CN109438263A - A kind of naphthalene and its application containing substituted biphenyl - Google Patents

A kind of naphthalene and its application containing substituted biphenyl Download PDF

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CN109438263A
CN109438263A CN201811432045.0A CN201811432045A CN109438263A CN 109438263 A CN109438263 A CN 109438263A CN 201811432045 A CN201811432045 A CN 201811432045A CN 109438263 A CN109438263 A CN 109438263A
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naphthalene
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ethylenediamine
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陈建军
程斌斌
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Southern Medical University
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    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a kind of naphthalenes containing substituted biphenyl, shown in the chemical structure of the naphthalene such as following formula (I), in formula (I), and R1It is hydrogen or Isosorbide-5-Nitrae-dioxane, R2It is ethylenediamine, N, N- dimethyl-ethylenediamine, N- tertbutyloxycarbonyl -1,2- ethylenediamine, hydroxyl, ethanol amine, acetyl ethylenediamine, D-Ser, allohydroxyproline, L-cysteine, 2- methylalanine.A kind of naphthalene 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

A kind of naphthalene and its application containing substituted biphenyl
Technical field
The present invention relates to organic compounds, and in particular to naphthalene compound, the compound are able to suppress apoptosis Be combineding with each other for receptor 1/ apoptosis ligand 1 (PD1/PD-L1), 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 naphthalene containing substituted biphenyl, which is able to suppress procedural thin 1/ apoptosis of born of the same parents' death receptor be combined with each other with 1 (PD1/PD-L1's), can be used for preparing PD1/PD-L1 inhibitor.
The scheme that the present invention solves above-mentioned technical problem is as follows:
A kind of naphthalene containing substituted biphenyl, shown in the chemical structure of the naphthalene such as following formula (I),
In formula (I), R1It is hydrogen or Isosorbide-5-Nitrae-dioxane, R2It is ethylenediamine, N, N- dimethyl-ethylenediamine, N- tertiary butyloxycarbonyl Base -1,2- ethylenediamine, hydroxyl, ethanol amine, acetyl ethylenediamine, D-Ser, allohydroxyproline, half Guang ammonia of L- Acid, 2- methylalanine.
2, a kind of naphthalene containing substituted biphenyl according to claim 1, which is characterized in that the naphthalene is following chemical combination One of object:
Work as R1It is hydrogen, R2When being ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2It is N, when N- dimethyl-ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being N- tertbutyloxycarbonyl -1,2- ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being hydroxyl, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being ethanol amine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being acetyl ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being D-Ser, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being allohydroxyproline, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being L-cysteine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being 2- methylalanine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2It is N, when N- dimethyl-ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being N- tertbutyloxycarbonyl -1,2- ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being ethanol amine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being acetyl ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being D-Ser, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being allohydroxyproline, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being L-cysteine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being 2- methylalanine, the chemical structure of the naphthalene is
The preparation method of above-mentioned naphthalene containing substituted biphenyl a kind of the following steps are included:
The preparation method of naphthalene containing substituted biphenyl of the invention, method includes the following steps: first by compound V and change It closes object IV progress light and prolongs reaction generation compound III；Then compound III and compound II is subjected to reduction amination and generates chemical combination Object I.
The reaction equation of the above method is as follows:
In above-mentioned reaction equation, R1It is hydrogen or Isosorbide-5-Nitrae-dioxane, R2It is ethylenediamine, N, the tertiary fourth of N- dimethyl-ethylenediamine, N- Oxygen carbonyl -1,2- ethylenediamine, hydroxyl, ethanol amine, acetyl ethylenediamine, D-Ser, allohydroxyproline, half Guang of L- Propylhomoserin, 2- methylalanine.
The above-mentioned naphthalene 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 naphthalene 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 Naphthalene 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 specific embodiment, the invention will be further described.
Specific embodiment
Embodiment 1 (preparation N1)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of compound III
By 4g compound V and 4.2g compound IV, 8.4g triphenyl phosphorus (PPh3) be added in 40ml anhydrous tetrahydro furan, it stirs It mixes 15 minutes, 8.4mL diisopropyl azodiformate (DIAD) is instilled in reaction solution on a small quantity in batches, is reacted 10 hours, it is thin Layer chromatography (TLC) monitoring, after reaction, reaction solution is poured into 100mL water, is extracted with ethyl acetate (100mL × 5), quiet Liquid separation is set, organic phase uses 5% sodium bicarbonate (NaHCO respectively3) (80mL × 3), saturated salt solution (80mL × 3) washing, so It is dry with anhydrous magnesium sulfate afterwards, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether): V (ethyl acetate) later =10:1 obtains yellow solid III 3g.
