CN109761952A - A kind of resorcinol methyl ether derivative and application thereof containing substituted biphenyl - Google Patents

A kind of resorcinol methyl ether derivative and application thereof containing substituted biphenyl Download PDF

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CN109761952A
CN109761952A CN201910136927.0A CN201910136927A CN109761952A CN 109761952 A CN109761952 A CN 109761952A CN 201910136927 A CN201910136927 A CN 201910136927A CN 109761952 A CN109761952 A CN 109761952A
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substituted biphenyl
methyl ether
containing substituted
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resorcinol
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陈建军
程斌斌
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Southern Medical University
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Southern Medical University
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Priority to PCT/CN2019/091193 priority patent/WO2020173016A1/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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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    • C07—ORGANIC CHEMISTRY
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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
    • 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
    • C07D207/12—Oxygen or sulfur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • 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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    • C07D405/02—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
    • 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 resorcinol methyl ether derivative containing substituted biphenyl, shown in the chemical structure of the compound such as following formula (I), in formula (I), R1It is amion acetic acid base, (R)-pyrrolidines -3- formyl, (R) -3- pyrrolidines alcohol radical, (S)-pyrrolidines -3- formyl, (S) -3- pyrrolidines alcohol radical, azetidine -3- carboxylic acid group, (3R, 5S) the fluoro- 3- hydroxypyrrole alkyl of -5- hydroxymethyl -3- pyrrolidines alcohol radical, trans- -4-, 3- methyl -3- azetidin alcohol radical, 4- (methylol) pyrrolidines -3- alcohol radical, N, N- dimethyl-ethylenediamine base, 3- hydroxypyrrole alkyl, 2- methylalanine base, 3- hydroxyazetidinium base, R2It is hydrogen, 1,4- dioxane.A kind of resorcinol methyl ether derivative containing substituted biphenyl of the present invention is able to suppress be combineding with each other for apoptosis receptor 1/ apoptosis ligand 1 (PD-1/PD-L1), it can be used for preparing PD-1/PD-L1 inhibitor, the significant effect of the inhibitor.

Description

A kind of resorcinol methyl ether derivative and application thereof containing substituted biphenyl
Technical field
The present invention relates to organic compounds, and in particular to a kind of resorcinol methyl ether derivative containing substituted biphenyl, this spreads out Biology is able to suppress be combineding with each other for apoptosis receptor 1/ apoptosis ligand 1 (PD-1/PD-L1), can 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, PD-1/PD-L1 becomes a most attracting target in anti-tumor drug design, while One of the cancer target of most prospect is had been cited as, thus is concerned.
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.
The compound of the skeleton containing resorcinol mainly includes coumarin kind compound, isoflavone compound, Phenylpropanoid Glycosides class Compound, resorcinol class Macrocyclic lactone compounds.Multiple studies have shown that the compound of the skeleton containing resorcinol has various aspects Biological use, such as coumarin kind compound represent one of psoralen, play the role of increase dermal melanin, be suitable for The treatment of leucoderma, structure is 7H- furans simultaneously [3,2-g] chromene -7- ketone, but the compound is in the photograph of ultraviolet radiator It penetrates down and can produce phototoxic reaction；One of isoflavone compound representative licoflavone, with stronger inhibition tyrosine enzyme activity Property, it can achieve yellow freckle removing and whitening effect of preferably dispelling, while licoflavone energy scavenging activated oxygen, there is stronger antioxygen energy Power, but licoflavone do not have 1/ apoptosis ligand 1 (PD-1/PD-L1) of targeted cell death receptor document and Patent report；Phenylpropanoids one of represent lilac phenolic glycoside, with significant anastalsis, and it is a kind of strong anti- Liver cytotoxic drug, the enzymatic activity and anti-lipid peroxidation effect for restoring microsomal enzyme system can promote hepatotoxicant to be metabolized and change Kind liver function is allowed to normalization, which contains β-D- glucopyranoside, the compound and the resorcinol two that we report The structure of methyl phenyl ethers anisole and pharmacological action have very big difference；One of the resorcinol class Macrocyclic lactone compounds representative big ring of resorcinol Lactone is mainly used for the treatment of bacterial infectious disease and respiratory tract infection, which contains 14 membered macrolides, the structure Lactone bond is easy hydrolysis in environment in vivo, reduces compound activity.
The PCT Patent Application of Publication No. WO2015/034820 A1 discloses entitled 1- ({ 3- bromo- 4- [(2- methyl- 3- phenyl) methoxyl group)) phenyl-methyl) following two anisol derivatives of resorcinol of piperidines -2- carboxylic acid structure formula (see should The embodiment 8 of patent application):
Above-mentioned PCT Patent Application discloses the derivative and is able to suppress 1/ programmed cell of apoptosis receptor Death ligand 1 (PD-1/PD-L1's) be combined with each other, and can be used for treating tumour.But disclosed in above-mentioned PCT Patent Application Compound is also undesirable to the inhibitory effect of PD-1/PD-L1, and the IC50 for using HTRF method to detect is only 146nM.Therefore, A kind of pair of ideal compound of PD-1/PD-L1 inhibitory effect is synthesized to be of great significance.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of resorcinol methyl ether derivative containing substituted biphenyl, this spreads out Biology is able to suppress 1/ apoptosis of apoptosis receptor be combineding with each other with 1 (PD-1/PD-L1), and imitates Fruit is significant.
The scheme that the present invention solves above-mentioned technical problem is as follows:
A kind of resorcinol methyl ether derivative containing substituted biphenyl, shown in the chemical structure of the derivative such as following formula (I),
In formula (I), R1It is amion acetic acid base, (R)-pyrrolidines -3- formyl, (R) -3- pyrrolidines alcohol radical, (S)-pyrroles Alkane -3- formyl, (S) -3- pyrrolidines alcohol radical, azetidine -3- carboxylic acid group, (3R, 5S) -5- hydroxymethyl -3- pyrrolidines The fluoro- 3- hydroxypyrrole alkyl of alcohol radical, trans- -4-, 3- methyl -3- azetidin alcohol radical, 4- (methylol) pyrrolidines -3- alcohol radical, N, N- dimethyl-ethylenediamine base, 3- hydroxypyrrole alkyl, 2- methylalanine base, 3- hydroxyazetidinium base, R2It is hydrogen, 1, 4- dioxane.
