CN109553617A - Wnt and Hedgehog signal path double inhibitors and its application - Google Patents
Wnt and Hedgehog signal path double inhibitors and its application Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention provides Wnt and Hedgehog signal path double inhibitors and its applications, and specifically there is provided a kind of heterocyclic compounds and its pharmaceutically acceptable salt with Wnt and Hedgehog signal path inhibitory activity, have structure shown in general formula I:The present invention also provides a kind of pharmaceutical compositions, and it includes the above-mentioned heterocyclic compounds and pharmaceutically acceptable carrier with Wnt and Hedgehog signal path inhibitory activity of therapeutically effective amount.The present invention also provides application of the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity in the drug that preparation treats or prevents Wnt and Hedgehog signal path exception.Heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity of the invention, is able to suppress Wnt and Hedgehog signal path, so as to improve because Wnt signal path or Hedgehog signal path it is not normal caused by illness.
Description
Technical field
The present invention relates to a kind of heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity and its application,
Belong to pharmaceutical technology field.
Background technique
Malignant tumour is to endanger one of main disease of human health, the annual malignant tumour new cases about 1090 in the whole world
Ten thousand, and patient about 6,700,000 dead due to malignant tumour every year.Anti-tumor drug research and development experienced great variety in recent years, with
Common anti-tumor drug is mainly cytotoxic drug on preclinical therapy, this kind anti-cancer drugs has the selectivity being difficult to avoid that
Difference, toxic side effect are strong, are also easy to produce the disadvantages of drug resistance.Recently as the progress at full speed of life science, malignant cell
The phase interaction of the interior regulation of signal transduction, cell cycle, the induction of Apoptosis, angiogenesis and cell and extracellular matrix
With etc. various basic processes be just gradually elucidated with.Relevant intracellular signal transduction pathway is proliferated to tumor cell differentiation with some
Key enzyme finds that selectively acting in specific target spot, is provided simultaneously with the novel elder generation of efficient, less toxic property as drug screening target spot
Lead the important directions that compound has become current anti-tumor drug research and development；Herceptin (trastuzumab), she replaces at horse
Buddhist nun (imatinib), the successful listing of the targeted drugs such as Gefitinib (gefitinib) and Erlotinib (erlotinib) is just
It is typical example.
The characteristics of transfer and regeneration are malignant tumours, and the problem for the treatment of malignant tumour.Even the targeting of a new generation
Drug is also little to the transfer of tumour and regeneration curative effect.Based on this, Wnt signal path and Hedgehog (Hh) signal are logical in recent years
The research on road receives scientific circles and more and more payes attention to, and is not only because Wnt signal path and Hh signal path is extremely living
Changing in many tumours includes the generation of basal-cell carcinoma, brain tumor, breast cancer, prostate cancer and some alimentary system malignant tumours
Development process has all served very important, it is often more important that, Wnt signal path and Hh signal path are embryonic development accesses,
To regulation tumor stem cell, thus controls metastases and play an important role with regeneration.
The discovery of Wnt signal path is earliest from the research to oncogenic virus and drosophila developmental mechanism.Wnt gene is in 1982
Year discovery, is initially the site as mouse mammary tumor virus preferential incorporation and certified, which can pass in iuntercellular
It is incremented by and grows and break up information, is a kind of oncogene, was named as Int gene (mouse Int-1 and Int-3) at that time.It is subsequently found
The aptery gene (wingless) of it and drosophila belongs to identical sources gene (orthologousgene), orders so that the two be combined
Entitled Wnt gene.So far it has been found that and cloning 19 kinds of Wnt gene family members, the signal that people are mediated Wnt gene turn
Guiding path is known as Wnt signal path.Wnt access is a very conservative signal transduction pathway.From unicellular lower eukaryote drosophila up to
Higher mammal, member have the homology of height.Wnt signal transduction pathway takes part in the tune of various biological process
Control, maintenance (Logan etc. of growth and morphological development, the stabilization of tissue, the balance of energetic supersession and stem cell including embryo
People, Annu.Rev.Cell.Dev.Biol., 2004,20,781-810).People have found in the research to stem cell in recent years,
Wnt signal path is for epidermal stem cells, intestinal stem cell, candidate stem cell, neural stem cell, embryonic stem cell and Tumor Stem
The maintenance of cell all plays important regulating and controlling effect (Reya et al., Nature, 2005,434,843-850).
Classical Wnt signal path is by ligand Wnts albumen outside after birth while the Frizzled receptor with 7 cell transmembranes
The conduction of Wnt/ β-catenin signal path is opened after combining with complementary receptor LRP5/6, and activates Dsh albumen in cytoplasm,
The Dsh albumen of activation can inhibit in the degradation complex by formation such as APC albumen, GSK-3 β, Axin, β-catenin key at
The activity for dividing GSK-3 β, makes β-catenin it not identified and be dropped so as to avoid Ubiquitin-proteasome by GSK-3 β phosphorylation
It solves, and then built up in cytoplasm (Boutros et al., Mech.Dev., 1999,83,27-37；Perrimon, Cell,
1994,76,781-784).It is begun to when β-catenin accumulates to a certain concentration in endochylema to cell nuclear transfer, and and born of the same parents
Transcription factor TCF/LEFs in core is exposed in conjunction with the startup factor for the downstream target gene for leading to β-cateninn and is swashed
Expression living, such as activate c-myc, cyclin-D1, survivin, gastrin, VEGF, ASEF and lead to abnormal cell proliferation.
