CN109336857A - A kind of flavones and its application containing substituted biphenyl - Google Patents
A kind of flavones and its application containing substituted biphenyl Download PDFInfo
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- CN109336857A CN109336857A CN201811342230.0A CN201811342230A CN109336857A CN 109336857 A CN109336857 A CN 109336857A CN 201811342230 A CN201811342230 A CN 201811342230A CN 109336857 A CN109336857 A CN 109336857A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The present invention relates to a kind of flavones containing substituted biphenyl, shown in the flavones chemical structure such as following formula (I), in formula (I), and R1It is methoxyl group, N- acetylethylenediamine base, ethylenediamine base, piperazinyl, acetylpiperazine base, ethyl piperazidine base, isopropyl piperazinyl, tert-butoxycarbonyl-piperazine base or Cyclopr. opylmethylpiperazine, R2It is hydrogen, fluorine or methyl, R3For hydrogen or Isosorbide-5-Nitrae-dioxane.A kind of flavones containing substituted biphenyl of the present invention is able to suppress be combineding with each other for apoptosis receptor 1/ apoptosis ligand 1 (PD1/PD-L1), can be used for preparing PD1/PD-L1 inhibitor, the significant effect of the inhibitor.
Description
Technical field
The present invention relates to organic compounds, and in particular to chromocor compound, it is dead which is able to suppress programmed cell
Be combineding with each other for receptor 1/ apoptosis ligand 1 (PD1/PD-L1) is died, can be used for treating tumour.
Background technique
Tumour immunotherapy is more and more used in field of cancer treatment.Currently, immunotherapy of tumors mainly uses
Drug be macromolecular biological antibody.Wherein the inhibitor (also referred to as immunologic test point inhibitor) of PD-1/PD-L1 is to a variety of
Tumour is effective.Therefore, in recent years, PD1/PD-L1 becomes a most attracting target in anti-tumor drug design, while also
It is listed in one of the cancer target of most prospect, thus is concerned.
PD-1 is found in apoptosis T hybridoma, due to related to Apoptosis, therefore is named as programmed cell
Death receptor 1.PD-1 is a kind of important immunosuppression molecule, is inhibiting the relevant antigen of the diseases such as tumour, virus infection special
Key effect is played in specific T cell response.The T cell of in-vivo tumour microenvironment induction infiltration over-expresses PD1, same with this
When, tumour cell over-expresses ligand PD-L1 and PD-L2.The combination of PD-1 and PD-L1 leads to tumor patient T cell effect function
It can lower, to inhibit anti-tumor immune response, result in the failure of T cell.PD-1/PD-L1 inhibitor can block PD-1
With the combination of PD-L1, negative regulation signal is interfered, restores the activity of T cell, to enhance immune response.The suppression of PD-1/PD-L1
Preparation (also referred to as immunologic test point inhibitor) is effective to kinds of tumors.Up to the present, FDA has had been approved by 6 kinds and has been immunized
Checkpoint inhibitor, they are all monoclonal antibody, including Ipilimumab (BMS research and development, anti-CTLA-4), Nivolumab
(BMS research and development, anti-PD-1), Pembrolizumab (Merck research and development, anti-PD-1), Atezolizumab (anti-PD-
L1, Roche research and development), Duvalumab (anti-PD-L1, AstraZeneca research and development), (anti-PD-L1, Pfizer and Merck are common by Avelumab
Research and development).Antibody-mediated immunologic test point retarding agent (ICB) kinds of tumors type such as advanced metastatic non-small cell lung cancer,
Good curative effect is shown in the clinical test of bladder transitional cell carcinoma and head and neck squamous cell carcinoma.These therapeutic schemes have been used
Standard as associated cancer treatment.However, current PD-1/PD-L1 monoclonal antibody is only to sub-fraction case and tumour
Type generates curative effect.
PD-1/PD-L1 antibody drug has the exclusive specificity of target spot and high efficiency etc. for its pharmacodynamics
The advantages of.However for its pharmacokinetics, the shortcomings that antibody drug also clearly, firstly, to linked groups and tumour
Cell permeable is poor, and metabolic half life is long, and oral administration biaavailability is low etc., secondly, antibody drug has immunogenicity, therefore meeting
Cause serious adverse reaction, moreover, antibody drug manufacture and to isolate and purify process very complicated, causes its production cost very high
It is high.With macromolecular antibody drug on the contrary, small molecule compound has many advantages in terms of pharmacodynamics, for example, small molecule
Compound has preferable oral administration biaavailability, high to linked groups and tumour cell permeability, half-life period rationally etc., and
Small molecule compound has many advantages, such as that toxicity is low, higher selectivity and validity, and therefore, small molecule tumour immunity class drug has
Prestige overcome macromolecular antibody drug there are the shortcomings that.In immunotherapy of tumors field, small molecule compound can both have been improved existing
Antibody drug existing for deficiency, can also be used in conjunction with antibody drug performance synergistic effect.As scientific research personnel is at small point
The great efforts made in the research of edema during pregnancy tumor immune drug, some efficient small molecule compounds are reported successively, some of them
Small molecule compound comes into clinical research.However, so far, without a small molecule tumour immunity drug by FDA batches
It is mutatis mutandis in cancer associated treatment.Therefore, the tumour immunotherapy based on small molecule is still that immunotherapy of tumors is most worth
One of the scientific domain of concern.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of flavones containing substituted biphenyl, which is able to suppress program
Property 1/ apoptosis of cell death receptor be combineding with each other with 1 (PD1/PD-L1), can be used for preparing PD1/PD-L1 suppression
Preparation.