A kind of one of preferably following compounds of resorcinol methyl ether derivative containing substituted biphenyl of the present invention:
Work as R1It is amion acetic acid base, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether containing substituted biphenyl is derivative The chemical structure of object is
Work as R1It is (R)-pyrrolidines -3- formyl, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is (R) -3- pyrrolidines alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is (S)-pyrrolidines -3- formyl, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is (S) -3- pyrrolidines alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is azetidine -3- carboxylic acid group, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is (3R, 5S) -5- hydroxymethyl -3- pyrrolidines alcohol radical, R2It is described containing substitution when being Isosorbide-5-Nitrae-dioxane The chemical structure of the resorcinol methyl ether derivative of biphenyl is
Work as R1It is the fluoro- 3- hydroxypyrrole alkyl of trans- -4-, R2It is described containing between substituted biphenyl when being Isosorbide-5-Nitrae-dioxane The chemical structure of benzenediol methyl ether derivative is
Work as R1It is 3- methyl -3- azetidin alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic containing substituted biphenyl The chemical structure of diphenol methyl ether derivative is
Work as R1It is 4- (methylol) pyrrolidines -3- alcohol radical, R2It is described containing between substituted biphenyl when being Isosorbide-5-Nitrae-dioxane The chemical structure of benzenediol methyl ether derivative is
Work as R1It is 3- hydroxypyrrole alkyl, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether containing substituted biphenyl The chemical structure of derivative is
Work as R1It is amion acetic acid base, R2When being hydrogen, the chemical structure of the resorcinol methyl ether derivative containing substituted biphenyl For
Work as R1It is (S)-pyrrolidines -3- formyl, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure be
Work as R1It is (R) -3- pyrrolidines alcohol radical, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is (R)-pyrrolidines -3- formyl, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure be
Work as R1It is (S) -3- pyrrolidines alcohol radical, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is azetidine -3- carboxylic acid group, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure be
Work as R1It is 2- methylalanine base, R2When being hydrogen, the chemistry of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
Work as R1It is N, N- dimethyl-ethylenediamine base, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure is
Work as R1It is (3R, 5S) -5- hydroxymethyl -3- pyrrolidines alcohol radical, R2When being hydrogen, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is the fluoro- 3- hydroxypyrrole alkyl of trans- -4-, R2When being hydrogen, the resorcinol methyl ether containing substituted biphenyl spreads out Biology chemical structure be
Work as R1It is 3- methyl -3- azetidin alcohol radical, R2When being hydrogen, the resorcinol methyl ether containing substituted biphenyl is derivative The chemical structure of object is
Work as R1It is 3- hydroxyazetidinium base, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is 3- hydroxypyrrole alkyl, R2When being hydrogen, the chemistry of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
The preparation method of above-mentioned resorcinol methyl ether derivative containing substituted biphenyl a kind of the following steps are included:
A kind of preparation method of resorcinol methyl ether derivative containing substituted biphenyl of the invention, this method includes following step It is rapid: compound VII and compound VI being subjected to light first and prolongs reaction generation compound V；Then by compound V and compound IV It carries out nucleophilic substitution and generates compound III；Final compound III and compound II carries out reductive amination process generationization Close object I.
The reaction equation of the above method is as follows:
In above-mentioned reaction equation, R1It is amion acetic acid base, (R)-pyrrolidines -3- formyl, (R) -3- pyrrolidines alcohol radical, (S) - Pyrrolidines -3- formyl, (S) -3- pyrrolidines alcohol radical, azetidine -3- carboxylic acid group, (3R, 5S) -5- hydroxymethyl -3- pyrrole Cough up the fluoro- 3- hydroxypyrrole alkyl of silane alcohol base, trans- -4-, 3- methyl -3- azetidin alcohol radical, 4- (methylol) pyrrolidines -3- Alcohol radical, N, N- dimethyl-ethylenediamine base, 3- hydroxypyrrole alkyl, 2- methylalanine base, 3- hydroxyazetidinium base, R2It is Hydrogen, 1,4- dioxane.
A kind of above-mentioned resorcinol methyl ether derivative containing substituted biphenyl is able to suppress 1/ journey of apoptosis receptor Programmed cell death ligand 1 (PD-1/PD-L1's) be combined with each other, and can be used for preparing PD-1/PD-L1 inhibitor, the inhibitor Antitumous effect it is significant.The PD-1/PD-L1 inhibitor is by a kind of resorcinol methyl ether containing substituted biphenyl Derivative and medically acceptable auxiliary material composition.
It is of the present invention a kind of containing substitution using the measurement of HTRF (homogeneous phase time discrimination fluorescence) technical standard operation sequence The resorcinol methyl ether derivative of biphenyl is to the inhibitory effect of PD-1/PD-L1, and the compound presses down PD-1/PD-L1 as the result is shown Significant effect processed is better than the prior art.
Below in conjunction with specific embodiment, the invention will be further described.
Specific embodiment
Embodiment 1 (preparation C1)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of compound V
By chloro- 2, the 4- 4-dihydroxy benzaldehyde (compound VII) of 4g 5- and 5g, (3- (dislike by 2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] two Own ring -6- base) -2- aminomethyl phenyl) methanol (compound VI), 8.4g triphenyl phosphorus (PPh3) 50ml anhydrous tetrahydro furan is added In, it stirs 15 minutes, 8.2mL diisopropyl azodiformate (DIAD) is instilled in reaction solution on a small quantity in batches, reaction 10 is small When, after reaction, reaction solution is poured into 100mL water, is extracted with ethyl acetate (100mL × 5) for thin-layer chromatography (TLC) monitoring It takes, stands liquid separation, organic phase uses 5% sodium bicarbonate (NaHCO respectively3) (80mL × 3), saturated salt solution (80mL × 3) wash It washs, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography V (petroleum ether): V (acetic acid later Ethyl ester)=10:1 obtains the chloro- 4- of white solid 5- (3- (2,3- dihydrobenzo [b] [1,4] two dislike own ring -6- base) -2- methyl benzyl Base) oxygroup)-Benzaldehyde,2-hydroxy (compound V) 6g.