And in normal somatic cell, intracytoplasmic β-catenin is most of to be tied with after birth attachment proteins E-cadherin and α-catenin
It closes and forms the adjusting that complex participates in cytoskeleton, maintain the adherency of homocellular, prevent cell from shifting, the free β-of small part
Catenin is degraded after complex phosphorylation in endochylema and is identified and degraded by Ubiquitin-proteasome, keeps β-catenin intracellular
Low-level state, so that Wnt signal path be made to be in close state.
Research finds when Wnt gene itself or access other any member factors, which change, makes its abnormal activation,
It is possible to cause the generation of tumour.For example, the regulatory factor for being widely present Wnt access in colorectal cancer patients includes APC, β-
The isogenic mutation of catenin, Axin, TCF, thus cause gene relevant to growth overexpression (Klaus et al.,
Nat.Rev.Cancer,2008,8,387-398).Lozzo etc. passes through swollen to more than 100 parts of normal and tumor tissues and 10 mankind
There is the excessive table of Wnt-5amRNA in breast cancer, lung cancer, prostate cancer and melanoma in the research discovery of oncocyte system
It reaches, the abnormal expression especially in breast cancer is obvious (Lozzo et al., Cancer Research, 1995,55,3495).
The abnormal activation of Wnt approach plays a significant role during cell carcinogenesis, tumour generation and tumor invasiveness, and
Block abnormal Wnt signal path that can inhibit tumor cell proliferation, inducing apoptosis of tumour cell.Therefore, Wnt signal path has
There is preferable antineoplastic target to act on.
Hedgehog signal path is a highly conserved intercellular signal transduction system, is sent out in drosophila within 1980
It is existing, reveal the furcella of many likeness in form hedgehogs since the pathway gene mutation of drosophila can lead to larva body surface, therefore is named as hedgehog
Access Hedgehog (Hh).Hh signal path is by Hh ligand, two transmembrane protein receptor patched membrane receptor
(PTCH) it is formed with smoothened transmembrane protein (SMO) and downstream transcription factor Gli albumen etc..PTCH
With two kinds of transmembrane proteins that SMO is on target cell membrane, wherein PTCH is the 12 cross-film eggs encoded by tumor suppressor gene PTCH
It is white, it is a kind of cell surface receptor, there is the double action be isolated and transduce Hh.SMO is 7 transmembrane proteins, in structure
It is similar to g protein coupled receptor family height, have the function of Hh signal of transduceing.PTCH and SMO is in Hh signal transduction process
Play the role of receptor, wherein PTCH is the receptor of Hh.When Hh is not present, PTCH prevents SMO indexing to cell membrane, to press down
The activity of SMO processed；And then inhibit the transcriptional expression of downstream gene.When Hh signal exists, Hh induces SMO carboxyl in conjunction with PTCH
Phosphorylation occurs for multiple serine/threonine residues at end, and SMO is caused to assemble and activate in cell surface, the SMO and driving egg of activation
White sample molecule Costal2 (Cos2) and serine/threonine kinases Fused (Fus), Suppressor offused (Sufu) form multiple
It closes object and dissociates from micro-pipe, transcriptional activation is played in the form of overall length, finally causes zinc finger sample transcription factor Gli
Activation, and the latter enters in nucleus the transcription for causing target gene.Therefore, in Hh signal path, Hh is the signal path
Starting point, and Gli is the terminal of the signal path as transcription factor；Hh and SMO as the exciting factor, PTCH as inhibit because
Son regulates and controls the activity of signal path.
Hh signal path is capable of the proliferation of inducing cell, this function is extremely important in embryonic development and organizational protection,
But between this access abnormal activation of adulthood and tumour, there is certain to contact.In all dead diseases due to cancer
About 25% tumour is related with the abnormal activation of Hh signal path in people.Including: basal-cell carcinoma, pith mother cells
Tumor, breast cancer, cancer of pancreas, lung cancer, colon cancer, oophoroma, melanoma, bladder cancer, rhabdomyosarcoma, prostate cancer, meninx
Tumor, sample preparation basal cell carcinoma syndrome etc. (Sachin Gupta et al., Ther.Adv.Med.Oncol.2010,2,237-
250.)。
Wnt signal path and Hedgehog signal path belong to embryo's access, thus have complexity between two accesses
Connection.For example, some researches show that the activation of Wnt signal path can raise the expression of rna binding protein CRD-BP, thus surely
Determine the m-RNA of Gli1, thus activate Hedgehog signal path (Noubissi et al., Cancer Res.2009,69,8572-
8578.)；There are also studies have shown that the activation of Hedgehog signal path, which can raise sFRP-1 albumen, (inhibits Wnt signal path
One glycoprotein) expression, to inhibit Wnt signal path (He et al., J.Biol.Chem.2006,281,35598-
35602.)；In addition, discovery has Wnt signal path and Hedgehog signal logical in the lung cancer in mice tumor model caused by smoking
Road is activated (Hassan et al., PLoS ONE.2006,1, e93.) simultaneously.
Therefore, either for the not normal caused illness of Wnt access, or cause for Hedgehog signal path is not normal
Illness or Wnt and two signal paths of Hedgehog it is not normal simultaneously caused by illness, compared to only inhibiting single signal
Access, while inhibiting Wnt signal path and Hedgehog signal path that will have better treatment use.
