saturated aqueous sodium sulfate producing to no longer including bubble, stir 1 hour, suction filtration, filtrate anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent and obtain brown oil (570mg, 100%).
2) synthesis of intermediate A 40-3:
Intermediate A 40-2 (200mg, 1.16mmol) is dissolved in tetrahydrofuran (THF) (5mL), adds 4, chloro-5-FU (the 193mg of 6-bis-, 1.16mmol), diisopropyl ethyl amine (447mg, 3.46mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=50:1), obtain pale solid (150mg, 43%). 1HNMR(400MHz，CDCl 3)δ8.22(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 A 40:
By intermediate A 40-3 (50mg, 0.16mmol), 2-naphthalene boronic acids (42mg, 0.24mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (91mg, 0.66mmol), four triphenyl phosphorus palladium (19mg, 0.016mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (36mg, 55%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(41) heterogeneous ring compound A41, it synthesizes by the following method:
1) synthesis of intermediate A 41-2:
A41-1 (200mg, 1.26mmol) is dissolved in tetrahydrofuran (THF) (5mL), adds 4, chloro-5-FU (the 211mg of 6-bis-, 1.26mmol), diisopropyl ethyl amine (490mg, 3.80mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=150:1), obtain yellow solid (120mg, 33%). 1HNMR(400MHz，CDCl 3)δ9.24(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 A 41:
By intermediate A 41-2 (50mg, 0.17mmol), A4-2 (66mg, 0.26mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (96mg, 0.69mmol), four triphenyl phosphorus palladium (20mg, 0.017mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain white solid (43mg, 65%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(42) heterogeneous ring compound A42, it synthesizes by the following method:
1) synthesis of intermediate A 42-2:
By A42-1 (1.0g, 5.92mmol) be dissolved in methylene dichloride (30mL), add triethylamine (896mg successively, 8.88mmol), Trifluoromethanesulfonic anhydride (2.5g, 8.88mmol), stirring at normal temperature is spent the night, and water adds cancellation, extraction into ethyl acetate three times, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, steaming desolventizes, and residuum is through column chromatography purification (sherwood oil: ethyl acetate=30:1), obtain white solid (1.65g, 93%).
2) synthesis of intermediate A 42-3:
A42-2 (1.35g is added in reaction flask, 4.49mmol), potassiumphosphate (1.27g, 5.99mmol), Pd (dba) 2 (114mg, 0.20mmol), XPhos (143mg, 0.30mmol), vacuumize, displacement nitrogen, add Nitromethane 99Min. (4mL), dioxane (25mL), be heated to 80 DEG C to stir 18 hours, be cooled to normal temperature, acetic acid (8mL) adds, zinc powder (2.93g, 45mmol) add, 35 DEG C are reacted 3 hours, cross the zinc powder filtering and do not reacted, water (30mL) adds, extraction into ethyl acetate twice, aqueous phase 1MNaOH adjusts PH=10, extraction into ethyl acetate three times, organic phase saturated common salt is washed, anhydrous sodium sulfate drying, steaming desolventizes, residuum is through column chromatography purification (sherwood oil: 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 tetrahydrofuran (THF) (1mL), adds 4, chloro-5-FU (the 167mg of 6-bis-, 1.0mmol), diisopropyl ethyl amine (260mg, 2.0mmol), 50 DEG C of stirrings are spent the night, be cooled to normal temperature, be spin-dried for solvent, residuum is through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1), obtain faint yellow solid (120mg, 38%).