Obtained compound as white solid V is identified using nuclear magnetic resoance spectrum, mass-spectrometric technique, qualification result are as follows:13C NMR(101MHz, CDCl3)δ193.65,162.90,160.93,143.04,142.65,142.46,134.99, 134.11,133.95,133.43,131.60,130.42,127.18, 125.59,122.52,118.19,116.84, 114.99,114.80,101.55,70.31,64.39,16.14.1H NMR(400MHz,CDCl3)δ10.34 (s,1H),7.93 (s, 1H), 7.74 (s, 1H), 7.70 (d, J=7.8Hz, 2H), 7.57 (d, J=7.7Hz, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.27 (d, J=1.8Hz, 1H), 6.94 (d, J=8.2Hz, 1H), 6.84 (d, J=1.9Hz, 1H), 6.81-6.77 (m, 1H), 6.63 (s, 1H), 5.22 (s, 2H), 5.20 (s, 2H), 4.33 (s, 4H), 2.30 (s, 3H) .ESI-MS:m/z=409.1 [M-1]-By above-mentioned qualification result it is found that gained white solid is compound V.
Step 2: the preparation of compound III
By 6g compound V and 3.5g 3- bromomethyl benzene cyanogen (compound IV), 3g potassium carbonate (K2CO3) be added 30ml it is anhydrous In DMF, stirring is heated to 80 DEG C, reacts 4 hours, and TLC monitoring after reaction, reactant is poured into 100mL water, second is used Acetoacetic ester (100mL × 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)=2:1 obtains compound as white solid III 5g.
Obtained compound III is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, CDCl3) δ 10.34 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.70 (d, J= 7.8Hz, 2H), 7.57 (d, J=7.7Hz, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 7.27 (d, J=1.8Hz, 1H), 6.94 (d, J=8.2Hz, 1H), 6.84 (d, J=1.9Hz, 1H), 6.81-6.77 (m, 1H), 6.63 (s, 1H), 5.22 (s, 2H), 5.20(s,2H),4.33(s,4H),2.30(s,3H).13C NMR(101MHz, CDCl3)δ186.55,160.47,159.88, 143.08,142.73,142.62,137.10,134.83,134.14,133.48,132.12,131.32,130.52, 130.21,129.73,127.25,125.63,122.44,119.37,118.14,117.04,116.91,113.13,98.72, 70.48,69.80,64.40,16.25. by above-mentioned qualification result it is found that gained white solid product be compound III.
Step 3: the preparation of compound C1
By 40mg compound III and 60mg glycine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring is heated to 60 DEG C, it reacts 4 hours, 42mg 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 (20 mL × 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C1 6mg。
Obtained C1 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.89 (s, 1H), 7.81-7.72 (m, 2H), 7.56 (t, J=7.8Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.37 (s, 1H), 7.22 (d, J=7.6Hz, 1H), 7.17 (d, J=7.7Hz, 1H), 7.02 (s, 1H), 6.92 (d, J=8.1Hz, 1H), 6.77 (s, 1H), 6.75 (d, J=7.9Hz, 1H), 5.24 (s, 2H), 5.18 (s, 2H), 4.29 (s, 4H), 3.77 (s, 2H), 3.51 (s, 2H), 2.22 (s, 3H) are by above-mentioned qualification result it is found that gained is white Solid product is compound C1.
Embodiment 2 (preparation C2)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C2
By 40mg compound III and 50mg (R)-pyrrolidines -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir It mixes, is heated to 60 DEG C, react 4 hours, 40mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C2 6mg.
Obtained C2 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.83 (dd, J=7.8,4.3Hz, 2H), 7.63 (t, J= 7.8Hz, 1H), 7.46 (d, J=6.6Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.6Hz, 1H), 7.18 (d, J= 6.5Hz, 1H), 7.09 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 6.77-6.70 (m, 1H),5.29(s,2H),5.22(s,2H),4.29(s,4H),3.56(s,2H),3.00– 2.86(m,2H),2.68(s,2H), 2.25 (s, 3H), 2.05-1.91 (m, 3H) are by above-mentioned qualification result it is found that gained white solid product is C2.
Embodiment 3 (preparation C3)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C3
By 40mg compound III and 55mg (R) -3- pyrrolidinol, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stirring, 60 DEG C are heated to, reacts 4 hours, 50mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC prison It surveys, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, extracted with ethyl acetate (20mL × 3), stand and divide 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C3 4mg.
Obtained C3 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.2Hz, 2H), 7.64 (t, J=7.8Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.25 (t, J=7.6Hz, 1H), 7.18 (d, J=7.3Hz, 1H), 7.08 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=1.9Hz, 1H), 6.76 (dd, J=8.2,2.0Hz, 1H), 5.29(s,2H),5.22(s,2H),4.70(s,1H),4.29(s,4H),4.20(s, 1H),3.60–3.50(m,2H),2.68 (s,1H),2.58(s,1H),2.42(s,1H),2.34(s,1H),2.25(s,3H),2.01–1.96(m,1H), 1.55(s, 1H) is by above-mentioned qualification result it is found that gained white solid product is C3.
Embodiment 4 (preparation C4)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C4
By 40mg compound III and 55mg (S)-pyrrolidines -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir It mixes, is heated to 60 DEG C, react 4 hours, 45mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C4 2mg.
Obtained C4 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.83 (s, 2H), 7.63 (t, J=7.7Hz, 1H), 7.46 (d, J=7.3Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.5Hz, 1H), 7.18 (d, J=6.5Hz, 1H), 7.09 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 6.76 (dd, J=8.2,2.1Hz, 1H), 5.29 (s, 2H), 5.22 (s, 2H), 4.29 (s, 4H), 3.56 (s, 2H), 2.92 (d, J=7.7 Hz, 2H), 2.68 (s, 2H), 2.24 (s, 3H), 2.02-1.92 (m, 3H) are by above-mentioned qualification result it is found that gained white solid product is C4.