However, up to now, concentrating on inhibiting single access to the research of Wnt and Hedgehog signal pathway inhibitor
The research of agent, such as Wnt signal path inhibitor LGK974 or Hedgehog signal pathway inhibitor Vismodegib, invention
People also discloses the compound of the tricyclic condensed skeleton of a kind of 6-5-6 before this, and the compound is only used as Wnt signal path inhibitor
(Bioorg.Med.Chem.2016,24,5861-5872., patent CN104557862A).There has been no press down simultaneously in the prior art
The compound of Wnt signal path and Hedgehog signal path processed is reported.
Summary of the invention
In view of the problems of the above-mentioned prior art, the purpose of the present invention is to propose to logical with Wnt and Hedgehog signal
The heterocyclic compound of road inhibitory activity and its application can inhibit Wnt signal path and Hedgehog signal path simultaneously, thus
Improve because Wnt signal path or Hedgehog signal path it is not normal caused by illness.
The purpose of the present invention is achieved by the following technical programs:
A kind of heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity and its pharmaceutically acceptable
Salt has structure shown in general formula I:
Wherein:
X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8；
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from by 1-3
The group of D-atom or halogeno-group replaces；
R4Selected from D-atom, halogen, cyano, C1-6Alkoxy；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl it is unsubstituted or by 1-3 be respectively selected from D-atom or
The group of halogeno-group replaces；
R6、R7、R8It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl
It is unsubstituted or replaced by the 1-3 group for being respectively selected from D-atom or halogeno-group with alkoxy；
M is selected from 0,1,2,3；
N is selected from 0,1,2；
Work as X1、X2、X3、X4、X5、X6、X7It is CH, and R4When for F, R5It cannot be methyl.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt has structure shown in general formula Ia:
Wherein:
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from by 1-3
The group of D-atom or halogeno-group replaces；
R4Selected from D-atom, halogen, cyano, C1-6Alkoxy；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl it is unsubstituted or by 1-3 be respectively selected from D-atom or
The group of halogeno-group replaces；
R6、R7It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl and
Alkoxy is unsubstituted or is replaced by the group that 1-3 are respectively selected from D-atom or halogeno-group；
M is selected from 0,1,2,3；
N is selected from 0,1,2；
Work as R4When for F, R5It cannot be methyl.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt has structure shown in general formula Ib:
Wherein:
X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8, and being wherein up to 4 is that N (preferably up to has 3
A is N, and more preferably up to having 2 is N), and at least one is N；
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from by 1-3
The group of D-atom or halogeno-group replaces；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl it is unsubstituted or by 1-3 be respectively selected from D-atom or
The group of halogeno-group replaces；
R6、R7、R8It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl
It is unsubstituted or replaced by the 1-3 group for being respectively selected from D-atom or halogeno-group with alkoxy；
M is selected from 0,1,2,3；
N is selected from 0,1,2.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8, and be wherein up to 3 and be
N；
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8, and be wherein up to 2 and be
N；
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8, and be wherein up to 1 and be
N；
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: R1、R2、R3For hydrogen atom.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: m, n are respectively and independently selected from 0 or 1.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: R6、R7For hydrogen atom.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt, it is characterised in that: R8For hydrogen atom.
Preferably, the above-mentioned heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity, and its pharmaceutically
Acceptable salt comprising one of following structural or a variety of combinations:
The present invention also provides a kind of pharmaceutical composition, above-mentioned it includes therapeutically effective amount has Wnt and Hedgehog
The heterocyclic compound and pharmaceutically acceptable carrier of signal path inhibitory activity.
The present invention also provides the heterocyclic compounds that compound A or above-mentioned has Wnt and Hedgehog signal path inhibitory activity
The application of object or pharmaceutical composition in the drug that preparation treats or prevents Wnt or Hedgehog signal path exception；It is described to control
The drug and its pharmaceutical composition for treating or preventing Wnt or Hedgehog signal path exception include treatment breast cancer, lung cancer, bladder
Cancer, cancer of pancreas, liver cancer, neck squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, fibroma, melanoma, prostate
Cancer, colorectal cancer, oophoroma, cervical carcinoma, the cancer of the esophagus, gastric cancer, myeloma, lymthoma, lymphoma mantle cell, cutaneous T-cell
Lymthoma, chronic and non-progressive anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, lung fiber
Change, renal fibrosis, liver fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukaemia, acute white blood
Disease, chronic leukemia, lymphatic leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferative illness, brain tumor,
One of astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, hypophysoma illness or several diseases
The drug and its pharmaceutical composition of disease.
Above-mentioned pharmaceutical composition refers to the above-mentioned jeterocyclic chemistry with Wnt and Hedgehog signal path inhibitory activity
Close the composition of object and its pharmaceutically acceptable salt or carrier as component.
Protrusion effect of the invention are as follows:
Known Wnt signal path inhibitor (LGK974) and Hedgehog signal pathway inhibitor (Vismodegib) are all
It can only inhibit one of Wnt signal path and Hedgehog signal path, cannot inhibit Wnt and Hedgehog signal logical simultaneously
Road.And the heterocyclic compound in the present invention can as effective antagonist of Wnt signal path and Hedgehog signal path
Wnt signal path and Hedgehog signal path are effectively blocked simultaneously, can be preferably applied to treat or prevent because Wnt signal is logical
Illness caused by road or Hedgehog signal path are not normal.