4) synthesis of product A 42:
By intermediate A 42-4 (53mg, 0.17mmol), A4-2 (66mg, 0.26mmol) be dissolved in dioxane/water (5mL/1mL), add salt of wormwood (96mg, 0.69mmol), four triphenyl phosphorus palladium (20mg, 0.017mmol), nitrogen replacement, 100 DEG C of stirrings are spent the night, be cooled to normal temperature, with suction filtered through kieselguhr, filtrate is diluted by ethyl acetate (15mL), anhydrous sodium sulfate drying, filtering sodium sulfate, be spin-dried for solvent, residuum is through column chromatography purification (methylene dichloride: methyl alcohol=100:1-50:1), obtain faint yellow solid (35mg, 66%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(43) heterogeneous ring compound A43, it synthesizes by the following method:
By A42 (17mg, 0.04mmol), salt of wormwood (2.8mg, 0.02mmol) is dissolved in DMSO (1mL), adds 30%H 2o 2(6mg, 0.05mmol), stirring at normal temperature 3 hours, is poured into water, suction filtration, and washing, normal hexane is washed, vacuum-drying, obtains faint yellow solid (14mg, 83%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(44) heterogeneous ring compound A44, it synthesizes by the following method:
By A42-4 (40mg, 0.13mmol), A26-3 (51mg, 0.39mmol), DIPEA (83mg, 0.64mmol) be dissolved in NMP (1.5mL), be heated to 130 DEG C of reaction 12h, be cooled to room temperature, add water, be extracted with ethyl acetate three times, merge organic phase, wash once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, remove solvent under reduced pressure, brown solid (20mg is obtained through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1), 38%) (spectrum data is in table 1) is resolved through nuclear magnetic spectrum, the solid obtained is compound
(45) heterogeneous ring compound A45, it synthesizes by the following method:
By A35-6 (50mg, 0.15mmol), A26-3 (97mg, 0.72mmol), DIPEA (93mg, 0.72mmol) be dissolved in NMP (1.5mL), be heated to 130 DEG C of reaction 8h, be cooled to room temperature, add water, be extracted with ethyl acetate three times, merge organic phase, wash once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain brown solid (25mg, 39%) through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(46) heterogeneous ring compound A46, it synthesizes by the following method:
By A33-6 (50mg in tube sealing, 0.15mmol) be dissolved in NMP (2mL), add A26-3 (97mg, 0.73mmol) with DIPEA (94mg, 0.73mmol), 120 DEG C of stirrings are spent the night, and are cooled to normal temperature, add water (10mL), ethyl acetate (10mL*3) extracts, and organic phase saturated aqueous common salt (20mL*6) is washed, anhydrous sodium sulfate drying, filtering sodium sulfate,, remove solvent under reduced pressure, through column chromatography purification (methylene dichloride: methyl alcohol=50:1-30:1), obtain brown oil (50mg, 78%).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(47) heterogeneous ring compound A47, it synthesizes by the following method:
1) synthesis of intermediate A 47-2:
Add A47-1 (10g, 50mmol) in the flask of 100mL, sulphur (3.22g, 100mmol), cyanamide (4.36g, 100mmol) and pyridine (40mL), be heated to 130 DEG C of reactions 90 minutes.Be cooled to room temperature, solid is leached, wash by ethyl acetate, dry dark brown solid (9.7g, 76%). 1HNMR(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), Isopentyl nitrite (11g, 95mmol) be dissolved in tetrahydrofuran (THF) 150mL, react 2h at 80 DEG C, be cooled to room temperature and add water, be extracted with ethyl acetate three times, merge organic phase, wash once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, remove solvent under reduced pressure, yellow solid (3.3g, 36%) is obtained through column chromatography purification (sherwood oil: ethyl acetate=10:1-5:1). 1HNMR(400MHz,CDCl 3)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 the ethyl acetate solution (3M, 5mL) of hydrogenchloride, at room temperature stirs 2h.Remove solvent under reduced pressure, obtain yellow solid (580mg, 100%). 1HNMR(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 A 47:
By A1-4 (50mg, 0.15mmol), A47-4 (107mg, 0.77mmol), DIPEA (198mg, 1.53mmol) are dissolved in NMP (2mL), react 8h at being heated to 120 DEG C.Be cooled to room temperature, add water, be extracted with ethyl acetate three times, merge organic phase, wash once with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, remove solvent under reduced pressure, brown solid compound (30mg, 45%) is obtained through column chromatography purification (sherwood oil: ethyl acetate=5:1-3:1).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
(48) heterogeneous ring compound A48, it synthesizes by the following method:
1) synthesis of intermediate A 48-2:
By A48-1 (180mg, 0.91mmol), duplex tetramethyl ethylene ketone boric acid ester (348mg, 1.37mmol), 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (II) (37mg, 0.045mmol), Potassium ethanoate (180mg, 1.83mmol) is dissolved in tetrahydrofuran (THF) (10mL).At 80 DEG C, react 8h under nitrogen protection, be cooled to room temperature, through diatomite filtration, remove solvent under reduced pressure, obtain black solid (300mg, content: 74%).