Embodiment 5 (preparation C5)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C5
By 40mg compound III and 56mg (S) -3- pyrrolidinol, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stirring, 60 DEG C are heated to, reacts 4 hours, 47mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC prison It surveys, after reaction, is spin-dried for solvent, reactant is poured into 100mL water, extracted with ethyl acetate (20mL × 3), stand and divide 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C5 2mg.
Obtained C5 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.1Hz, 2H), 7.64 (t, J=7.7Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.25 (t, J=7.4Hz, 1H), 7.18 (d, J=7.6Hz, 1H), 7.08 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 6.79 (s, 1H), 6.76 (d, J=8.2Hz, 1H), 5.28 (s, 2H), 5.22(s,2H),4.68(s,1H),4.29(s,4H),4.20(s,1H),3.58–3.50(m, 2H),2.68(s,1H),2.59 (s, 1H), 2.43 (s, 1H), 2.34 (s, 1H), 2.25 (s, 3H), 2.02-1.97 (m, 1H), 1.54 (s, 1H) are by above-mentioned identification As a result it is found that gained white solid product is C5.
Embodiment 6 (preparation C6)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C6
By 40mg compound III and 58mg azetidine -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, stir It mixes, is heated to 60 DEG C, react 4 hours, 52mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C6 7mg.
Obtained C6 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.98 (s, 1H), 7.91-7.79 (m, 2H), 7.64 (t, J=7.7Hz, 1H), 7.44 (d, J=7.1Hz, 1H), 7.25 (d, J=4.7Hz, 1H), 7.23 (s, 1H), 7.18 (d, J=7.6Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.78 (s, 1H), 6.76 (d, J=7.9Hz, 1H), 5.29 (s, 2H), 5.21 (s, 2H), 4.29 (s, 4H), 3.51 (s, 4H), 3.39 (s, 2H), 3.20 (s, 1H), 2.24 (s, 3H) can by above-mentioned qualification result Know, gained white solid product is C6.
Embodiment 7 (preparation C7)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C7
By 40mg compound III and 56mg (3R, 5S) -5- hydroxymethyl -3- pyrrolidinol, 2 drop glacial acetic acid be added 5ml without In water 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, was spin-dried for solvent, reactant is poured into 100mL water, 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 chromatography V (methylene chloride): V (methanol)=20:1 later Obtain compound as white solid C7 8mg.
Obtained C7 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.83 (d, J=6.3Hz, 2H), 7.63 (t, J=7.8Hz, 1H), 7.45 (d, J=6.8 Hz, 1H), 7.34 (s, 1H), 7.25 (t, J=7.5Hz, 1H), 7.18 (d, J=6.7Hz, 1H), 7.07 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 6.76 (dd, J=8.2,2.1Hz, 1H), 5.77 (s, 1H), 5.28 (d, J=6.5Hz, 2H), 5.22 (s, 2H), 4.67 (s, 1H), 4.33 (s, 1H), 4.29 (s, 4H), 4.10 (s, 1H), 3.92 (d, J=13.5Hz, 1H), 3.42 (s, 1H), 3.26 (s, 1H), 3.01 (dd, J=9.1,5.6 Hz, 1H), 2.80 (d, J=4.9Hz, 1H), 2.24 (s, 3H), 2.16-2.08 (m, 1H), 1.72 (dd, J=15.8,9.2Hz, 2H) By above-mentioned qualification result it is found that gained white solid product is C7.
Embodiment 8 (preparation C8)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C8
By the fluoro- 3- hydroxyl pyrrolidine of the trans- -4- of 40mg compound III and 60mg, 5ml anhydrous methanol is added in 2 drop glacial acetic acid In, stirring is heated to 60 DEG C, reacts 4 hours, 55mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white Color solid chemical compound C8 3mg.
Obtained C8 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.95 (s, 1H), 7.84 (t, J=7.8Hz, 2H), 7.63 (t, J=7.7Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.32 (s, 1H), 7.26 (t, J=7.6Hz, 1H), 7.18 (d, J=7.8Hz, 1H), 7.10 (s, 1H), 6.93 (d, J=8.1Hz, 1H), 6.79 (s, 1H), 6.76 (d, J=8.2Hz, 1H), 5.29 (d, J= 6.1Hz, 2H), 5.23 (s, 2H), 4.87-4.73 (dd, J=53.2,5.4Hz, 1H), 4.29 (s, 4H), 4.16 (dd, J= 24.4,5.4Hz, 1H), 3.58 (d, J=10.0Hz, 1H), 3.52 (d, J=6.3Hz, 2H), 3.07-3.01 (m, 1H), 2.85-2.76 (m, 1H), 2.64 (dd, J=11.5,5.4Hz, 1H), 2.29 (d, J=35.2Hz, 3H), 2.18 (dd, J= 9.4,5.5Hz, 1H) by above-mentioned qualification result it is found that gained white solid product be C8.
Embodiment 9 (preparation C9)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C9
By 40mg compound III and 58mg 3- methyl -3- aza ring butanol, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, Stirring is heated to 60 DEG C, reacts 4 hours, 48mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white Solid chemical compound C9 2mg.
Obtained C9 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.84 (d, J=8.0Hz, 2H), 7.64 (t, J=7.8Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J=6.6Hz, 1H), 7.07 (s, 1H), 6.93 (d, J= 8.2Hz, 1H), 6.78 (d, J=2.0Hz, 1H), 6.76 (dd, J=8.2,2.1Hz, 1H), 5.28 (s, 2H), 5.22 (s, 2H), 4.29 (s, 4H), 3.53 (d, J=14.7Hz, 2H), 3.25-3.11 (m, 2H), 2.90 (s, 2H), 2.24 (s, 3H), 1.37 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is C9.
Embodiment 10 (preparation C10)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C10
By 40mg compound III and 60mg4- (methylol) pyrrolidines -3- alcohol, 5ml anhydrous methanol is added in 2 drop glacial acetic acid In, stirring is heated to 60 DEG C, reacts 4 hours, 48mg 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 (methylene chloride) later: V (methanol)=20:1 obtains white Color solid chemical compound C10 3mg.