Obtained yellow solid is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 10.14 (s, 1H), 8.30 (s, 1H), 7.99-7.94 (m, 2H), 7.87 (d, J=8.5Hz, 1H), 7.53 (dd, J=6.4,2.6Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.43-7.40 (m, 1H), 7.38 (dd, J=3.9, 2.3Hz,3H),7.37–7.36(m,1H),7.35–7.31(m,2H),5.28(s,2H),2.34(s,3H).13C NMR (101MHz,CDCl3)δ191.95,159.49,143.07,141.80,138.20,134.64,134.37,134.20, 132.44,131.24,130.37,129.36,128.10,128.08,128.03,127.79,126.91,125.68,123.67, 120.19,107.26,69.32,16.18. by above-mentioned qualification result it is found that gained yellow solid be compound III.
Step 2: the preparation of compound N 1
By 40mg compound III and 50mg ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to 60 DEG C, it reacts 4 hours, 40mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction knot Shu Hou is spin-dried for solvent, and reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands liquid separation, organic phase point Not with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid N1 10mg。
Obtained compound N 1 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.82 (d, J=4.0Hz, 1H), 7.80 (d, J=3.5Hz, 1H), 7.77 (s, 1H), 7.54 (s, 1H), 7.51-7.48 (m, 2H), 7.46 (d, J=7.6Hz, 2H), 7.40 (d, J=7.4Hz, 1H), 7.35 (d, J=1.4Hz, 1H), 7.33 (s, 1H), 7.30 (d, J=7.5Hz, 1H), 7.28-7.25 (m, 1H), 7.23 (s, 1H), 5.27 (s, 2H), 3.84 (s, 2H), 2.82 (t, J=5.7Hz, 2H), 2.67 (t, J=5.5Hz, 2H), 2.24 (s, 3H) are by upper Qualification result is stated it is found that gained white solid product is compound N 1.
Embodiment 2 (preparation N2)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of N2
By 40mg compound III and 60mg N, N- dimethyl-ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir It mixes, is heated to 60 DEG C, react 4 hours, 42mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC Monitoring, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands and divides Liquid, organic phase use 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then uses anhydrous magnesium sulfate It is dry, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white solid 2 8mg of compound N.
Obtained N2 is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 7.78 (d, J=3.7Hz, 1H), 7.76 (d, J=3.2Hz, 1H), 7.74 (s, 1H), 7.53 (dd, J=6.9,2.0Hz, 1H), 7.48 (dd, J=3.9,2.8Hz, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.41-7.37 (m, 2H), 7.36 (d, J=1.3Hz, 1H), 7.31 (dd, J=5.5,3.0Hz, 3H), 7.28-7.24 (m, 1H), 5.23 (s, 2H), 3.99 (s, 2H), 2.78 (t, J=6.1Hz, 2H), 2.50 (t, J=6.1Hz, 2H), 2.43 (s, 1H), 2.32 (s,3H),2.25(s,6H).13C NMR(101MHz,CDCl3)δ156.73,142.92,141.93,135.51,135.24, 134.33,133.64,130.12,129.38,129.26,129.01,128.04,128.00,127.19,126.94,126.81, 126.46,125.58,119.04,106.89,69.12,58.94,53.97,46.42,45.4 4,16.14.ESI-MS:m/z= 425.8[M+1]+By above-mentioned qualification result it is found that gained white solid product is N2.
Embodiment 3 (preparation N3)
Structural formula isThe preparation method of compound is by following steps Composition:
Step 1: the preparation of N3
By 40mg compound III and 62mg N- tertbutyloxycarbonyl -1,2- ethylenediamine, 5ml is added without water beetle in 2 drop glacial acetic acid In alcohol, stirring is heated to 60 DEG C, reacts 4 hours, 45mg sodium cyanoborohydride (NaBH is then added3CN), room temperature reaction 12 is small When, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, extracted with ethyl acetate (20mL × 3), Liquid separation is stood, organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) washing, then with anhydrous Magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white Color solid chemical compound N3 9mg.
Obtained N3 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 7.80 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.55 (dd, J=6.5, 2.5Hz, 1H), 7.51-7.49 (m, 1H), 7.48 (d, J=2.0Hz, 1H), 7.47 (d, J=1.8Hz, 1H), 7.42 (d, J= 1.3Hz, 1H), 7.41-7.37 (m, 2H), 7.33 (dd, J=4.4,2.5Hz, 3H), 7.30 (dd, J=6.7,2.2Hz, 1H), 5.24 (s, 2H), 3.96 (s, 2H), 3.31 (d, J=5.2Hz, 2H), 2.83 (t, J=5.8Hz, 2H), 2.35 (s, 3H), 2.04 (s,1H),1.52(s,9H).13C NMR(101MHz,CDCl3)δ156.84,156.20,142.95,141.95,135.26, 134.33,133.76,130.15,129.42,129.31,129.03,128.10,128.02,127.13,127.08,126.87, 126.51,125.63,119.18,106.97,79.16,69.14,53.48,48.51,40.2 4,28.46,16.18. is by above-mentioned Qualification result is it is found that gained white solid product is N3.