Detailed description of the invention
Fig. 1 is that the heterocyclic compound A1 with Wnt and Hedgehog signal path inhibitory activity of embodiment 8 believes Wnt
The cell of number access inhibits test result curve graph；
Fig. 2 is that the heterocyclic compound A5 with Wnt and Hedgehog signal path inhibitory activity of embodiment 8 believes Wnt
The cell of number access inhibits test result curve graph；
Fig. 3 is the heterocyclic compound A with Wnt and Hedgehog signal path inhibitory activity of embodiment 8 to Wnt signal
The cell of access inhibits test result curve graph；
Fig. 4 is A1 pair of heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity of embodiment 9
The cell of Hedgehog signal path inhibits test result curve graph；
Fig. 5 is A5 pair of heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity of embodiment 9
The cell of Hedgehog signal path inhibits test result curve graph；
Fig. 6 is A pair of heterocyclic compound with Wnt and Hedgehog signal path inhibitory activity of embodiment 9
The cell of Hedgehog signal path inhibits test result curve graph.
Specific embodiment
In order to which technical characteristic of the invention, purpose and beneficial effect are more clearly understood, now to skill of the invention
Art scheme carries out described further below, but should not be understood as that limiting the scope of the invention.Institute in following embodiments
Experimental method is stated, is conventional method unless otherwise specified；The reagent and material unless otherwise specified can be from business ways
Diameter obtains.
In following embodiments, solvent for use and drug are that analysis is pure or chemical pure；Solvent is passed through using preceding
Re-distillation；Anhydrous solvent is handled according to standard method or literature method.Column chromatography silica gel (100-200 mesh) and thin layer
Chromatographic silica gel (GF254) is Haiyang Chemical Plant, Qingdao and Yantai chemical plant product；If not otherwise specified, it is all made of petroleum ether (60-
90 DEG C)/ethyl acetate (v/v) be used as eluant, eluent；The ethanol solution of color developing agent iodine or phosphomolybdic acid；All extractants are without saying
It is bright to use anhydrous Na2SO4It is dry.1HNMR is recorded with varian-400 type Nuclear Magnetic Resonance, and TMS is internal standard.The U.S. LC-MS
1100 type HPLC- ESI- MSn combined instrument (LC-MSDTrap) of Agilent company record, Diode Array Detector
Device (DAD), Detection wavelength 214nm and 254nm, ion trap mass spectrometry (source ESI).HPLC column is AgelaDurashellC18 (4.6
× 50mm, 3.5 μm)；Mobile phase is 0.1%NH4HCO3Aqueous solution: acetonitrile (in 5 minutes from 5:95 to 95:5)；Flow velocity is
1.8mL/min。
Embodiment 1
The present embodiment provides a kind of heterocyclic compound A1 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
1) synthesis of intermediate A 1-2:
By the chloro- 3- nitropyridine -5- methyl formate (220mg, 1mmol) of 2-, phenyl boric acid (146mg, 1.2mmol), Pd
(dppf)Cl2(59mg, 0.08mmol) and potassium phosphate trihydrate (532mg, 2mmol) are added to THF (20mL) and water (4mL)
In the mixed solvent, nitrogen protection, at 70 DEG C react overnight.It is diluted with ethyl acetate (100mL), then uses saturated salt solution
(50mL) is washed, after organic phase is dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum ether: ethyl acetate=50:
1 arrives 10:1), obtain a white solid (240mg, 85%).1H NMR(400MHz,CDCl3)δ9.40(s,1H),8.69(s,1H),
7.62-7.60(m,2H),7.51-7.49(m,3H),4.03(s,3H)。
2) synthesis of intermediate A 1-3:
Bis- (diphenyl phosphine) ethane (368mg, 0.92mmol) of intermediate A 1-2 (200mg, 0.77mmol) and 1,2- are added
To in n,N-dimethylacetamide (5mL), nitrogen protection is reacted overnight at 150 DEG C.It is diluted with ethyl acetate (100mL), then
It is washed with saturated salt solution (30mL*5), after organic phase is dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum
Ether: ethyl acetate=10:1 to 5:1), obtain a faint yellow solid (110mg, 62%).1H NMR(400MHz,CDCl3)δ9.22
(s, 1H), 8.41 (d, J=8.4Hz, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 7.61-7.58 (m, 1H), 7.52 (d, J=
8.4Hz,1H),7.39-7.35(m,1H),4.01(s,3H)。
3) synthesis of intermediate A 1-4:
Intermediate A 1-3 (110mg, 0.48mmol) is dissolved in the mixed solvent of tetrahydrofuran (10mL) and methanol (1mL)
In, 1N LiOH (2.5mL, 2.5mmol) then is added dropwise, is reacted overnight under room temperature.Ethyl acetate (20mL) is added into reaction solution
With water (15mL), water phase 1N HCl tune pH=5-6, there is solid precipitation, filter, vacuum drying, obtain a yellow solid (80mg,
77%).
4) synthesis of product A1:
By intermediate A 1-4 (40mg, 0.19mmol), intermediate A 1-5 (by Bioorg.Med.Chem.2016,24,
The synthetic route of 5861-5872. obtains, 49mg, 0.23mmol), DIPEA (49mg, 0.38mmol) and HATU (108mg,
It 0.29mmol) is added in DMF (1mL), reaction overnight, is diluted with water (20mL), there is solid precipitation at room temperature, is filtered, gained
Solid obtains a white solid (55mg, 70%) through column chromatographic purifying (methylene chloride: methanol=50:1 to 20:1).By nuclear-magnetism
Spectrum analysis (spectrum data is shown in Table 1), obtained solid are compound A1.