Obtained C10 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.95 (d, J=6.6Hz, 1H), 7.84 (t, J=7.6Hz, 2H), 7.64 (t, J =7.7Hz, 1H), 7.46 (d, J=7.4Hz, 1H), 7.33 (s, 1H), 7.25 (t, J=7.6Hz, 1H), 7.18 (d, J= 6.5Hz, 1H), 7.08 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 6.76 (dd, J=8.2, 2.1Hz,1H),5.28(s,2H),5.22(s,2H),4.73(s,1H),4.54 (s,1H),4.29(s,4H),4.21(s,1H), 3.82 (s, 1H), 3.60 (d, J=6.0Hz, 1H), 3.51 (s, 2H), 3.45 (dd, J=10.5,5.8Hz, 1H), 3.26 (s, 1H), 2.68 (s, 1H), 2.34 (s, 1H), 2.25 (s, 3H), 2.03-1.96 (m, 1H) are by above-mentioned qualification result it is found that gained White solid product is C10.
Embodiment 11 (preparation C11)
Structural formula isThe preparation method of compound is by following steps group At:
Step 1: the preparation of C11
By 40mg compound III and 61mg 3- hydroxyl pyrrolidine, 2 drop glacial acetic acid are added in 5ml anhydrous methanol, and stirring adds Heat reacts 4 hours to 60 DEG C, 47mg 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C11 3mg。
Obtained C11 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.2Hz, 2H), 7.64 (t, J=7.8Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.25 (t, J=7.6Hz, 1H), 7.18 (d, J=7.4Hz, 1H), 7.08 (s, 1H), 6.93 (d, J=8.2Hz, 1H), 6.79 (d, J=1.9Hz, 1H), 6.76 (dd, J=8.2,1.9Hz, 1H), 5.28(s,2H),5.22(s,2H),4.69(s,1H),4.29(s,4H),4.20(s, 1H),3.61–3.51(m,2H),2.68 (s,1H),2.59(s,1H),2.43(s,1H),2.33(s,1H),2.25(s,3H),2.01–1.97(m,1H), 1.55(s, 1H) is by above-mentioned qualification result it is found that gained white solid product is C11.
Embodiment 12 (preparation C12)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of 5- chlorine-2-hydroxyl -4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzaldehyde
By chloro- 2, the 4- 4-dihydroxy benzaldehyde of 4g 5- and 5g 2- methyl-3-phenyl benzil alcohol, 8.2g triphenyl phosphorus (PPh3) It is added in 50ml anhydrous tetrahydro furan, stirs 15 minutes, 8.2mL diisopropyl azodiformate (DIAD) is dripped on a small quantity in batches Enter in reaction solution, react 10 hours, thin-layer chromatography (TLC) monitoring after reaction, reaction solution is poured into 100mL water, second is used Acetoacetic ester (100mL × 5) extraction, stands liquid separation, and organic phase uses 5% sodium bicarbonate (NaHCO respectively3) (80mL × 3), saturation Saline solution (80mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, ethyl acetate is removed under reduced pressure, carry out column chromatography later V (petroleum ether): V (ethyl acetate)=10:1 obtains 5- chlorine-2-hydroxyl -4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) Benzaldehyde 5.5g.
Obtained white solid is identified using NMR techniques, qualification result are as follows:1H NMR (400MHz, CDCl3) δ 11.47 (s, 1H), 9.73 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J=6.8,2.1Hz, 1H), 7.46 (t, J=7.2Hz, 2H), 7.41-7.37 (m, 1H), 7.35 (d, J=1.5Hz, 1H), 7.33 (s, 1H), 7.33-7.29 (m,2H),7.28(s,1H),6.66(s,1H),5.24(s,2H),2.28(s, 3H).13C NMR(101MHz,CDCl3)δ 193.73,162.90,160.90,143.00,141.59,133.98,133.46,130.40,129.35, 128.09, 127.35,126.93,125.68,114.97,114.77,101.53,70.27,16.15. by above-mentioned qualification result it is found that gained White solid is 5- chlorine-2-hydroxyl -4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzaldehyde.
Step 2: 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile preparation
By 5.5g 5- chlorine-2-hydroxyl -4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) benzaldehyde and 3.2g 3- Bromomethyl benzene cyanogen, 3g potassium carbonate (K2CO3) be added in 30ml anhydrous DMF, stirring is heated to 80 DEG C, reacts 4 hours, TLC prison It surveys, after reaction, reactant is poured into 100mL water, extracted with ethyl acetate (100mL × 3), stand liquid separation, organic phase 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 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) methyl) benzonitrile 4.8g.
By obtained 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) Methyl) benzonitrile identified using NMR techniques, qualification result are as follows:
1H NMR(400MHz,CDCl3)δ10.35(s,1H),7.94(s,1H),7.75(s,1H),7.72(s,1H), 7.70 (s, 1H), 7.57 (t, J=7.8Hz, 1H), 7.46 (t, J=7.2Hz, 3H), 7.40 (d, J=7.1Hz, 1H), 7.33 (d, J=9.7Hz, 3H), 7.28 (s, 1H), 6.65 (s, 1H), 5.24 (s, 2H), 5.22 (s, 2H), 2.29 (s, 3H) are by upper Qualification result is stated it is found that gained white solid product is 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- Base) methoxyl group) phenoxy group) methyl) benzonitrile.
Step 3: the preparation of compound C12
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 60mg glycine, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, react 4 hours, so 42mg sodium cyanoborohydride (NaBH is added afterwards3CN), react at room temperature 12 hours, TLC monitoring after reaction, is spin-dried for solvent, will Reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), and liquid separation is stood, and organic phase uses 5% NaHCO respectively3 The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, acetic acid second is removed under reduced pressure Ester, carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C12 6mg.