The scheme that the present invention solves above-mentioned technical problem is as follows:
A kind of flavones containing substituted biphenyl, shown in the chemical structure of the flavones such as following formula (I),
In formula (I), in formula (I), R1It is methoxyl group, N- acetylethylenediamine base, ethylenediamine base, piperazinyl, acetylpiperazine
Base, ethyl piperazidine base, isopropyl piperazinyl, tert-butoxycarbonyl-piperazine base or Cyclopr. opylmethylpiperazine base, R2It is hydrogen, fluorine or first
Base, R3For hydrogen or Isosorbide-5-Nitrae-dioxane.
One of preferably following compounds of flavones of the present invention:
R1It is methoxyl group, R2It is hydrogen, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is hydrogen, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is methyl, R3Chemical structure for Isosorbide-5-Nitrae-dioxane, the flavones is
R1It is acetylpiperazine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones isR1It is ethyl piperazidine base, R2It is methyl, R3For hydrogen, the chemical structure of the flavones
ForR1It is Cyclopr. opylmethylpiperazine base, R2It is methyl, R3For hydrogen, the flavones
Chemical structure is
R1It is isopropyl piperazinyl, R2It is methyl, R3Chemical structure for hydrogen, the flavones isR1It is tert-butoxycarbonyl-piperazine, R2It is methyl, R3For hydrogen, the chemistry of the flavones
Structure is
R1It is piperazinyl, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is N- acetylethylenediamine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is fluorine, R3Chemical structure for hydrogen, the flavones is
R1It is ethylenediamine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
The preparation method of above-mentioned flavones containing substituted biphenyl a kind of the following steps are included:
The preparation method of flavones containing substituted biphenyl of the invention, method includes the following steps: first by o-hydroxy
Ethyl ketone and paraformaldehyde, hydrochloric acid carry out chloromethylation and generate compound II；Then it is anti-compound II to be subjected to nucleophilic displacement of fluorine
Compound III should be generated；Compound III and compound IV is subjected to chalcone reaction again and generates compound V, final compound V
And iodine, reaction generates compound I in dimethyl sulfoxide.
The reaction equation of the above method is as follows:
In the reaction equation, R1It is methoxyl group, N- acetylethylenediamine base, ethylenediamine base, piperazinyl, acetylpiperazine base, second
Base piperazinyl, isopropyl piperazinyl, tert-butoxycarbonyl-piperazine base or Cyclopr. opylmethylpiperazine, R2It is hydrogen, fluorine or methyl, R3For
Hydrogen or Isosorbide-5-Nitrae-dioxane.
The above-mentioned flavones containing substituted biphenyl is able to suppress 1/ apoptosis ligand 1 of apoptosis receptor
(PD1/PD-L1) be combined with each other, can be used for preparing PD1/PD-L1 inhibitor, and the antitumous effect of the inhibitor is significant.It is described
PD1/PD-L1 inhibitor be made of the flavones containing substituted biphenyl and medically acceptable auxiliary material.
Contain substituted biphenyl using the measurement of HTRF (homogeneous phase time discrimination fluorescence) technical standard operation sequence is of the present invention
Flavones to the inhibitory effect of PD1/PD-L1, such compound has preferable inhibitory effect to PD1/PD-L1 as the result is shown.
Below in conjunction with the drawings and specific embodiments, the invention will be further described.
Detailed description of the invention
Fig. 1 is a kind of inhibition concentration curve graph of the flavones containing substituted biphenyl of the present invention to PD1/PD-L1,
In, Fig. 1 is HT10 concentration inhibiting rate curve graph.
Specific embodiment
Embodiment 1 (preparation HT3)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound II
20g o-hydroxyacetophenone and 5.2g paraformaldehyde (HCOH) are added in 60ml concentrated hydrochloric acid (HCl), stirred, heating
It to 50 DEG C, reacts 10 hours, thin-layer chromatography (TLC) monitoring after reaction, reaction solution is poured into 100mL water, with acetic acid second
Ester (100mL × 5) extraction, stands liquid separation, and organic phase uses 5% sodium bicarbonate (NaHCO respectively3) (80mL × 3), saturated common salt
Water (80mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains 10 grams of white solid.
Obtained white solid is identified using nuclear magnetic resoance spectrum, qualification result are as follows:1H NMR(400MHz,
CDCl3) δ 12.32 (s, 1H), 7.74 (d, J=2.2Hz, 1H), 7.50 (dd, J=8.6,2.2Hz, 1H), 6.98 (d, J=
8.6Hz, 1H), 4.57 (s, 2H), 2.65 (s, 3H) are by above-mentioned qualification result it is found that gained white solid is compound II.
Step 2: the preparation of compound III
100mg compound II and 105mg acetylpiperazine is added in 5ml methylene chloride (DCM), stirring is heated to 40 DEG C,
Reaction 2 hours, TLC monitoring, after reaction, be spin-dried for solvent, reactant be poured into 100mL water, with ethyl acetate (20mL ×
3) it extracts, stands liquid separation, organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then
It is dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 100mg.
Obtained compound III is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.13 (s, 1H), 7.60 (s, 1H), 7.37 (d, J=8.4Hz, 1H), 6.84
(d, J=8.5Hz, 1H), 3.54 (d, J=4.2Hz, 2H), 3.40 (s, 4H), 2.56 (s, 3H), 2.39-2.31 (m, 4H),
2.00(s,3H).13C NMR(101MHz,CDCl3)δ204.45,168.97,161.51,137.32,131.01,127.92,
119.26,118.17,61.78,52.77,52.42,46.07,41.22,26.57,21.12. ESI-MS:m/z=277.7 [M+
1]+By above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 3: the preparation of CET10
100mg compound III and 40mg potassium hydroxide (KOH) is added in 5ml methanol, stirring to solution colour turns yellow,
80mg compound IV is added, is reacted 24 hours, TLC monitoring adjusts reaction solution pH=7 with concentrated hydrochloric acid, use after reaction
Ethyl acetate (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution
(20mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether):
V(ethyl acetate)=10:1 obtains yellow solid CET10 80mg.