Embodiment 2
The present embodiment provides a kind of heterocyclic compound A2 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
1) synthesis of intermediate A 2-2:
By the chloro- 3- nitropyridine (316mg, 2mmol) of 2-, 4- boric acid methyl benzoate (432mg, 2.4mmol), Pd
(PPh3)4(185mg, 0.16mmol) and potassium carbonate (552mg, 4mmol) are added to 1,4- dioxane (20mL) and water
The in the mixed solvent of (4mL), nitrogen protection are reacted overnight at 90 DEG C.It is diluted with ethyl acetate (100mL), then is eaten with saturation
Salt water (50mL) is washed, after organic phase is dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum ether: ethyl acetate
=20:1 to 10:1), obtain a yellow solid (440mg, 85%).1H NMR(400MHz,CDCl3) δ 8.90 (d, J=4.0Hz,
1H), 8.22 (d, J=8.0Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.64 (d, J=8.0Hz, 2H), 7.52-7.49 (m,
1H),3.95(s,3H)。
2) synthesis of intermediate A 2-3:
Intermediate A 2-2 (200mg, 0.77mmol) and DPPE (463mg, 1.16mmol) are added in DMAc (3mL),
Nitrogen protection is reacted overnight at 150 DEG C.It is diluted, then washed with saturated salt solution (30mL*5), is had with ethyl acetate (100mL)
After machine is mutually dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum ether: ethyl acetate=5:1 to 3:1), one is obtained
Yellow solid (125mg, 71%).1H NMR (400MHz, DMSO-d6) δ 11.72 (s, 1H), 8.53 (d, J=4.0Hz, 1H),
8.29 (d, J=8.4Hz, 1H), 8.19 (s, 1H), 7.99 (d, J=8.4Hz, 1H), 7.85 (d, J=8.0Hz, 1H), 7.50-
7.46(m,1H),3.92(s,3H)。
3) synthesis of intermediate A 2-4:
Intermediate A 2-3 (125mg, 0.55mmol) is dissolved in the mixed solvent of tetrahydrofuran (10mL) and methanol (1mL)
In, 1N LiOH (3mL, 3mmol) then is added dropwise, is reacted overnight under room temperature.Ethyl acetate (20mL) and water are added into reaction solution
(15mL), water phase 1N HCl tune pH5-6, there is solid precipitation, filters, and vacuum drying obtains a yellow solid (65mg, 55%).
4) synthesis of product A2:
By intermediate A 2-4 (35mg, 0.16mmol), intermediate A 1-5 (43mg, 0.2mmol), DIPEA (41mg,
0.32mmol) it is added in DMF (1mL) with HATU (91mg, 0.24mmol), reaction overnight, is diluted with water (20mL) at room temperature,
Then it is extracted with ethyl acetate (50mL), organic phase is washed with saturated salt solution (20mL*4) again.Organic phase is dry through anhydrous sodium sulfate
After dry, filtering, concentration, through column chromatographic purifying (methylene chloride: methanol=50:1 to 20:1), obtain a white solid (15mg,
22%).(spectrum data is shown in Table 1) is parsed by nuclear magnetic spectrum, obtained solid is compound A2.
Embodiment 3
The present embodiment provides a kind of heterocyclic compound A3 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
1) synthesis of intermediate A 3-2:
By the chloro- 3- nitrobenzene methyl (300mg, 1.4mmol) of 4-, pyridine -4- boric acid (258mg, 2.1mmol), Pd
(PPh3)4(127mg, 0.11mmol) and cesium fluoride (426mg, 2.8mmol) are added to the mixed of isopropanol (20mL) and water (4mL)
In bonding solvent, nitrogen protection is reacted overnight at 90 DEG C.It is concentrated under reduced pressure, is diluted with ethyl acetate (100mL), then eaten with saturation
Salt water (50mL) is washed.After organic phase is dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum ether: ethyl acetate
=3:1), obtain a yellow solid (220mg, 61%).1H NMR(400MHz,CDCl3) δ 8.71 (d, J=5.2Hz, 2H), 8.61
(s, 1H), 8.33 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.25 (d, J=5.6Hz, 2H), 4.01 (s,
3H).
2) synthesis of intermediate A 3-3:
Intermediate A 3-2 (200mg, 0.77mmol) and DPPE (617mg, 1.55mmol) are added in DMAc (3mL),
Nitrogen protection is reacted overnight at 150 DEG C.It is diluted with ethyl acetate (100mL), then washed with saturated salt solution (30mL*5).Have
After machine is mutually dried over anhydrous sodium sulfate, filters, being concentrated, through column chromatographic purifying (petroleum ether: ethyl acetate=1:1 to 1:2), one is obtained
Yellow solid (104mg, 59%).