Embodiment 4 (preparation N4)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N4
40mg compound III is added in 5ml anhydrous methanol, then 45mg sodium cyanoborohydride is added in stirring (NaBH3CN), it reacts at room temperature 12 hours, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, uses Ethyl acetate (20mL × 3) extraction, stands liquid separation, and organic phase uses 5% NaHCO3 (20mL × 3), saturated salt solution respectively (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)=6:1 obtains compound as white solid N4 15mg.Obtained compound N 4 is used into nuclear magnetic resoance spectrum Technology identified, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 7.80 (dd, J=8.8,2.7Hz, 3H), 7.54 (dd, J=6.7,2.2Hz, 1H), 7.52-7.49 (m, 1H), 7.46 (d, J=7.5Hz, 2H), 7.43-7.40 (m, 1H), 7.39 (d, J=1.6Hz, 1H), 7.37(s,1H),7.34–7.31(m,3H),7.31–7.28(m,1H),5.25(s,2H),4.85(s,2H),2.34(s,3H) .13C NMR(101MHz,CDCl3)δ157.01,142.96,141.92,136.17,135.18,134.34,134.04, 130.16,129.46,129.39,128.93,128.07,128.01,127.22,126.84,125.89,125.61,125.53, 119.28,106.96,69.14,65.48,16.16.
By above-mentioned qualification result it is found that gained white solid product is compound N 4.
Embodiment 5 (preparation N5)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N5
By 40mg compound III and 50mg ethanol amine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to 60 DEG C, it reacts 4 hours, 47mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction knot Shu Hou is spin-dried for solvent, and reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands liquid separation, organic phase point Not with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid N5 6mg。
Obtained compound N 5 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 7.78 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.53 (dd, J=6.7,2.2Hz, 1H), 7.48 (t, J=1.4Hz, 1H), 7.45 (s, 1H), 7.45 (s, 1H), 7.40 (dd, J=5.5,1.8Hz, 1H), 7.38 (d, J= 1.6Hz, 1H), 7.37 (d, J=1.4Hz, 1H), 7.33-7.30 (m, 3H), 7.28 (t, J=3.2Hz, 1H), 5.23 (s, 2H), 3.96(s,2H),3.74–3.69(m,2H),2.90–2.84(m,2H),2.63(s,2H),2.32(s,3H).13CNMR (101MHz,CDCl3)δ156.88,142.94,141.92,135.19,134.78,134.32,133.77,130.14, 129.38,129.28,128.96,128.06,127.99,127.13,127.06,126.83,126.63,125.60,119.23, 106.92,69.13,60.74,53.38,50.43,16.15. by above-mentioned qualification result it is found that gained white solid product be change Close object N5.
Embodiment 6 (preparation N6)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N6
By 40mg compound III and 55mg acetyl ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir, heating To 60 DEG C, reacts 4 hours, 48mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, instead After answering, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, it is organic Mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it takes out Filter, is removed under reduced pressure ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid N6 7mg.Obtained compound N 6 is identified using NMR techniques, qualification result are as follows:13C NMR(101MHz, CDCl3)δ173.39,157.73,142.92,141.80,134.87,134.69,134.23,130.17,129.74,129.54, 129.34,128.61,128.05,127.93,127.89,127.10,126.84,126.10,125.59,119.98,106.78, 69.08,51.80,47.66,36.90,22.92,16.11.1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.76(t,J =8.8Hz, 2H), 7.46 (s, 1H), 7.44 (dd, J=6.0,2.3Hz, 3H), 7.41 (s, 1H), 7.37 (dd, J=5.4, 1.8Hz,1H),7.34–7.31(m,2H),7.29–7.25(m,3H),6.17(s,2H),5.13(s,2H),4.11(s,2H), 3.44 (d, J=3.7Hz, 2H), 3.05 (s, 2H), 2.25 (s, 3H), 1.95 (s, 3H) are by above-mentioned qualification result it is found that gained White solid product is compound N 6.
Embodiment 7 (preparation N7)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N7
By 40mg compound III and 50mg D-Ser, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to It 60 DEG C, reacts 4 hours, 49mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction After, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase are stood Respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, Ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid N7 11mg.Obtained compound N 7 is identified using NMR techniques, qualification result are as follows:1H NMR(400MHz, DMSO) δ 7.85 (dd, J=9.1,3.5Hz, 3H), 7.57-7.51 (m, 3H), 7.47 (t, J=7.4Hz, 2H), 7.40 (d, J= 7.2Hz, 1H), 7.34 (d, J=7.3Hz, 2H), 7.29 (dd, J=7.6,4.7Hz, 2H), 7.22 (d, J=7.4Hz, 1H), 5.28 (s, 2H), 4.10 (dd, J=29.0,13.3Hz, 2H), 3.72-3.64 (m, 2H), 3.19 (d, J=5.3Hz, 1H), 2.24 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is compound N 7.