Obtained CET10 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.82 (s, 1H), 8.36 (d, J=15.3Hz, 1H), 7.88 (s, 1H),
7.78-7.73 (m, 1H), 7.63 (d, J=15.3Hz, 1H), 7.51 (dd, J=8.5,1.5Hz, 1H), 7.45 (d, J=
7.4Hz, 2H), 7.40 (d, J=7.3Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.31
(s, 1H), 7.04 (d, J=8.5Hz, 1H), 3.67 (s, 2H), 3.50 (s, 4H), 2.48 (s, 4H), 2.39 (s, 3H), 2.11
(s,3H).13C NMR(101MHz,CDCl3)δ193.43,168.73,162.91,143.77,143.31,141.37,137.34,
135.66,134.46,132.14,130.03,129.16,128.15,128.10,127.05,125.90,121.90,119.59,
118.46,61.97,52.89,52.59,46.15,41.29,21.23,16.98.ESI-MS: m/z=455.6 [M+1]+By upper
Qualification result is stated it is found that gained yellow solid product is CET10.
Step 4: the preparation of HT3
By 50mg CET10 and 30mg iodine (I2) be added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100
DEG C, it reacts 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL
× 3) it extracts, stands liquid separation, organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), so
It is dry with anhydrous magnesium sulfate afterwards, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=5:1 obtains yellow
Color solid HT3 5mg.
Obtained HT3 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.18 (d, J=1.9Hz, 1H), 7.74 (dd, J=8.6,2.1Hz, 1H),
7.50 (d, J=2.6Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 7.39 (dd, J=6.0,2.3Hz,
2H),7.37–7.35(m,2H),7.34(s,1H),6.53(s,1H),3.64(s,4H),3.47(s,2H),2.50–2.43(m,
4H),2.30(s,3H),2.08(s,3H).13C NMR(101MHz,CDCl3)δ178.29,168.95,166.68,155.86,
143.60,141.08,135.17,134.71,134.20,133.69,132.30,129.18,128.43,128.26,127.23,
125.89,125.61,123.45,118.24,112.26,61.88,52.93,52.57,46.19,41.33,21.23,
[18.32.ESI-MS:m/z=453.8 M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT1.
Embodiment 2 (preparation HT2)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of CET1
100mg compound III and 40mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
100mg compound IV reacts 24 hours, TLC monitoring, after reaction, adjusts reaction solution pH=7 with concentrated hydrochloric acid, uses acetic acid
Ethyl ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL ×
3) it washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)
=3:1 obtains yellow solid CET1 70mg.
Obtained CET1 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.83 (s, 1H), 8.34 (d, J=15.2Hz, 1H), 7.86 (s, 1H), 7.72
(s, 1H), 7.61 (d, J=15.1Hz, 1H), 7.50 (d, J=8.5Hz, 1H), 7.37-7.30 (m, 2H), 7.03 (d, J=
8.5Hz, 1H), 6.94 (d, J=8.2Hz, 1H), 6.83 (s, 1H), 6.78 (d, J=8.2Hz, 1H), 4.33 (s, 4H), 3.66
(s, 2H), 3.52 (d, J=11.4Hz, 4H), 2.47 (s, 4H), 2.41 (s, 3H), 2.11 (s, 3H) can by above-mentioned qualification result
Know, gained yellow solid product is CET1.
Step 2: the preparation of HT2
50mg CET1 and 25mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT2 4mg.
Obtained HT2 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.19 (d, J=1.4Hz, 1H), 7.75 (s, 1H), 7.53-7.45 (m, 2H),
7.39 (dd, J=14.8,6.9Hz, 2H), 6.95 (d, J=8.2Hz, 1H), 6.88 (d, J=1.8Hz, 1H), 6.83 (dd, J=
8.2,1.9Hz,1H),6.53(s,1H),4.34(s,4H),3.66(s,4H),3.50(s,2H),2.49(s,4H),2.34(s,
3H), 2.10 (s, 3H) are by above-mentioned qualification result it is found that gained yellow solid product is HT2.
Embodiment 3 (preparation HT1)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of CET12
100mg compound III and 40mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
74mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET12 65mg.
Obtained CET12 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.80 (s, 1H), 8.35 (d, J=15.3Hz, 1H), 7.89 (s, 1H), 7.77
(d, J=5.7Hz, 1H), 7.65 (d, J=15.4Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.45 (d, J=7.3Hz, 2H),
7.40 (d, J=7.1Hz, 1H), 7.37-7.33 (m, 3H), 7.32 (s, 1H), 7.02 (d, J=8.5Hz, 1H), 3.53 (s,
2H), 2.70 (s, 4H), 2.50 (s, 4H), 2.40 (s, 3H), 2.27 (s, 1H), 0.49-0.42 (m, 4H) .ESI-MS:m/z=
441.7[M+1]+By above-mentioned qualification result it is found that gained yellow solid product is CET12.
Step 2: the preparation of HT1
50mg CET12 and 29mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT1 5mg.