Obtained C12 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 8.03 (s, 1H), 7.89 (d, J=7.5Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.66-7.61 (m, 1H), 7.48 (dd, J=13.9,6.7Hz, 3H), 7.40 (d, J=7.2Hz, 1H), 7.30 (dd, J =16.0,7.2Hz, 3H), 7.25-7.19 (m, 2H), 7.13 (s, 1H), 5.33 (s, 2H), 5.28 (s, 2H), 3.96 (s, 2H), 3.51 (s, 2H), 2.24 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is compound C1.
Embodiment 13 (preparation C13)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C13
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 50mg (S)-pyrrolidines -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, Then 40mg sodium cyanoborohydride (NaBH is added in reaction 4 hours3CN), react at room temperature 12 hours, TLC monitoring, reaction terminates Afterwards, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase difference are stood With 5% NaHCO3(20mL × 3), saturated salt solution (20 mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C13 6mg。
Obtained C13 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.87-7.81 (m, 2H), 7.64 (d, J=7.9Hz, 1H), 7.48 (dd, J=14.0,7.3Hz, 3H), 7.40 (d, J=7.1Hz, 1H), 7.31 (dd, J=16.0,7.9Hz, 4H), 7.22 (d, J=7.7Hz, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 3.57 (s, 2H), 2.98-2.86 (m, 2H), 2.68 (s, 2H), 2.36-2.29 (m, 1H), 2.24 (s, 3H), 1.99 (d, J=5.8Hz, 2H) can by above-mentioned qualification result Know, gained white solid product is C13.
Embodiment 14 (preparation C14)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C14
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 52mg (R) -3- pyrrolidinol, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, instead It answers 4 hours, 50mg 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, organic phase is used respectively 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, decompression Ethyl acetate is removed, carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C14 4mg.
Obtained C14 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.5Hz, 2H), 7.64 (t, J=7.8Hz, 1H), 7.48 (dd, J=13.9,7.2Hz, 3H), 7.40 (d, J=7.2Hz, 1H), 7.31 (dd, J=15.4,7.3Hz, 4H), 7.22 (d, J=7.6Hz, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 4.69 (s, 1H), 4.20 (s, 1H), 3.55 (d, J=10.3Hz, 2H), 2.68 (s, 1H), 2.59 (s, 1H), 2.43 (s, 1H), 2.34 (s, 1H), 2.24 (s, 3H), 2.00 (d, J=7.1Hz, 1H), 1.55 (s, 1H) are by above-mentioned qualification result it is found that gained white solid product is C14.
Embodiment 15 (preparation C15)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C15
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 50mg (R)-pyrrolidines -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, Then 40mg sodium cyanoborohydride (NaBH is added in reaction 4 hours3CN), react at room temperature 12 hours, TLC monitoring, reaction terminates Afterwards, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase difference are stood With 5% NaHCO3(20mL × 3), saturated salt solution (20 mL × 3) washing, it is then dry with anhydrous magnesium sulfate, it filters, subtracts Pressure removes ethyl acetate, and carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C15 6mg。
Obtained C15 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.83 (d, J=5.8Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.48 (dd, J=13.7,7.0Hz, 3H), 7.40 (d, J=6.9Hz, 1H), 7.31 (dd, J=15.7,7.8Hz, 4H), 7.21(s,1H),7.11(s,1H),5.30(s,2H), 5.25(s,2H),3.59(s,2H),2.93(s,2H),2.68(s, 2H), 2.34 (s, 1H), 2.24 (s, 3H), 1.99 (d, J=4.6Hz, 2H) are by above-mentioned qualification result it is found that gained white solid Product is C15.
Embodiment 16 (preparation C16)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C16
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 56mg (S) -3- pyrrolidinol, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, instead It answers 4 hours, 47mg 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, organic phase is used respectively 5% NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, decompression Ethyl acetate is removed, carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C16 2mg.
Obtained C16 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.6Hz, 2H), 7.65 (d, J=7.8Hz, 1H), 7.48 (dd, J=13.9,7.2Hz, 3H), 7.40 (d, J=7.2Hz, 1H), 7.31 (dd, J=15.7,7.8Hz, 4H), 7.22 (d, J=7.5Hz, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 4.70 (s, 1H), 4.20 (s, 1H), 3.56 (d, J=9.2Hz, 2H), 2.68 (s, 1H), 2.60 (s, 1H), 2.43 (s, 1H), 2.33 (s, 1H), 2.24 (s, 3H), 2.00 (d, J=7.3Hz, 1H), 1.55 (s, 1H) are by above-mentioned qualification result it is found that gained white solid product is C16.
Embodiment 17 (preparation C17)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C17
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 58mg azetidine -3- carboxylic acid, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, Then 52mg sodium cyanoborohydride (NaBH is added in reaction 4 hours3CN), react at room temperature 12 hours, TLC monitoring, reaction terminates Afterwards, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase point are stood Not 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C17 7mg。
Obtained C17 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.99 (s, 1H), 7.84 (t, J=7.0Hz, 2H), 7.64 (t, J=7.7Hz, 1H), 7.47 (t, J=7.7 Hz, 3H), 7.38 (d, J=7.5Hz, 1H), 7.30 (dd, J=17.7,8.0Hz, 4H), 7.22 (d, J=7.5Hz, 1H), 7.09 (s, 1H), 5.29 (s, 2H), 5.24 (s, 2H), 3.52 (s, 2H), 3.40 (s, 2H), 3.21 (s, 2H), 3.17 (s, 1H), 2.23 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is C17.
Embodiment 18 (preparation C18)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound C18
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 60mg 2- methylalanine, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, reaction 4 hours, 42mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, after reaction, rotation Reactant is poured into 100mL water by dry solvent, is extracted with ethyl acetate (20mL × 3), and liquid separation is stood, and organic phase uses 5% respectively NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, is removed under reduced pressure Ethyl acetate, carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C18 6mg.
Obtained C18 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 8.04 (s, 1H), 7.90 (d, J=7.8Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.47 (t, J=7.4Hz, 3H), 7.39 (t, J=7.3Hz, 1H), 7.36-7.24 (m, 3H), 7.22 (d, J=6.6Hz, 1H), 7.12 (s, 1H), 5.30 (s, 4H), 3.87 (s, 2H), 2.24 (s, 3H), 1.27 (s, 6H) are by above-mentioned qualification result it is found that gained white solid product is compound C18.