Embodiment 8 (preparation N8)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N8
By 40mg compound III and 60mg allohydroxyproline, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, Stirring is heated to 60 DEG C, reacts 4 hours, 50mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), quiet Liquid separation is set, organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) washing, then with anhydrous sulphur Sour magnesium is dry, filters, ethyl acetate is removed under reduced pressure, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white Solid chemical compound N8 12mg.Obtained compound N 8 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, DMSO) δ 7.84 (t, J=8.8Hz, 3H), 7.56-7.50 (m, 3H), 7.47 (t, J=7.3Hz, 2H), 7.40 (d, J=7.3Hz, 1H), 7.35 (d, J=1.4Hz, 1H), 7.33 (s, 1H), 7.31-7.25 (m, 2H), 7.22 (d, J= 6.8Hz, 1H), 5.28 (s, 2H), 5.00 (s, 1H), 4.26-4.18 (m, 2H), 3.87 (d, J=13.6Hz, 1H), 3.00 (d, J =10.0Hz, 1H), 2.80 (s, 1H), 2.44-2.39 (m, 1H), 2.24 (s, 3H), 2.06-1.93 (m, 1H), 1.84 (d, J= 10.3Hz, 1H) by above-mentioned qualification result it is found that gained white solid product be compound N 8.
Embodiment 9 (preparation N9)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N9
By 40mg compound III and 50mg L-cysteine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir, heating To 60 DEG C, reacts 4 hours, 46mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, instead After answering, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, it is organic Mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it takes out Filter, is removed under reduced pressure ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid N9 2mg.Obtained compound N 9 is identified using NMR techniques, qualification result are as follows:1H NMR(400MHz, DMSO) δ 7.83 (t, J=7.1Hz, 3H), 7.53 (d, J=10.2Hz, 3H), 7.47 (t, J=7.4Hz, 2H), 7.40 (d, J= 7.2Hz, 1H), 7.34 (d, J=7.1Hz, 2H), 7.28 (dd, J=13.0,4.7Hz, 2H), 7.22 (d, J=7.4Hz, 1H), 5.27 (s, 2H), 3.99 (dd, J=41.4,13.4Hz, 3H), 3.35 (s, 1H), 2.81 (d, J=5.6Hz, 1H), 2.24 (s, 3H) is by above-mentioned qualification result it is found that gained white solid product is compound N 9.
Embodiment 10 (preparation N10)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of N10
By 40mg compound III and 50mg 2- methylalanine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring adds Heat reacts 4 hours to 60 DEG C, 43mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, After reaction, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, has Machine mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, It filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white solid chemical combination Object N10 7mg.Obtained compound N 10 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, DMSO) δ 7.92 (s, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.58 (d, J=8.4Hz, 1H), 7.53 (d, J= 6.2Hz, 2H), 7.47 (t, J=7.4Hz, 2H), 7.40 (d, J=7.5Hz, 1H), 7.35 (t, J=8.9Hz, 2H), 7.30 (d, J=7.4Hz, 2H), 7.22 (d, J=7.5Hz, 1H), 5.28 (s, 2H), 4.06 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H) By above-mentioned qualification result it is found that gained white solid product is compound N 10.
Embodiment 11 (preparation YN1)
Structural formula isThe preparation method of compound is by following steps Composition:
Step 1: the preparation of compound III
By 4g compound V and 5.5g compound IV, 8.5g triphenyl phosphorus (PPh3) be added in 40ml anhydrous tetrahydro furan, it stirs It mixes 15 minutes, 8.6mL diisopropyl azodiformate (DIAD) is instilled in reaction solution on a small quantity in batches, is reacted 10 hours, it is thin Layer chromatography (TLC) monitoring, after reaction, reaction solution is poured into 100mL water, is extracted with ethyl acetate (100mL × 5), quiet Liquid separation is set, organic phase uses 5% sodium bicarbonate (NaHCO respectively3) (80mL × 3), saturated salt solution (80mL × 3) washing, so It is dry with anhydrous magnesium sulfate afterwards, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether): V (ethyl acetate) later =10:1 obtains yellow solid III 4g
Obtained yellow solid III is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 10.13 (s, 1H), 8.30 (s, 1H), 7.98-7.94 (m, 2H), 7.86 (d, J=8.5Hz, 1H), 7.48 (dd, J=5.9,3.2Hz, 1H), 7.37-7.33 (m, 2H), 7.29 (d, J=2.6Hz, 1H), 7.28 (s, 1H), 6.95 (d, J=8.2Hz, 1H), 6.88 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.3,2.1Hz, 1H), 5.26 (s, 2H), 4.34 (s, 4H), 2.34 (s, 3H) are by above-mentioned qualification result it is found that gained yellow solid is compound III.