2) synthesis of product A 48:
By A1-4 (50mg, 0.15mmol), A48-2 (54mg, 0.23mmol), four triphenyl phosphorus palladiums (18mg, 0.015mmol), salt of wormwood (74mg, 0.53mmol) is dissolved in dioxane (5mL) and water (1mL).At 100 DEG C, 8h is reacted under nitrogen protection.Be cooled to room temperature, diatomite filtration, add water, be extracted with ethyl acetate three times, merge organic phase, wash once with saturated sodium-chloride water solution, anhydrous sodium sulphate, remove solvent under reduced pressure, obtain white solid (24mg, 39%) through column chromatography purification (sherwood oil: ethyl acetate=2:1-1:1).Resolve (spectrum data is in table 1) through nuclear magnetic spectrum, the solid obtained is compound
The analytic structure of table 1 heterogeneous ring compound A1-A48 and spectral data
Embodiment 2
The present embodiment measures the rejection ability of heterogeneous ring compound A1-A48 to Wnt signal path with Wnt signal path inhibit activities that embodiment 1 prepares.
LWnt3A cell (CRL-2647, ATCC) is cultivated in the DMEM substratum (Gibico) containing 10% foetal calf serum (Hyclone).The HEK293STF stable clone cell HEK293 cell of TCF fluorescence report plasmid (transfection has " Super-TopFlash ") is cultivated in perfect medium (the DMEM substratum containing 4mML-glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 6 μ g/mL blasticidins and 10% foetal calf serum).Gather in the crops respectively when LWnt3A cell and HEK293STF stable clone cell cultures are 90% to degree of converging, and mix with the ratio of 1:1.The mixed cell culture liquid in 100 μ L/ holes joins in 96 orifice plates, makes final cell concn be 12000 cells/well, and then cultivates 24h.Test compound DMSO stepwise dilution, and then be diluted to wanted concentration with DMEM substratum.Get 20 μ L compound solutions to join and be aforesaidly equipped with in 96 orifice plates of cell culture fluid, then in 37 DEG C of hatching 48h.50 μ L luciferase solution (Brigh-Glo, Promega) are added, jolting 5 minutes under normal temperature in last every hole.Luminous signal microplate reader (PHERAstarFS, BMG) measures, and then calculates the IC of compound according to the suppression result of different concns compound to luminous signal 50value (tiring).Result is as shown in table 2 (part heterogeneous ring compound A1-A43 is to the result of the rejection ability determination experiment of Wnt signal path).IC 50be worth lower, the activity representing this heterogeneous ring compound is higher.
Table 2
Numbering IC 50(μM) Numbering IC 50(μM) Numbering IC 50(μM)
A1 0.0014 A16 0.027 A30 0.023
A2 0.0029 A17 >1 A31 0.001
A3 0.036 A18 0.48 A32 0.002
A4 0.0003 A19 0.014 A33 0.0014
A5 0.0021 A20 0.211 A34 0.003
A6 0.0047 A21 0.014 A35 0.004
A7 0.0074 A22 0.014 A36 0.0005
A8 0.0015 A23 0.015 A37 0.0024
A9 0.0028 A24 0.037 A38 0.005
A10 0.285 A25 >1 A39 0.129
A11 0.0016 A26 0.0015 A40 >1
A12 0.0003 A27 0.937 A41 0.055
A13 0.099 A28 0.017 A42 0.0007
A14 0.0059 A29 0.577 A43 0.075
A15 0.019
From upper table 2, the heterogeneous ring compound in the present invention, as effective antagonist of Wnt signal path, can effectively block Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal.