3) synthesis of intermediate A 3-4:
Intermediate A 3-3 (104mg, 0.46mmol) is dissolved in the mixed solvent of tetrahydrofuran (10mL) and methanol (1mL)
In, 1N LiOH (2mL, 2mmol) then is added dropwise, is reacted overnight under room temperature.Ethyl acetate (20mL) and water are added into reaction solution
(15mL), water phase 1N HCl tune pH=5-6, there is solid precipitation.Filtering, vacuum drying, obtain a yellow solid (37mg,
37%).1H NMR(400MHz,DMSO-d6) δ 11.88 (s, 1H), 8.99 (s, 1H), 8.39 (d, J=4.8Hz, 1H), 8.34
(d, J=8.4Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=5.2Hz, 1H), 7.83 (d, J=8.4Hz, 1H)
4) synthesis of product A3:
By intermediate A 3-4 (67mg, 0.32mmol), intermediate A 1-5 (83mg, 0.38mmol), DIPEA (82mg,
It 0.64mmol) is added in DMF (2mL) with HATU (182mg, 0.48mmol), reaction is stayed overnight at room temperature.It is dilute with water (20mL)
It releases, is then extracted with ethyl acetate (50mL).Organic phase is washed with saturated salt solution (20mL*4) again, be dried over anhydrous sodium sulfate,
After filtering, concentration, column chromatographic purifying (methylene chloride: methanol=50:1 to 20:1) obtains a yellow solid (15mg, 11%).Through
Nuclear magnetic spectrum parsing (spectrum data is shown in Table 1) is crossed, obtained solid is compound A-13.
Embodiment 4
The present embodiment provides a kind of heterocyclic compound A4 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
By A4-1 (being obtained by the synthetic route of patent WO2017062688A1,46mg, 0.2mmol) and A4-2 (by
Bioorg.Med.Chem.2016,24,5861-5872. synthetic route obtain, 42mg, 0.2mmol) it is dissolved in DMF (2mL),
HATU (76mg, 0.2mmol) and DIPEA (129mg, 1.0mmol) is added.It is stirred overnight under room temperature, is added water (30mL), uses second
Acetoacetic ester (30mL*3) extraction, merges organic phase, is washed with saturated salt solution (30mL*3), anhydrous sodium sulfate dries, filters, filtrate
Through column chromatographic purifying (methylene chloride: methanol=30:1) after reduced pressure, light yellow solid (60mg, 71%) is obtained.By nuclear-magnetism
Spectrum analysis (spectrum data is shown in Table 1), obtained solid are compound A4.
Embodiment 5
The present embodiment provides a kind of heterocyclic compound A5 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
By A5-1 (being obtained by the synthetic route of patent WO2017062688A1,45mg, 0.2mmol) and A4-2 (42mg,
It 0.2mmol) is dissolved in DMF (2mL), HATU (76mg, 0.2mmol) and DIPEA (129mg, 1.0mmol) is added.It is stirred under room temperature
It mixes overnight, is added water (30mL), extracted with ethyl acetate (30mL*3), merge organic phase, washed with saturated salt solution (30mL*3),
Anhydrous sodium sulfate dries, filters, and through column chromatographic purifying (methylene chloride: methanol=30:1) after filtrate decompression concentration, obtains white solid
Body (38mg, 46%).(spectrum data is shown in Table 1) is parsed by nuclear magnetic spectrum, obtained solid is compound A-45.
Embodiment 6
The present embodiment provides a kind of heterocyclic compound A6 with Wnt and Hedgehog signal path inhibitory activity, are
It synthesizes by the following method:
1) synthesis of intermediate A 6-2:
A6-1 (80mg, 0.5mmol) and A4-2 (105mg, 0.5mmol) are dissolved in DMF (2mL), HATU is added
(190mg, 0.5mmol) and DIPEA (323mg, 2.5mmol).It is stirred overnight under room temperature, is added water (30mL), uses ethyl acetate
(30mL*3) extraction, merges organic phase, is washed with saturated salt solution (30mL*3), anhydrous sodium sulfate dries, filters, and filtrate decompression is dense
Through column chromatographic purifying (methylene chloride: methanol=30:1) after contracting, white solid (160mg, 91%) is obtained.1H NMR(400MHz,
DMSO) δ 11.49 (s, 1H), 9.19 (t, J=5.6Hz, 1H), 8.32 (s, 1H), 8.22-8.15 (m, 2H), 8.02 (s, 1H),
7.91 (d, J=9.2Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.48-7.40 (m, 1H),
7.22-7.16 (m, 1H), 4.57 (d, J=5.6Hz, 2H)
2) synthesis of product A6:
A6-2 (50mg, 0.14mmol) and 4- pyridine boronic acid (21mg, 0.17mmol) are dissolved in dioxane (2mL) and water
In (0.5mL), Pd (dppf) Cl is added2(5mg, 0.007mmol), dppf (4mg, 0.007mmol) and potassium phosphate (59mg,
0.28mmol).It under nitrogen protection, is replaced five times with nitrogen, is heated to 100 DEG C, reacted 12 hours.After being cooled to room temperature, decompression
Through column chromatographic purifying (methylene chloride: methanol=30:1) after concentration, gray solid (30mg, 53%) is obtained.By nuclear magnetic spectrum solution
It analyses (spectrum data is shown in Table 1), obtained solid is compound A6.
Embodiment 7
The present embodiment provides a kind of heterocyclic compound A with Wnt and Hedgehog signal path inhibitory activity, be by
The method synthesis of document (Bioorg.Med.Chem.2016,24,5861-5872.).
Table 1 lists the analytic structure and spectral data of the compound of embodiment 1-7 acquisition.
Table 1
Embodiment 8
The heterocycle with Wnt and Hedgehog signal path inhibitory activity that embodiment 1-7 is prepared in the present embodiment
Compound A1-A6 and compound A are measured the rejection ability of Wnt signal path.