Step 2: the preparation of compound YN1
By 50mg compound III and 50mg ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to 60 DEG C, it reacts 4 hours, 60mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction knot Shu Hou is spin-dried for solvent, and reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands liquid separation, organic phase point Not with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid YN1 11mg。
Obtained compound YN1 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.81 (d, J=5.9Hz, 1H), 7.79 (d, J=5.4Hz, 1H), 7.76 (s, 1H), 7.49 (d, J=7.3Hz, 3H), 7.29-7.22 (m, 2H), 7.18 (d, J=7.6Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.80 (d, J=2.0Hz, 1H), 6.77 (dd, J=8.2,2.1Hz, 1H), 5.24 (s, 2H), 4.29 (s, 4H), 3.18 (s, 2H), 2.76 (d, J=5.7Hz, 2H), 2.64 (d, J=5.6Hz, 2H), 2.25 (s, 3H) by above-mentioned qualification result it is found that Gained white solid product is compound YN1.
Embodiment 12 (preparation YN2)
Structural formula isThe preparation method of compound is by following steps Composition:
Step 1: the preparation of YN2
By 40mg compound III and 58mg N, N- dimethyl-ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir It mixes, is heated to 60 DEG C, react 4 hours, 46mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC Monitoring, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands and divides Liquid, organic phase use 5% NaHCO respectively3The washing of (20mL × 3), saturated salt solution (20mL × 3), then uses anhydrous magnesium sulfate It is dry, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white solid Compound YN2 8mg.
Obtained YN2 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 7.77 (d, J=3.0Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 7.73 (s, 1H), 7.51-7.45 (m, 2H), 7.30 (d, J=2.5Hz, 1H), 7.28 (s, 1H), 7.26 (dd, J=8.8,2.4Hz, 2H), 6.94 (d, J=8.2Hz, 1H), 6.88 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.2,2.1Hz, 1H), 5.21 (s, 2H), 4.33 (s, 4H), 3.99 (s, 2H), 2.78 (t, J=6.1Hz, 2H), 2.54 (s, 1H), 2.51 (d, J=5.9Hz, 2H), 2.33 (s,3H),2.26(s,6H).13C NMR(101MHz,CDCl3)δ156.79,143.00,142.56,142.34,135.31, 135.17,135.03,134.46,133.69,130.16,129.26,128.97,127.81,127.14,127.01,126.58, 125.51,122.56,119.11,118.22,116.80,106.87,69.13,64.39,58.67,53.83,46.11, 45.30,16.15. by above-mentioned qualification result it is found that gained white solid product be YN2.
Embodiment 13 (preparation YN3)
Structural formula isThe preparation method of compound is by following Step composition:
Step 1: the preparation of YN3
By 40mg compound III and 64mg N- tertbutyloxycarbonyl -1,2- ethylenediamine, 5ml is added without water beetle in 2 drop glacial acetic acid In alcohol, stirring is heated to 60 DEG C, reacts 4 hours, 45mg sodium cyanoborohydride (NaBH is then added3CN), room temperature reaction 12 is small When, TLC monitoring after reaction, is spin-dried for solvent, reactant is poured into 100mL water, extracted with ethyl acetate (20mL × 3), Liquid separation is stood, organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) washing, then with anhydrous Magnesium sulfate is dry, filters, ethyl acetate is removed under reduced pressure, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white Color solid chemical compound YN3 9mg.
Obtained YN3 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 7.77 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.49 (dd, J=6.0, 3.0Hz, 1H), 7.46 (dd, J=8.4,1.5Hz, 1H), 7.31 (d, J=1.7Hz, 1H), 7.28 (d, J=2.6Hz, 2H), 7.26 (d, J=2.4Hz, 1H), 6.95 (d, J=8.2Hz, 1H), 6.90 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.2, 2.0Hz, 1H), 5.21 (s, 2H), 4.31 (d, J=4.8Hz, 4H), 3.94 (s, 2H), 3.29 (d, J=5.3Hz, 2H), 2.81 (t, J=5.8Hz, 2H), 2.34 (s, 3H), 2.11 (s, 1H), 1.49 (s, 9H)13C NMR(101MHz,CDCl3)δ156.82, 156.17,143.03,142.59,142.35,135.30,135.18,135.09,134.44,133.73,130.17,129.26, 128.97,127.81,127.08,127.06,126.51,125.54,122.56,119.17,118.24,116.83,106.92, 79.15 69.14,64.39,53.44,48.46,40.18,28.41,16.17. by above-mentioned qualification result it is found that gained white is consolidated Body product is YN3.