Obtained HT1 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.16 (d, J=7.8Hz, 2H), 7.91 (d, J=7.8Hz, 1H), 7.77 (t, J
=6.6Hz, 2H), 7.66 (d, J=7.4Hz, 2H), 7.61 (t, J=9.2Hz, 2H), 7.52 (t, J=7.5Hz, 2H), 7.44
(d, J=7.2Hz, 1H), 6.92 (s, 1H), 3.66 (s, 4H), 3.49 (s, 2H), 2.48 (d, J=3.7Hz, 4H), 2.10 (s,
3H) .ESI-MS:m/z=439.7 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT1.
Embodiment 4 (preparation HT4)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound III
100mg compound II and 93mg ethyl piperazidine is added in 5ml methylene chloride (DCM), stirring is heated to 40 DEG C,
Reaction 2 hours, TLC monitoring, after reaction, be spin-dried for solvent, reactant be poured into 100mL water, with ethyl acetate (20mL ×
3) it extracts, stands liquid separation, organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then
It is dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 90mg.
Obtained compound III is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.27 (s, 1H), 7.69 (s, 1H), 7.45 (d, J=8.5Hz, 1H), 6.96
(d, J=8.5Hz, 1H), 3.58 (s, 2H), 3.03-2.75 (m, 8H), 2.66 (s, 3H), 1.38 (t, J=7.2Hz, 3H),
0.93-0.80 (m, 2H) is by above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 2: the preparation of CET8
90mg compound III and 40mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
83mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET8 60mg.
Obtained CET8 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.80 (s, 1H), 8.35 (d, J=15.3Hz, 1H), 7.87 (s, 1H), 7.76
(d, J=5.7Hz, 1H), 7.64 (d, J=15.3Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.46 (t, J=7.3Hz, 2H),
7.40 (d, J=7.1Hz, 1H), 7.38-7.33 (m, 3H), 7.32 (s, 1H), 7.02 (d, J=8.5Hz, 1H), 3.53 (s,
2H), 2.78-2.42 (m, 10H), 2.39 (s, 3H), 1.13 (t, J=7.1Hz, 3H) .ESI-MS:m/z=441.2 [M+1]+.
By above-mentioned qualification result it is found that gained yellow solid product is CET8.
Step 3: the preparation of HT4
50mg CET12 and 28mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT4 6mg.
Obtained HT4 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 7.74 (d, J=8.5Hz, 1H), 7.51 (d, J=9.5Hz,
2H), 7.47 (d, J=7.9Hz, 2H), 7.42 (d, J=5.2Hz, 2H), 7.37 (d, J=7.6Hz, 3H), 6.54 (s, 1H),
(3.66 s, 2H), 2.57 (d, J=22.2Hz, 8H), 2.50 (s, 2H), 2.32 (s, 3H), 1.14 (t, J=7.1Hz, 3H)
.ESI-MS:m/z=439.8 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT4.
Embodiment 5 (preparation HT5)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound III
100mg compound II and 120mg 1- cyclopropyl methyl piperazine is added in 5ml methylene chloride (DCM), is stirred, heating
It to 40 DEG C, reacts 2 hours, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, ethyl acetate is used
(20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) are washed
It washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 80mg.
Obtained compound III is identified using mass-spectrometric technique, qualification result are as follows: ESI-MS:m/z=289.2
[M+1]+
By above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 2: the preparation of CET7
80mg compound III and 39mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
75mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET7 68mg.
Obtained CET7 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.80 (s, 1H), 8.35 (d, J=15.3Hz, 1H), 7.88 (s, 1H), 7.76
(d, J=5.5Hz, 1H), 7.64 (d, J=15.3Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.46 (t, J=7.2Hz, 2H),
7.40 (d, J=6.9Hz, 1H), 7.35 (dd, J=6.6,3.7Hz, 3H), 7.32 (s, 1H), 7.02 (d, J=8.5Hz, 1H),
3.54 (s, 2H), 2.59 (s, 8H), 2.39 (s, 3H), 2.33 (d, J=6.4Hz, 2H), 0.91 (d, J=4.6Hz, 1H), 0.54
(d, J=7.6Hz, 2H), 0.14 (d, J=4.7Hz, 2H) .ESI-MS:m/z=467.7 [M+1]+It can by above-mentioned qualification result
Know, gained yellow solid product is CET7.
Step 2: the preparation of HT5
50mg CET7 and 27mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT1 8mg.
Obtained HT5 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 7.74 (d, J=8.5Hz, 1H), 7.51 (d, J=9.7Hz,
2H), 7.47 (d, J=7.8Hz, 2H), 7.42 (d, J=5.3Hz, 2H), 7.38 (t, J=5.8Hz, 3H), 6.54 (s, 1H),
3.67 (s, 2H), 2.62 (s, 8H), 2.37 (d, J=5.8Hz, 2H), 2.32 (s, 3H), 0.95-0.87 (m, 1H), 0.56 (d, J
=7.6Hz, 2H), 0.16 (d, J=4.6Hz, 2H) .ESI-MS:m/z=465.8 [M+1]+By above-mentioned qualification result it is found that institute
Obtaining yellow solid product is HT5.
Embodiment 6 (preparation HT6)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound III
100mg compound II and 105mg isopropyl piperazine is added in 5ml methylene chloride (DCM), stirring is heated to 40
DEG C, it reacts 2 hours, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, ethyl acetate is used
(20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) are washed
It washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 66mg.
Obtained compound III is identified using mass-spectrometric technique, qualification result are as follows: ESI-MS:m/z=277.1
[M+1]+
By above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 2: the preparation of CET6
66mg compound III and 41mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
78mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET6 45mg.