LWnt3A cell (CRL-2647, ATCC) culture is in the DMEM culture medium for containing 10% fetal calf serum (Hyclone)
(Gibico) in.(transfection has " Super-TopFlash " TCF fluorescence report plasmid to HEK293STF stable clone cell
HEK293 cell) it cultivates and (contains 4mML- glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 6 μ in complete medium
The DMEM culture medium of g/mL blasticidin S and 10% fetal calf serum) in.When LWnt3A cell and HEK293STF stable clone are thin
Born of the same parents cultivate to convergence degree be 90% when harvest respectively, and with the ratio of 1:1 mixing.The mixed cell culture liquid in 100 holes μ L/ is added
Into 96 orifice plates, makes 12000 cells/wells of final cell concentration, be then further cultured for for 24 hours.Test compound with DMSO by
Grade dilution, is then diluted to wanted concentration with DMEM culture medium again.20 μ L compound solutions are taken to be added to above-mentioned equipped with cell
In 96 orifice plates of culture solution, then in 37 DEG C of hatching 48h.Be added in last every hole 50 μ L luciferase solution (Brigh-Glo,
Promega), shaken 5 minutes under room temperature.Luminous signal is measured with microplate reader (PHERAstarFS, BMG).To synthesized chemical combination
Object is tested, and when compound is not added, LWnt3A cell secretes Wnt3A protein activation Wnt signal path, expresses fluorescence egg
White, fluorescence signal value is set as 100% at this time；The test compound of various concentration is added, the compound of various concentration believes Wnt
The inhibitory activity of number access is different, and when Wnt signal path is totally constrained, fluorescence signal value is set as 0%.With fluorescence signal
Value is ordinate, curve graph is done using test compound concentration as abscissa, it can be concluded that fluorescence signal value is from curve graph
Compound concentration when 50%, i.e. half-inhibitory concentration IC50Value.IC50Value is lower, and the activity for representing the heterocyclic compound is higher.
By taking A1 and A5 and compound A as an example, to the suppression result curve graph of Wnt signal path as shown in Fig. 1 and Fig. 2 and Fig. 3；Remaining
The test chart of compound is essentially identical.(heterocyclic compound A1-A6 and compound A are to Wnt and Hedgehog for whole result such as table 2
The result of the rejection ability measurement experiment of signal path) shown in.Wherein, LGK974 and Vismodegib is control compound,
LGK974 is known Wnt signal path inhibitor, is currently under the second stage of clinic；Vismodegib is known Hedgehog
Signal pathway inhibitor has been approved by the FDA in the United States listing in 2012.
Embodiment 9
The heterocycle with Wnt and Hedgehog signal path inhibitory activity that embodiment 1-7 is prepared in the present embodiment
Compound A1-A6 and compound A are measured the rejection ability of Hedgehog signal path.
NIH3T3 cell is cultivated in the DMEM (11965, Gibico) containing 10%FBS (Hyclone).GRE- firefly
Fireworm fluorescein plasmid is obtained via in the octuple cell transcription factor GLI-1 response element implantation MCS of amplification.Monoclonal is
It is verified by the small molecule agonist SAG that recombination Su Nike hedgehog pathway albumen and structural formula are shown below.It is verified
Selected clone is for detecting hedgehog pathway signal.
The NIH3T3 cell for expressing GRE- firefly element is maintained in complete culture solution.When needing to do analysis detection
When, cell is added in 96 orifice plates, final every hole about one Wan Wuqian containing cell.96 orifice plates are being cultured 48 hours.Detectedization
Object is closed by DMSO and detection buffer by serial dilution.10nM SAG is as hedgehog pathway agonist.Subsequent 100 microlitres include
The analysis buffer of test compound and agonist is carefully added into containing in cell in 96 orifice plates, and cultivates 48 at 37 degrees Celsius
Hour.
After 48 hours of incubation, 40 microlitres of firefly luciferases are added into each hole.96 orifice plates are at room temperature
Jog 5 minutes.Luminous signal is recorded by plate reader.The activity of compound calculates by it to the blocking of luminous signal.It is right
Synthesized compound is tested, and when only compound is not added in addition SAG, Hedgehog signal path is activated completely by SAG,
Fluorescin is expressed, fluorescence signal value is set as 100% at this time；The test compound of SAG and various concentration is added simultaneously, it is different
The compound of concentration is different to the inhibitory activity of Hedgehog signal path, when Hedgehog signal path is totally constrained,
Fluorescence signal value is set as 0%.Using fluorescence signal value as ordinate, curve graph is done using test compound concentration as abscissa, from
In curve graph it can be concluded that fluorescence signal value be 50% when compound concentration, i.e. half-inhibitory concentration IC50Value.IC50Value is got over
Low, the activity for representing the heterocyclic compound is higher.Suppression by taking A1 and A5 and compound A as an example, to Hedgehog signal path
Result curve figure processed is as shown in Fig. 4 and Fig. 5 and Fig. 6；The test chart of remaining compound is essentially identical.Whole result such as 2 (heterocycle of table
Result of the compound A1-A6 and compound A to the rejection ability measurement experiment of Wnt and Hedgehog signal path) shown in.Its
In, LGK974 and Vismodegib are control compound, and LGK974 is known Wnt signal path inhibitor, is currently under
It is the second stage of clinical；Vismodegib is known Hedgehog signal pathway inhibitor, has been approved by the FDA in the United States within 2012
City.