Embodiment 14 (preparation YN4)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of YN4
By 40mg compound III and 52mg ethanol amine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to 60 DEG C, it reacts 4 hours, 47mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction knot Shu Hou is spin-dried for solvent, and reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), stands liquid separation, organic phase point Not with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid YN4 7mg。
Obtained compound YN4 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 7.76 (d, J=8.6Hz, 2H), 7.71 (s, 1H), 7.49 (dd, J=6.2,2.8Hz, 1H), 7.45 (dd, J=8.4,1.4Hz, 1H), 7.30 (d, J=2.5Hz, 1H), 7.28 (s, 1H), 7.27 (dd, J=6.4,2.5Hz, 2H), 6.95 (d, J=8.2Hz, 1H), 6.89 (d, J=2.0Hz, 1H), 6.83 (dd, J=8.2,2.1Hz, 1H), 5.21 (s, 2H), 4.33(s,4H),3.96(s,2H),3.73–3.68(m,2H),2.88–2.84(m,2H),2.51(s,2H),2.33(s,3H) .13C NMR(101MHz,CDCl3)δ156.87,143.01,142.57,142.35,135.30,135.14,134.83, 134.45,133.75,130.17,129.25,128.95,127.81,127.11,127.04,126.59,125.53,122.56, 119.22,118.23,116.81,106.90,69.14,64.39,60.77,53.38,50.4 2,16.16. is tied by above-mentioned identification Fruit is it is found that gained white solid product is compound YN4.
Embodiment 15 (preparation YN5)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of YN5
By 40mg compound III and 59mg acetyl ethylenediamine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir, heating To 60 DEG C, reacts 4 hours, 46mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, instead After answering, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, it is organic Mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it takes out Filter, is removed under reduced pressure ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid YN5 7mg.Obtained compound YN5 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 7.83 (s, 1H), 7.76 (t, J=9.6Hz, 2H), 7.46 (d, J=8.5Hz, 1H), 7.42 (t, J= 4.6Hz, 1H), 7.25-7.21 (m, 4H), 6.91 (d, J=8.2Hz, 1H), 6.84 (d, J=2.0Hz, 1H), 6.78 (dd, J= 8.2,2.0Hz,1H),5.77(s,2H),5.11(s,2H),4.30(s,4H),4.13(s,2H),3.44(s,2H),3.07(s, 2H),2.27(s,3H),1.96(s,3H).13C NMR(101MHz,CDCl3)δ173.59,157.78,143.00,142.57, 142.33,135.18,134.83,134.74,134.36,130.20,129.76,129.74,129.64,128.58,127.99, 127.71,127.07,125.71,125.52,122.52,120.02,118.19,116.81,106.77,69.09,64.36, 51.89,47.95,37.01,22.93,16.14. by above-mentioned qualification result it is found that gained white solid product be compound YN5.
Embodiment 16 (preparation YN6)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of YN6
By 40mg compound III and 54mg D-Ser, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to It 60 DEG C, reacts 4 hours, 50mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, reaction After, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase are stood Respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, Ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid YN6 11mg.Obtained compound YN6 is identified using NMR techniques, qualification result are as follows:1H NMR(400MHz, DMSO) δ 7.88-7.78 (m, 3H), 7.55 (d, J=9.8Hz, 1H), 7.50 (dd, J=8.4,4.9Hz, 2H), 7.30-7.24 (m, 2H), 7.18 (d, J=6.8Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.81 (d, J=2.0Hz, 1H), 6.77 (dd, J =8.2,2.1Hz, 1H), 5.25 (s, 2H), 4.29 (s, 4H), 4.17-4.06 (m, 2H), 3.69 (dd, J=11.9,5.5Hz, 2H), 3.21 (d, J=5.8Hz, 1H), 2.25 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is chemical combination Object YN6.