Obtained CET6 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.80 (s, 1H), 8.35 (d, J=15.3Hz, 1H), 7.89 (s, 1H), 7.77
(d, J=5.7Hz, 1H), 7.65 (d, J=15.4Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.45 (d, J=7.3Hz, 2H),
7.40 (d, J=7.1Hz, 1H), 7.37-7.33 (m, 3H), 7.32 (s, 1H), 7.02 (d, J=8.5Hz, 1H), 3.53 (s,
2H), 2.70 (s, 4H), 2.50 (s, 4H), 2.40 (s, 3H), 2.27 (s, 1H), 0.49-0.42 (m, 4H) .ESI-MS:m/z=
455.8[M+1]+By above-mentioned qualification result it is found that gained yellow solid product is CET6.
Step 2: the preparation of HT6
40mg CET12 and 22mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT6 3mg.
Obtained HT6 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.21 (s, 1H), 7.72 (d, J=8.5Hz, 1H), 7.51 (d, J=10.0Hz,
2H), 7.47 (d, J=7.6Hz, 2H), 7.42 (d, J=5.4Hz, 2H), 7.40-7.35 (m, 3H), 6.54 (s, 1H), 3.68
(s, 2H), 2.68 (s, 8H), 2.32 (s, 3H), 2.03 (dd, J=13.5,8.3Hz, 1H), 1.17 (s, 6H) .ESI-MS:m/z
=453.8 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT6.
Embodiment 7 (preparation HT8)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound III
100mg compound II and 70mg piperazine is added in 5ml methylene chloride (DCM), stirring, is heated to 40 DEG C, reaction 2
Hour, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, extracted with ethyl acetate (20mL × 3)
It takes, stands liquid separation, organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then uses nothing
Water magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 56mg.
Obtained compound III is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, MeOD) δ 8.12 (s, 1H), 7.66 (d, J=8.6Hz, 1H), 7.05 (d, J=8.6Hz,
1H), 4.40 (s, 2H), 3.57 (dd, J=13.9,4.3Hz, 8H), 2.69 (s, 3H)
By above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 2: the preparation of CET11
56mg compound III and 27mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
52mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET11 44mg.
Obtained CET11 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.84 (s, 1H), 8.37 (d, J=15.2Hz, 1H), 7.84 (s, 1H), 7.77
(dd, J=6.9,2.0Hz, 1H), 7.61 (d, J=15.3Hz, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H),
7.42 (d, J=5.0Hz, 1H), 7.40-7.37 (m, 1H), 7.36 (s, 1H), 7.33 (d, J=1.5Hz, 1H), 7.32 (s,
1H), 7.04 (d, J=8.5Hz, 1H), 3.57 (s, 2H), 3.18 (s, 4H), 2.73 (s, 4H), 2.39 (s, 3H) are by above-mentioned mirror
Result is determined it is found that gained yellow solid product is CET11.
Step 2: the preparation of HT8
40mg CET11 and 24mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT8 8mg.
Obtained HT8 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, MeOD) δ 8.31 (s, 1H), 8.12 (s, 1H), 7.63-7.59 (m, 1H), 7.48 (d, J=
7.6Hz, 2H), 7.45 (d, J=5.1Hz, 2H), 7.41 (d, J=6.7Hz, 2H), 7.37 (d, J=7.5Hz, 2H), 6.60 (s,
1H), 3.65 (s, 2H), 2.95 (d, J=4.3Hz, 4H), 2.55 (s, 4H), 2.39 (s, 3H) .ESI-MS:m/z=411.4 [M+
1]+By above-mentioned qualification result it is found that gained yellow solid product is HT8.
Embodiment 8 (preparation HT7)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound III
100mg compound II and 152mg 1- tert-butoxycarbonyl-piperazine is added in 5ml methylene chloride (DCM), stirring adds
Heat is reacted 2 hours to 40 DEG C, and TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily compound III 95mg.
Obtained compound III is identified using NMR techniques, qualification result are as follows:
1H NMR(400MHz,CDCl3)δ12.19(s,1H),7.89(s,1H),7.45–7.33(m,1H),6.86(d,J
=8.5Hz, 1H), 3.63 (s, 2H), 3.51 (s, 4H), 2.75-2.23 (m, 7H), 1.37 (s, 9H) can by above-mentioned qualification result
Know, gained yellow oil product is compound III.
Step 2: the preparation of compound V
95mg compound III and 32mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
61mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid compound V 40mg.
Obtained V is identified using mass-spectrometric technique, qualification result are as follows:
ESI-MS:m/z=513.3 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product is compound V.
Step 3: the preparation of HT7
40mg compound V and 20mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C,
Reaction 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL ×
3) it extracts, stands liquid separation, organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then
It is dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=1:1 obtains yellow
Solid HT1 7mg.
Obtained HT7 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.19 (s, 1H), 7.76 (d, J=8.5Hz, 1H), 7.51 (s, 1H), 7.50-
7.45 (m, 3H), 7.42 (d, J=5.4Hz, 2H), 7.37 (d, J=7.5Hz, 3H), 6.54 (s, 1H), 3.65 (s, 2H), 3.46
(s,4H),2.44(s,4H),2.32(s,3H),1.48(s,9H).13C NMR(101MHz,CDCl3)δ178.29,166.58,
155.82,154.71,143.63,141.12,135.46,134.70,134.25,133.78,132.25,129.22,128.45,
128.23,127.24,125.88,125.69,123.42,118.16,112.33,79.59,62.10,52.77,28.37,
[18.31.ESI-MS:m/z=511.2 M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT7.