Embodiment 19 (preparation C19)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of compound C19
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 60mg N, N- dimethyl-ethylenediamine base, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, it reacts 4 hours, 42mg 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 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C19 6mg。
Obtained C19 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.99 (s, 1H), 7.83 (d, J=7.7Hz, 2H), 7.64 (s, 1H), 7.48 (dd, J=15.0,7.8Hz, 3H), 7.40 (d, J=7.3Hz, 1H), 7.31 (dd, J=14.8,7.2Hz, 4H), 7.22 (d, J =7.4Hz, 1H), 7.11 (s, 1H), 5.29 (s, 2H), 5.26 (s, 2H), 3.51 (s, 2H), 2.48 (d, J=4.1Hz, 2H), 2.37 (d, J=5.4Hz, 2H), 2.24 (s, 3H), 2.17 (s, 6H) are by above-mentioned qualification result it is found that gained white solid product For compound C19.
Embodiment 20 (preparation C20)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C20
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 56mg (3R, 5S) -5- hydroxymethyl -3- pyrrolidinol, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, stir It mixes, is heated to 60 DEG C, react 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), 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 (methylene chloride) later: V (methanol)=20:1 obtains white solid Compound C20 8mg.
Obtained C20 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.83 (d, J=6.8Hz, 2H), 7.64 (d, J=7.8Hz, 1H), 7.48 (dd, J=12.8,5.7Hz, 3H), 7.40 (d, J=7.3Hz, 1H), 7.37-7.26 (m, 4H), 7.22 (d, J= 7.2Hz, 1H), 7.08 (s, 1H), 5.28 (d, J=6.6Hz, 2H), 5.24 (s, 2H), 4.67 (s, 1H), 4.34 (s, 1H), 4.09 (s, 1H), 3.92 (d, J=13.8Hz, 1H), 3.51 (s, 2H), 3.26 (s, 1H), 3.00 (s, 1H), 2.81 (s, 1H), 2.24 (s, 3H), 2.11 (s, 1H), 1.71 (s, 1H), 1.45 (s, 1H) are by above-mentioned qualification result it is found that gained white solid produces Object is C20.
Embodiment 21 (preparation C21)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C21
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and the fluoro- 3- hydroxyl pyrrolidine of the trans- -4- of 60mg, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to It 60 DEG C, reacts 4 hours, 55 mg 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 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C21 3mg。
Obtained C21 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=8.0Hz, 2H), 7.63 (t, J=7.8Hz, 1H), 7.48 (dd, J=14.7,7.4Hz, 3H), 7.40 (d, J=7.2Hz, 1H), 7.36-7.27 (m, 4H), 7.22 (d, J= 7.4Hz, 1H), 7.11 (s, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 4.87-4.72 (m, 1H), 4.16 (dd, J=24.3, 5.5Hz, 1H), 3.58 (d, J=10.1Hz, 2H), 3.08-3.02 (m, 1H), 2.85-2.76 (m, 1H), 2.75-2.68 (m, 1H), 2.24 (s, 3H), 2.18 (dd, J=9.5,5.5Hz, 1H) are by above-mentioned qualification result it is found that gained white solid product is C21。
Embodiment 22 (preparation C22)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C22
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 58mg 3- methyl -3- aza ring butanol, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, it reacts 4 hours, 48mg 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 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C22 2mg。
Obtained C22 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.84 (d, J=7.7Hz, 2H), 7.64 (t, J=7.7Hz, 1H), 7.47 (t, J=7.9 Hz, 3H), 7.39 (t, J=7.4Hz, 1H), 7.32 (d, J=8.1Hz, 2H), 7.28 (d, J= 7.6Hz, 2H), 7.22 (d, J=7.4Hz, 1H), 7.09 (s, 1H), 5.29 (s, 2H), 5.24 (s, 2H), 5.16 (s, 1H), 3.55 (s, 2H), 3.20 (s, 2H), 2.91 (s, 2H), 2.24 (s, 3H), 1.37 (s, 3H) are by above-mentioned qualification result it is found that institute Obtaining white solid product is C22.
Embodiment 23 (preparation C23)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C23
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 58mg 3- hydroxyazetidinium alcohol, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, Then 48mg sodium cyanoborohydride (NaBH is added in reaction 4 hours3CN), react at room temperature 12 hours, TLC monitoring, reaction terminates Afterwards, it is spin-dried for solvent, reactant is poured into 100mL water, is extracted with ethyl acetate (20mL × 3), liquid separation, organic phase point are stood Not 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 (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C23 2mg。
Obtained C23 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.99 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.64 (t, J=7.8Hz, 1H), 7.47 (t, J=7.8Hz, 3H), 7.40 (d, J=7.2Hz, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.30-7.23 (m, 2H), 7.22 (d, J=7.6Hz, 1H), 7.09 (s, 1H), 5.29 (s, 2H), 5.24 (s, 2H), 4.21 (d, J=6.5Hz, 1H), 3.51 (s, 4H), 2.80 (s, 2H), 2.24 (s, 3H) are by above-mentioned qualification result it is found that gained white solid product is C23。
Embodiment 24 (preparation C24)
Structural formula isThe preparation method of compound comprises the steps of:
Step 1: the preparation of C24
By 40mg 3- ((the chloro- 2- formyl -5- of 4- ((2- methyl-[1,1'- biphenyl] -3- base) methoxyl group) phenoxy group) first Base) benzonitrile and 56mg 3- hydroxyl pyrrolidine, 2 drop glacial acetic acid are added in 5ml anhydrous methanols, and stirring is heated to 60 DEG C, reaction 4 hours, 47mg sodium cyanoborohydride (NaBH is then added3CN), react at room temperature 12 hours, TLC monitoring, after reaction, rotation Reactant is poured into 100mL water by dry solvent, is extracted with ethyl acetate (20mL × 3), and liquid separation is stood, and organic phase uses 5% respectively NaHCO3The washing of (20mL × 3), saturated salt solution (20mL × 3), it is then dry with anhydrous magnesium sulfate, it filters, is removed under reduced pressure Ethyl acetate, carry out column chromatography V (methylene chloride) later: V (methanol)=20:1 obtains compound as white solid C24 2mg.