Embodiment 17 (preparation YN7)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of YN7
By 40mg compound III and 61mg allohydroxyproline, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, Stirring is heated to 60 DEG C, reacts 4 hours, 50mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), quiet Liquid separation is set, organic phase uses 5% NaHCO respectively3(20mL × 3), saturated salt solution (20mL × 3) washing, then with anhydrous sulphur Sour magnesium is dry, filters, ethyl acetate is removed under reduced pressure, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white Solid chemical compound YN7 12mg.Obtained compound YN7 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, DMSO) δ 7.82 (dd, J=16.4,7.6Hz, 3H), 7.50 (t, J=7.8Hz, 3H), 7.29-7.24 (m, 2H), 7.18 (d, J=6.6Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.81 (d, J=2.0Hz, 1H), 6.77 (dd, J =8.2,2.1Hz, 1H), 5.25 (s, 2H), 4.84 (s, 1H), 4.29 (s, 4H), 4.22 (s, 1H), 4.16 (d, J=13.0Hz, 1H), 3.75 (d, J=12.8Hz, 1H), 2.91 (d, J=10.0Hz, 1H), 2.68 (dd, J=5.8,3.7Hz, 1H), 2.41- 2.38 (m, 1H), 2.25 (s, 3H), 2.04-1.98 (m, 1H), 1.84-1.80 (m, 1H) are by above-mentioned qualification result it is found that gained White solid product is compound YN7.
Embodiment 18 (preparation YN8)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of YN8
By 40mg compound III and 51mg L-cysteine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir, heating To 60 DEG C, reacts 4 hours, 45mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, instead After answering, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, it is organic Mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it takes out Filter, is removed under reduced pressure ethyl acetate, and carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains compound as white solid YN8 2mg.Obtained compound YN8 is identified using NMR techniques, qualification result are as follows:13C NMR (101MHz,DMSO)δ172.32,143.37,142.91,142.05,135.88,134.89,134.41,134.00,133.72, 130.03,129.67,128.78,128.10,127.81,127.35,127.31,127.22,125.86,124.95,124.82, 124.71,122.55,119.32,118.14,117.19,107.54,68.90,64.51,50.90,26.43,16.25.1H NMR (400MHz, DMSO) δ 7.82 (dd, J=13.2,8.1Hz, 3H), 7.51 (t, J=9.8Hz, 3H), 7.28-7.22 (m, 2H), 7.18 (d, J=7.4Hz, 1H), 6.95-6.91 (m, 1H), 6.82-6.75 (m, 2H), 5.25 (s, 2H), 4.29 (s, 4H), 3.98 (dd, J=42.4,13.5Hz, 3H), 3.34 (s, 1H), 2.80 (s, 1H), 2.25 (s, 3H) are tied by above-mentioned identification Fruit is it is found that gained white solid product is compound YN8.
Embodiment 19 (preparation YN9)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of YN9
By 40mg compound III and 53mg 2- methylalanine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring adds Heat reacts 4 hours to 60 DEG C, 45mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, After reaction, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation is stood, has Machine mutually respectively with 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, It filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether) later: V (ethyl acetate)=2:1 obtains white solid chemical combination Object YN9 7mg.Obtained compound YN9 is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, DMSO) δ 7.92 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.58 (d, J=8.5Hz, 1H), 7.53 (d, J= 2.2Hz, 1H), 7.49 (d, J=7.4Hz, 1H), 7.32-7.28 (m, 1H), 7.26 (d, J=7.5Hz, 1H), 7.19 (d, J= 6.8Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.80 (d, J=2.0Hz, 1H), 6.77 (dd, J=8.2,2.0Hz, 1H), 5.26 (s, 2H), 4.29 (s, 4H), 4.07 (s, 2H), 2.25 (s, 3H), 1.40 (s, 6H) are by above-mentioned qualification result it is found that institute Obtaining white solid product is compound YN9.
The inhibitory effect research of embodiment 20, the naphthalene 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 Method, using HTRF method rapidly and efficiently detect compound prepared by embodiment 1~11 (number is followed successively by N1~N10, YN1~ YN9) to the inhibitory effect of PD1/PD-L1.HTRF (homogeneous phase time discrimination fluorescence) detection technique is based on time-resolved fluorescence (TRF) and the high throughput screening drug opened of the big technical principle of fluorescence resonance energy transfer (FRET) two.Time resolution is glimmering Light (TRF) passes through delay using lanthanide series long half time in rare earth element, the fluorescence characteristic longer than the common fluorescent duration 50-100 microsecond excludes background, to reflect sample actual conditions.Fluorescence resonance energy transfer (FRET) refers in two differences Fluorophor in, if the emission spectrum of a fluorophor (donor Donor) and another group (receptor Acceptor) Absorption spectrum have certain overlapping, (generally less than when the distance between the two fluorophors is suitable), so that it may it observes The phenomenon that shifting to fluorescent energy from donor to receptor, i.e., when being excited with the excitation wavelength of former group, can be observed latter The fluorescence of a group transmitting.Briefly, the energy mediated exactly under the excited state of donor groups by a pair of of dipole from The process that donor is shifted to receptor.The condition that effective energy transfer occurs between for energy supply body-acceptor (D-A) is severe It carves, specifically includes that the emission spectrum of (1) energy donor must be overlapped with the absorption spectrum of energy acceptor；(2) energy donor with The fluorescence chromophore of energy acceptor must arrange in the right way；(3) it must be connect enough between energy donor, energy acceptor Closely, the probability that energy transfer occurs so