Embodiment 9 (preparation HT11)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of CET2
100mg compound III and 41mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
80mg compound IV reacts 24 hours, TLC monitoring, after reaction, reaction solution pH=7 is adjusted with concentrated hydrochloric acid, with acetic acid second
Ester (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3)
Washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)=
3:1 obtains yellow solid CET2 70mg.
Obtained CET2 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.77 (s, 1H), 8.08 (d, J=15.6Hz, 1H), 7.82 (d, J=
15.0Hz, 2H), 7.67 (d, J=6.8Hz, 1H), 7.57 (d, J=7.2Hz, 2H), 7.50 (dd, J=15.5,7.8Hz, 4H),
7.43 (d, J=7.5Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.01 (d, J=8.5Hz, 1H), 3.65 (s, 2H), 3.49
(d, J=18.3Hz, 4H), 2.46 (s, 4H), 2.08 (s, 3H) .ESI-MS:m/z=459.7 [M+1]+By above-mentioned qualification result
It is found that gained yellow solid product is CET2.
Step 2: the preparation of HT11
50mg CET12 and 27mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (20mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT11 5mg.
Obtained HT11 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.17 (s, 1H), 7.87 (d, J=7.1Hz, 1H), 7.77 (d, J=8.0Hz,
1H), 7.63 (d, J=7.4Hz, 1H), 7.59 (s, 1H), 7.56 (d, J=8.8Hz, 2H), 7.51 (t, J=7.3Hz, 2H),
7.46 (d, J=7.2Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 6.96 (s, 1H), 3.67 (s, 4H), 3.50 (s, 2H), 2.49
(s, 4H), 2.11 (s, 3H) .ESI-MS:m/z=457.6 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product
For HT11.
Embodiment 10 (preparation HT10 and HT14)
Structural formula isWithChemical combination
The preparation method of object comprises the steps of:
Step 1: the preparation of compound III
300mg compound II is added in 20ml methylene chloride (DCM), stirring is to being completely dissolved, 249mg N- acetyl group
Ethylenediamine is added on a small quantity in batches, and 0 DEG C is reacted 2 hours, and TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into
It in 100mL water, is extracted with ethyl acetate (20mL × 3), stands liquid separation, organic phase uses 5% NaHCO respectively3(20mL×3)、
Saturated salt solution (20mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure and obtains yellow oily
Compound III 310mg.
Obtained compound III is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.22 (s, 1H), 7.72 (s, 1H), 7.47 (dd, J=8.6,1.9Hz, 1H),
6.98 (d, J=8.5Hz, 1H), 6.01 (s, 1H), 3.79 (s, 2H), 3.51 (s, 1H), 3.40 (dd, J=11.5,5.7Hz,
2H), 2.82 (t, J=5.8Hz, 2H), 2.66 (d, J=14.9Hz, 3H), 2.01 (s, 3H)
By above-mentioned qualification result it is found that gained yellow oil product is compound III.
Step 2: the preparation of CET3
310mg compound III and 140mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, then plus
Enter 270mg compound IV, react 24 hours, TLC monitoring adjusts reaction solution pH=7 with concentrated hydrochloric acid, use second after reaction
Acetoacetic ester (80mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(40mL × 3), saturated salt solution (40mL
× 3) it washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether):
V(ethyl acetate)=2:1 obtains yellow solid CET3 170mg.
Obtained CET3 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.30 (d, J=18.5Hz, 2H), 7.90 (d, J=7.3Hz, 1H), 7.81 (d,
J=15.3Hz, 1H), 7.54 (d, J=8.4Hz, 1H), 7.42 (d, J=7.0Hz, 3H), 7.38 (d, J=7.0Hz, 1H),
7.27-7.13 (m, 3H), 6.97 (d, J=8.5Hz, 1H), 4.01 (s, 2H), 3.52 (d, J=4.1Hz, 2H), 3.01 (s,
2H),2.34(s,3H),1.96(s,3H).13C NMR(101MHz,CDCl3)δ193.47,171.76,163.72,144.25,
143.38,141.45,137.44,136.03,134.11,132.38,131.62,129.19,128.15,127.05,126.18,
125.84,123.38,121.45,119.97,118.91,51.35,47.19,36.91,23.07,16.94.
By above-mentioned qualification result it is found that gained yellow solid product is CET3.
Step 3: the preparation of HT10
160mg CET3 and 90mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (40mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT10 50mg.
Obtained HT10 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.26 (s, 1H), 7.74 (d, J=8.4Hz, 1H), 7.51 (d, J=8.6Hz,
2H), 7.46 (d, J=7.4Hz, 2H), 7.42 (d, J=6.6Hz, 2H), 7.37 (t, J=7.2Hz, 3H), 6.57 (s, 1H),
6.53 (s, 1H), 4.04 (s, 2H), 3.68 (d, J=13.9Hz, 1H), 3.46 (d, J=5.2Hz, 2H), 2.94 (t, J=
5.2Hz,2H),2.31(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ178.13,170.84,166.88,
155.98,143.67,141.06,134.89,134.26,133.58,132.36,129.20,128.46,128.24,127.26,
125.91,125.22,123.60,118.55,112.28,52.11,47.80,38.33,23. 13,18.32.ESI-MS:m/z=
427.7[M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT10.
Step 3: the preparation of HT14
40mg HT11 and 10mg potassium hydroxide is added in 5ml deionized water, stirring, is heated to 100 DEG C, reaction 12 is small
When, TLC monitoring adjusts reaction solution pH=7 with concentrated hydrochloric acid, is extracted with ethyl acetate (40mL × 3), stood after reaction
Liquid separation, saturated salt solution (20mL × 3) washing is then dry with anhydrous magnesium sulfate, filters, ethyl acetate is removed under reduced pressure, later
It carries out column and chromatographs V(petroleum ether): V(ethyl acetate)=1:1 obtains yellow solid HT14 6mg.