Claims (10)

1. there is a heterogeneous ring compound for Wnt signal path inhibit activities, and pharmacy acceptable salt, isotropic substance, isomer and crystalline structure, there is the structure shown in general formula I:
Wherein, A is by 1-3 R 4group replace or unsubstituted 6 yuan of aromatic rings, 10 yuan of aromatic rings or 5-10 unit containing 1-4 heteroatomic hetero-aromatic ring, it is one or more that the heteroatoms of described hetero-aromatic ring comprises in N, O and S;
B is hydrogen atom, cyano group, halogen, hydroxyl, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8alkoxyl group, C 2-8ester group, by 1-3 R 5group replace or unsubstituted phenyl ring, by 1-3 R 5group replacement or unsubstituted 5-6 unit are containing 1-3 heteroatomic hetero-aromatic ring or by 1-3 R 5group replace or unsubstituted 5-7 unit containing 1-2 heteroatomic saturated heterocyclic, it is one or more that the heteroatoms of described hetero-aromatic ring and heterocycle comprises in N, O and S;
U is by 1-3 R 6group replace or unsubstituted 6-12 unit aromatic ring, 5-12 unit hetero-aromatic ring, 5-7 unit heterocycle and phenyl ring or 5-7 unit heterocycle and 5-6 unit hetero-aromatic ring, described heterocycle, hetero-aromatic ring contain the heteroatoms that 1-4 is independently selected from N, O and S;
R 1, R 2, R 3the C being separately selected from hydrogen atom, being substituted with a substituent or not being substituted with a substituent 1-6alkyl, described substituting group comprises halogen, hydroxyl, cyano group, C 1-3alkyl, C 3-5cycloalkyl and C 1-31-3 in alkoxyl group;
R 4, R 5, R 6separately be selected from halogen, cyano group, hydroxyl, C 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group, C 2-8containing 1-3 heteroatomic Heterocyclylalkyl, it is one or more that described heteroatoms comprises in N, O and S;
Or, R 4, R 5, R 6separately be selected from by hydrogen, halogen, hydroxyl, cyano group, C 1-3alkyl, C 1-3alkoxyl group and C 3-8the C that 1-3 group in cycloalkyl replaces 1-8alkyl, C 3-8cycloalkyl, C 1-8alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8sulfuryl, C 1-8amide group, C 1-8urea groups, C 1-8oxo urea groups, C 1-8sulfoamido, C 1-8ester group, C 2-8containing 1-3 heteroatomic Heterocyclylalkyl, it is one or more that described heteroatoms comprises in N, O and S.
2. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1, is characterized in that U is by 1-3 R 6group replace or unsubstituted following groups in any one:
3. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1, is characterized in that A is by 1-3 R 4group replace or unsubstituted following groups in any one:
4. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1, is characterized in that B is any one in following groups:
5. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1, is characterized in that this heterogeneous ring compound comprises:
6. the combined utilization composition with the heterogeneous ring compound of Wnt signal path inhibit activities described in any one of claim 1-5, comprises the composition combination of one or more in the described heterogeneous ring compound with Wnt signal path inhibit activities and pharmacy acceptable salt, isotropic substance, isomer or crystal formation and antitumor drug, antibacterials, antiviral, medicine for parasitic disease, central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament being carried out combined utilization and obtain.
7. the heterogeneous ring compound with Wnt signal path inhibit activities described in any one of claim 1-5 and the application in the medicine preparing antagonism Wnt signal path of pharmacy acceptable salt, isotropic substance, isomer or crystal formation thereof.
8. application according to claim 7, is characterized in that: the medicine of described antagonism Wnt signal path is that treatment comprises mammary cancer, lung cancer, bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, the medicine of a kind of illness in schistosomicide and malaria or the combination of several illness.
9. the application of combined utilization composition in the medicine preparing antagonism Wnt signal path of the heterogeneous ring compound of the Wnt of having signal path inhibit activities according to claim 6.
10. application according to claim 9, is characterized in that: the medicine of described antagonism Wnt signal path is that treatment comprises mammary cancer, lung cancer, bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute leukemia, chronic leukemia, lymphoid leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, the medicine of a kind of illness in schistosomicide and malaria or the combination of several illness.
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