just can be high.HTRF is chela and the mark that europium (Eu) element with cave-shaped structure is utilized Remember that object is used as an energy acceptor as an energy donor (Donor) and XL665 (improved allophycocyanin) (Acceptor), it is time resolution between the donor based on Eu cryptate and XL665 receptor (the second fluorescent marker) The high throughput screening drug that fluorescence (TRF) and fluorescence resonance energy transfer (FRET) characteristic are opened.In fluorescence resonance energy In transfer, the service life of acceptor emission fluorescence is equal and the service life of the transmitting fluorescence of donor.Because the fluorescence decay period of Eu is longer, So emit fluorescence for a long time for knowing from experience induction XL665 receptor containing Eu, the fluorescence generated after receptor excitation just can continue compared with For a long time, itself short-life scattering fluorescence can be distinguished by time resolution in this way, in this way from short life fluorescence background Just it is easily discriminated out FRET signal.When causing two fluorophors close due to bio-molecular interaction, in excitation The portion of energy release captured by Eu cryptate, launch wavelength 620nm；Another part energy transfer is to receptor (Acceptor) on, launch wavelength 665nm.Only the FRET as caused by donor (Donor) is generated the transmitting light of 665nm.? In HTRF detection kit, the energy donor of Eu cryptate is capable of the combination PD-L1 albumen of specificity, XL665 energy by Body is capable of the combination PD-1 albumen of specificity, to form the compound of four polymerizations.Further Donor's and Acceptor Distance, energy can be transferred on Acceptor from Donor, and Acceptor is made to generate fluorescence；If test compound can hinder Both disconnected to combine, then with the increase of test compound concentration, the ratio of 665nm/620nm is reduced；After stable system to be detected The variation of measurement fluorescent value can quantify the potency IC of blocking agent50；Detection is two fluorescence 665nm and 620nm of HTRF, immediately Between resolved fluorometric (TRF), when the ratio of 665nm/620nm reduces, the effect of blocking agent is higher.HTRF detection kit is exactly Comprehensively utilize the specific binding reaction of antigen-antibody, resonance energy transfer between receptor donor and develop, it is highly sensitive, quickly It is disposable, the high-throughput detection technique of low background.
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%.
Following table list measured in PD-1/PD-L1 homogeneous phase time discrimination fluorescence (HTRF) binding assay it is of the invention The IC of embodiment 1- embodiment 1950.The IC of compound50It is denoted as between 1 μM to 10 μM ++；The IC50 of compound is in 10 μ Be denoted as between M to 100 μM+.Specifically it see the table below:
The inhibitory effect of compound N 1~N10, YN1~YN9 to PD1/PD-L1
According to above-mentioned Vitro Experimental Results, we are it can be concluded that a kind of naphthalene containing substituted biphenyl described in patent, such change It closes object and is able to suppress be combineding with each other for apoptosis receptor 1/ apoptosis ligand 1 (PD1/PD-L1).

Claims (4)

1. a kind of naphthalene containing substituted biphenyl, shown in the chemical structure of the naphthalene such as following formula (I),
In formula (I), R1It is hydrogen or Isosorbide-5-Nitrae-dioxane, R2It is ethylenediamine, N, N- dimethyl-ethylenediamine, tertbutyloxycarbonyl -1 N-, 2- ethylenediamine, hydroxyl, ethanol amine, acetyl ethylenediamine, D-Ser, allohydroxyproline, L-cysteine, 2- first Base alanine.
2. a kind of naphthalene containing substituted biphenyl according to claim 1, which is characterized in that the naphthalene is in following compounds One kind:
Work as R1It is hydrogen, R2When being ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2It is N, when N- dimethyl-ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being N- tertbutyloxycarbonyl -1,2- ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being hydroxyl, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being ethanol amine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being acetyl ethylenediamine, the chemical structure of the naphthalene is
R1When being hydrogen, R2When being D-Ser, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being allohydroxyproline, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being L-cysteine, the chemical structure of the naphthalene is
Work as R1It is hydrogen, R2When being 2- methylalanine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2It is N, when N- dimethyl-ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being N- tertbutyloxycarbonyl -1,2- ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being ethanol amine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being acetyl ethylenediamine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being D-Ser, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being allohydroxyproline, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being L-cysteine, the chemical structure of the naphthalene is
Work as R1It is Isosorbide-5-Nitrae-dioxane, R2When being 2- methylalanine, the chemical structure of the naphthalene is。
3. naphthalene 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 Naphthalene and medically acceptable auxiliary material composition.
CN201811432045.0A 2018-11-28 2018-11-28 A kind of naphthalene and its application containing substituted biphenyl Pending CN109438263A (en)

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