Obtained HT14 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.27 (s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.48 (d, J=8.3Hz,
2H), 7.48 (d, J=7.3Hz, 2H), 7.43 (d, J=6.6Hz, 2H), 7.40 (t, J=7.1Hz, 3H), 6.59 (s, 1H),
6.51 (s, 1H), 3.98 (s, 2H), 3.76 (d, J=13.9Hz, 1H), 3.50 (d, J=5.2Hz, 2H), 2.83 (t, J=
5.2Hz, 2H), 2.29 (s, 3H) are by above-mentioned qualification result it is found that gained yellow solid product is HT14.
Embodiment 11 (preparation HT9)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of CET4
100mg compound II and 60mg potassium hydroxide is added in 5ml methanol, stirring to solution colour turns yellow, and adds
117mg compound IV reacts 24 hours, TLC monitoring, after reaction, adjusts reaction solution pH=7 with concentrated hydrochloric acid, uses acetic acid
Ethyl ester (50mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3(30mL × 3), saturated salt solution (30mL ×
3) it washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column later and chromatograph V(petroleum ether): V(ethyl acetate)
=2:1 obtains yellow solid CET4 90mg.
Obtained CET4 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 12.86 (s, 1H), 8.36 (d, J=15.3Hz, 1H), 7.94 (s, 1H),
7.78-7.74 (m, 1H), 7.65 (d, J=15.3Hz, 1H), 7.51 (dd, J=8.5,1.6Hz, 1H), 7.46 (d, J=
7.5Hz, 2H), 7.41 (d, J=7.2Hz, 1H), 7.37-7.33 (m, 3H), 7.32 (s, 1H), 7.06 (d, J=8.5Hz, 1H),
4.47 (s, 2H), 3.44 (d, J=7.0Hz, 3H), 2.40 (s, 3H)
By above-mentioned qualification result it is found that gained yellow solid product is CET4.
Step 2: the preparation of HT9
40mg CET4 and 28mg iodine is added in 5ml dimethyl sulfoxide (DMSO), stirring is heated to 100 DEG C, instead
It answers 24 hours, TLC monitoring, after reaction, with saturated aqueous sodium sulfite quenching reaction, with ethyl acetate (40mL × 3)
Extraction, stands liquid separation, and organic phase uses 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), is then used
Anhydrous magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carries out column later and chromatographs V(petroleum ether): V(ethyl acetate)It is solid that=1:1 obtains yellow
Body HT9 6mg.
Obtained HT9 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 7.72 (dd, J=8.6,1.6Hz, 1H), 7.53-7.47 (m,
2H),7.47–7.32(m,7H),6.52(s,1H),4.57(s,2H),3.41(s,3H),2.29(s,3H).13C NMR
(101MHz,CDCl3)δ177.58(s),165.96(s),155.32(s),142.93(s),140.41(s),134.97(s),
133.56(s),133.03(s),132.59(s),131.57(s),128.52(s),127.76(s),127.53(s),126.54
(s),125.18(s),123.79(s),122.73(s),117.64(s),111.62(s),72.96(s),57.54(s),17.62
(s) .ESI-MS:m/z=356.7 [M+1]+By above-mentioned qualification result it is found that gained yellow solid product is HT9.
The inhibitory effect research of embodiment 12, the flavones containing substituted biphenyl to PD1/PD-L1
The inhibitory effect to PD1/PD-L1 of the compounds of this invention tests proved with the following method.
These effects show that the compounds of this invention is obvious to the inhibitory effect of PD1/PD-L1, can be used for treating cancer, special
It is not treatment Metastatic Nsclc, bladder transitional cell carcinoma and head and neck squamous cell carcinoma.The specific test method is as follows:
One, experiment purpose and principle
With reference to Publication No. CN108593615A patent application specification [0016], [0017] and [0034] section side
It is right rapidly and efficiently to detect compound prepared by embodiment 1~11 (number is followed successively by HT1~HT10) using HTRF method for method
The inhibitory effect of PD1/PD-L1.HTRF (homogeneous phase time discrimination fluorescence) detection technique is based on time-resolved fluorescence (TRF) and glimmering
The high throughput screening drug that the big technical principle of photoresonance energy transfer (FRET) two is opened.Time-resolved fluorescence (TRF) benefit
With lanthanide series long half time in rare earth element, the fluorescence characteristic longer than the common fluorescent duration is micro- by delay 50-100
Second excludes background, to reflect sample actual conditions.Fluorescence resonance energy transfer (FRET) refers in two different fluorescent bases
In group, if the absorption light of the emission spectrum of a fluorophor (donor Donor) and another group (receptor Acceptor)
Spectrum has certain overlapping, (generally less than when the distance between the two fluorophors is suitable), so that it may observe fluorescence energy
When exciting with the excitation wavelength of former group, the latter group hair can be observed in the phenomenon that amount is shifted from donor to receptor
The fluorescence penetrated.Briefly, exactly under the excited state of donor groups from the energy that a pair of of dipole mediates from donor to by
The process of body transfer.Energy supply body-acceptor (D-A) occur between effective energy transfer condition be it is harsh, mainly
Including: the emission spectrum of (1) energy donor and the absorption spectrum of energy acceptor must be overlapped；(2) energy donor and energy acceptor
Fluorescence chromophore must arrange in the right way；(3) must be close enough between energy donor, energy acceptor, it sends out in this way
The probability of raw energy transfer just can be high.HTRF is the chela that europium (Eu) element with cave-shaped structure is utilized and marker as one
A energy donor (Donor) and XL665 (improved allophycocyanin) are used as an energy acceptor (Acceptor), are to be based on
Time-resolved fluorescence (TRF) and fluorescence between the donor and XL665 receptor (the second fluorescent marker) of Eu cryptate is total
The high throughput screening drug that vibration energy transfer (FRET) characteristic is opened.In fluorescence resonance energy transfer, acceptor emission is glimmering