Rejection ability measurement experiment of the table 2 heterocyclic compound A1-A6 and compound A to Wnt and Hedgehog signal path
Result
By upper table 2 as it can be seen that known Wnt signal path inhibitor (LGK974) and Hedgehog signal pathway inhibitor
(Vismodegib) can only all inhibit one of Wnt signal path and Hedgehog signal path, cannot inhibit simultaneously Wnt and
Hedgehog signal path.And the heterocyclic compound in the present invention, as having for Wnt signal path and Hedgehog signal path
Antagonist is imitated, can effectively block Wnt signal path and Hedgehog signal path simultaneously, treatment or pre- can be preferably applied to
It is anti-because Wnt signal path or Hedgehog signal path it is not normal caused by illness.
Claims (10)
1. a kind of heterocyclic compound and its pharmaceutically acceptable salt with Wnt and Hedgehog signal path inhibitory activity,
With structure shown in general formula I:
Wherein:
X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8；
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from deuterium original by 1-3
The group of son or halogeno-group replaces；
R4Selected from D-atom, halogen, cyano, C1-6Alkoxy；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from D-atom or halogenated by 1-3
The group of base replaces；
R6、R7、R8It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl and alkane
Oxygroup is unsubstituted or is replaced by the group that 1-3 are respectively selected from D-atom or halogeno-group；
M is selected from 0,1,2,3；
N is selected from 0,1,2；
Work as X1、X2、X3、X4、X5、X6、X7It is CH, and R4When for F, R5It cannot be methyl.
2. the heterocyclic compound and its medicine according to claim 1 with Wnt and Hedgehog signal path inhibitory activity
Acceptable salt on has structure shown in general formula Ia:
Wherein:
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from deuterium original by 1-3
The group of son or halogeno-group replaces；
R4Selected from D-atom, halogen, cyano, C1-6Alkoxy；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from D-atom or halogenated by 1-3
The group of base replaces；
R6、R7It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl and alcoxyl
Base is unsubstituted or is replaced by the group that 1-3 are respectively selected from D-atom or halogeno-group；
M is selected from 0,1,2,3；
N is selected from 0,1,2；
Work as R4When for F, R5It cannot be methyl.
3. the heterocyclic compound and its medicine according to claim 1 with Wnt and Hedgehog signal path inhibitory activity
Acceptable salt on has structure shown in general formula Ib:
Wherein:
X1、X2、X3、X4、X5、X6、X7It is each independently selected from N or CR8, and being wherein up to 4 is N, and at least one is N；
R1、R2、R3It is each independently selected from hydrogen atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from deuterium original by 1-3
The group of son or halogeno-group replaces；
R5Selected from hydrogen atom, D-atom, C1-6Alkyl, the alkyl is unsubstituted or is respectively selected from D-atom or halogenated by 1-3
The group of base replaces；
R6、R7、R8It is respectively and independently selected from hydrogen atom, D-atom, cyano, halogen, C1-6Alkyl, C1-6Alkoxy, the alkyl and alkane
Oxygroup is unsubstituted or is replaced by the group that 1-3 are respectively selected from D-atom or halogeno-group；
M is selected from 0,1,2,3；
N is selected from 0,1,2.
4. the heterocyclic compound according to claim 1-3 with Wnt and Hedgehog signal path inhibitory activity
Object and its pharmaceutically acceptable salt, it is characterised in that: R1、R2、R3For hydrogen atom.
5. the heterocyclic compound according to claim 1-4 with Wnt and Hedgehog signal path inhibitory activity
Object and its pharmaceutically acceptable salt, it is characterised in that: m, n are respectively and independently selected from 0 or 1.
6. the heterocyclic compound according to claim 1-5 with Wnt and Hedgehog signal path inhibitory activity
Object and its pharmaceutically acceptable salt, it is characterised in that: R6、R7For hydrogen atom.
7. according to claim 1 or the described in any item jeterocyclic chemistries with Wnt and Hedgehog signal path inhibitory activity of 3-6
Close object and its pharmaceutically acceptable salt, it is characterised in that: R8For hydrogen atom.
8. the heterocyclic compound according to claim 1-7 with Wnt and Hedgehog signal path inhibitory activity
Object and its pharmaceutically acceptable salt comprising one of following structural or a variety of combinations:
9. a kind of pharmaceutical composition, it includes the claim 1-8 of therapeutically effective amount it is described in any item have Wnt and
The heterocyclic compound and pharmaceutically acceptable carrier of Hedgehog signal path inhibitory activity.
10. with the heterocycle of Wnt and Hedgehog signal path inhibitory activity described in compound A or claim any one of 1-8
It is different to treat or prevent Wnt and/or Hedgehog signal path in preparation for compound or pharmaceutical composition as claimed in claim 9
Application in normal drug；It is described treat or prevent Wnt or Hedgehog signal path exception drug include treat breast cancer,
Lung cancer, bladder cancer, cancer of pancreas, liver cancer, neck squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, fibroma, melanin
Tumor, prostate cancer, colorectal cancer, oophoroma, cervical carcinoma, the cancer of the esophagus, gastric cancer, myeloma, lymthoma, lymphoma mantle cell,
Skin T cell lymphoma, chronic and non-progressive anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis
Change, pulmonary fibrosis, renal fibrosis, liver fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukaemia,
Acute leukemia, chronic leukemia, lymphatic leukemia, myelogenous leukemia, myelodysplastic syndrome, bone marrow proliferation venereal disease
One of disease, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, hypophysoma illness
Or the drug and its pharmaceutical composition of several illnesss, the structure of the compound A are as follows:
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