The service life of light is equal and the service life of the transmitting fluorescence of donor.Because the fluorescence decay period of Eu is longer, containing Eu for know from experience
Induction XL665 receptor emits fluorescence for a long time, the fluorescence generated after receptor excitation just can last longer, when passing through in this way
Between differentiate can distinguish it is short-life itself scattering fluorescence, be just easily discriminated out FRET from short life fluorescence background in this way
Signal.When causing two fluorophors close due to bio-molecular interaction, captured in excitation by Eu cryptate
Portion of energy release, launch wavelength 620nm；In another part energy transfer to receptor (Acceptor), launch wavelength is
665nm.Only the FRET as caused by donor (Donor) is generated the transmitting light of 665nm.In HTRF detection kit, Eu cave-shapedization
The energy donor for closing object is capable of the combination PD-L1 albumen of specificity, and XL665 energy acceptor is capable of the combination PD-1 egg of specificity
It is white, to form the compound of four polymerizations.Further the distance of Donor and Acceptor, and energy can turn from Donor
It moves on on Acceptor, Acceptor is made to generate fluorescence；If test compound can block the two to combine, with test chemical combination
The ratio of the increase of object concentration, 665nm/620nm reduces；The variation that fluorescent value is measured after stable system to be detected can quantify to hinder
The potency IC of disconnected agent50；Detection is two fluorescence 665nm and 620nm of HTRF, i.e. time-resolved fluorescence (TRF), works as 665nm/
The ratio of 620nm reduces, and the effect of blocking agent is higher.HTRF detection kit exactly comprehensively utilizes the specificity of antigen-antibody
Association reaction, resonance energy transfer between receptor donor and develop, highly sensitive, quickly disposable, the high-throughput detection of low background
Technology.
Two, reagent essential information
Three, experiment reagent prepares
Four, experimentation
(1) into 96 orifice plates, the chemical compound diluted liquid of 2 μ l is added in every hole, and 1000rpm is centrifuged 1min.
(2) 4 μ l (2.5X) PD-1 mixed liquors are added to every hole, 1000rpm is centrifuged 1min.
(3) 4ul (2.5X) PD-L1 mixed liquor is added to every hole, 1000rpm is centrifuged 1min, and incubation at room temperature 15min. (4) is every
Hole is added 10 μ l (2X) and tests mixed liquor, and 1000rpm is centrifuged 1min.
(5) it is incubated at room temperature 120min, reads fluorescent value (Ex:320nM using Tecan microplate reader；Em:620and
665nM) inhibiting rate, inhibiting rate (Inibition) %=(1- (each hole 665nm/620nm signal is calculated according to the following formula in (6)
Value-low control cell mean)/(the low control cell mean of height control cell mean -)) * 100.Wherein high control group is without adding
Compound processing, is only added reaction system group with equivalent concentration DMSO solution；Low control group is not have PD-1 mixed liquor, is only added
Equivalent detection detects mixed liquor.In the detection architecture, DMSO final concentration of 0.5%.With GraphPad Prism5 software
Calculate half amount of suppression IC50。
Activity Results are surveyed as shown in table 1-2:
1 compound HT1~HT13 of table is in 1 μM of inhibitory effect to PD1/PD-L1
Inhibitory effect IC of 2 part of compounds of table to PD1/PD-L150
According to above-mentioned Vitro Experimental Results, we it can be concluded that a kind of flavones containing substituted biphenyl described in patent, such
Compound is able to suppress be combineding with each other for apoptosis receptor 1/ apoptosis ligand 1 (PD1/PD-L1),
Middle HT10 is significant to the inhibitory effect of PD1/PD-L1.
Claims (4)
1. a kind of flavones containing substituted biphenyl, shown in the chemical structure of the flavones such as following formula (I),
In formula (I), R1Be methoxyl group, N- acetylethylenediamine base, ethylenediamine base, piperazinyl, acetylpiperazine base, ethyl piperazidine base,
Isopropyl piperazinyl, tert-butoxycarbonyl-piperazine base or Cyclopr. opylmethylpiperazine base, R2It is hydrogen, fluorine or methyl, R3For hydrogen or Isosorbide-5-Nitrae-two
Six ring group of oxygen.
2. a kind of flavones containing substituted biphenyl according to claim 1, which is characterized in that the flavones is following chemical combination
One of object:
R1It is methoxyl group, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is hydrogen, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is methyl, R3Chemical structure for Isosorbide-5-Nitrae-dioxane, the flavones is
R1It is acetylpiperazine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is ethyl piperazidine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is Cyclopr. opylmethylpiperazine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is isopropyl piperazinyl, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is tert-butoxycarbonyl-piperazine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is piperazinyl, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is N- acetylethylenediamine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
R1It is acetylpiperazine base, R2It is fluorine, R3Chemical structure for hydrogen, the flavones is
R1It is ethylenediamine base, R2It is methyl, R3Chemical structure for hydrogen, the flavones is
3. flavones described in claims 1 or 2 is preparing the application in PD1/PD-L1 inhibitor.
4. application according to claim 3, which is characterized in that the PD1/PD-L1 inhibitor is as described in claim 1
Flavones and medically acceptable auxiliary material composition.
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