Obtained C24 is identified using NMR techniques, qualification result are as follows:
1H NMR (400MHz, DMSO) δ 7.96 (s, 1H), 7.84 (t, J=7.4Hz, 2H), 7.64 (t, J=7.8Hz, 1H), 7.48 (dd, J=13.7,7.1Hz, 3H), 7.39 (t, J=7.2Hz, 1H), 7.31 (dd, J=15.3,7.3Hz, 4H), 7.22 (d, J=7.5Hz, 1H), 7.10 (s, 1H), 5.29 (s, 2H), 5.25 (s, 2H), 4.68 (s, 1H), 4.20 (s, 1H), 3.55 (d, J=9.9Hz, 2H), 2.68 (t, J=8.2Hz, 1H), 2.59 (d, J=5.5Hz, 1H), 2.42 (d, J=5.8Hz, 1H), 2.34 (s, 1H), 2.24 (s, 3H), 2.01-1.98 (m, 1H), 1.54 (s, 1H) are by above-mentioned qualification result it is found that gained White solid product is C24.
Embodiment 25, a kind of resorcinol methyl ether derivative containing substituted biphenyl of the present invention are to PD-1/PD-L1's Inhibitory effect research
The inhibitory effect to PD-1/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 PD-1/PD-L1, can be used for treating cancer, Especially treat 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 rapidly and efficiently detects compound prepared by Examples 1 to 24 (number is followed successively by C1~C24) to PD- using HTRF method The inhibitory effect of 1/PD-L1.HTRF (homogeneous phase time discrimination fluorescence) detection technique is based on time-resolved fluorescence (TRF) and fluorescence The high throughput screening drug that the big technical principle of Resonance energy transfer (FRET) two is opened.Time-resolved fluorescence (TRF) utilizes Lanthanide series long half time in rare earth element, the fluorescence characteristic longer than the common fluorescent duration, by postponing 50-100 microsecond Background is excluded, to reflect sample actual conditions.Fluorescence resonance energy transfer (FRET) refers in two different fluorophors In, if the absorption spectrum of the emission spectrum of a fluorophor (donor Donor) and another group (receptor Acceptor) There is certain overlapping, (generally less than when the distance between the two fluorophors is suitable), so that it may observe fluorescent energy When exciting with the excitation wavelength of former group, the transmitting of the latter group can be observed in the phenomenon that shifting from donor to receptor Fluorescence.Briefly, from the energy that a pair of of dipole mediates from donor to receptor exactly under the excited state of donor groups The process of transfer.The condition that effective energy transfer occurs between for energy supply body-acceptor (D-A) is harsh, main packet Include: (1) emission spectrum of energy donor must be overlapped with the absorption spectrum of energy acceptor；(2) energy donor and energy acceptor Fluorescence chromophore must arrange in the right way；(3) must be close enough between energy donor, energy acceptor, occur in this way The probability of energy transfer just can be high.HTRF is the chela that europium (Eu) element with cave-shaped structure is utilized and marker as one Energy donor (Donor) and XL665 (improved allophycocyanin) are used as an energy acceptor (Acceptor), are based on Eu Time-resolved fluorescence (TRF) and fluorescence resonance between the donor and XL665 receptor (the second fluorescent marker) of cryptate The high throughput screening drug that energy transfer (FRET) characteristic is opened.In fluorescence resonance energy transfer, acceptor emission fluorescence The equivalent service life for emitting fluorescence with donor in service life.Because the fluorescence decay period of Eu is longer, luring for knowing from experience containing Eu Lead XL665 receptor and emit fluorescence for a long time, the fluorescence generated after receptor excitation just can last longer, pass through the time in this way Resolution can distinguish itself short-life scattering fluorescence, just be easily discriminated out FRET letter from short life fluorescence background in this way Number.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 testization The increase of object concentration is closed, the ratio of 665nm/620nm reduces；The variation that fluorescent value is measured after stable system to be detected can measure Change the potency IC of blocking agent50；Detection is two fluorescence 665nm and 620nm of HTRF, i.e. time-resolved fluorescence (TRF), when The ratio of 665nm/620nm reduces, and the effect of blocking agent is higher.HTRF detection kit, exactly comprehensively utilizes antigen-antibody Specific binding reaction, resonance energy transfer between receptor donor and develop, highly sensitive, quick disposable, the high pass of low background Measure detection technique.
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, is incubated at room temperature 15min.
(4) 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).
(6) inhibiting rate, inhibiting rate (Inibition) %=(1- (each hole 665nm/620nm signal is calculated according to the following formula 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 Enter equivalent detection detection 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 2450.The IC of compound50Be denoted as between 100nM to 10nM+；The IC of compound50? It is denoted as between 10nM to 1nM ++.Specifically it see the table below:
Inhibitory effect of the compound C1~C24 to PD-1/PD-L1
According to above-mentioned Vitro Experimental Results, we are it can be concluded that a kind of resorcinol containing substituted biphenyl of the present invention Methyl ether derivative is able to suppress the mutual knot of 1/ apoptosis ligand 1 (PD-1/PD-L1) of apoptosis receptor It closes, and ({ 3- is bromo- by compound 1- disclosed in PCT Patent Application of the significant effect better than Publication No. WO2015/ 034820A1 4- [(2- methyl -3- phenyl) methoxyl group)) phenyl }-methyl) piperidines -2- carboxylic acid.

Claims (4)

1. a kind of resorcinol methyl ether derivative containing substituted biphenyl, shown in the chemical structure of the derivative such as following formula (I),
In formula (I), R1It is amion acetic acid base, (R)-pyrrolidines -3- formyl, (R) -3- pyrrolidines alcohol radical, (S)-pyrrolidines -3- Formyl, (S) -3- pyrrolidines alcohol radical, azetidine -3- carboxylic acid group, (3R, 5S) -5- hydroxymethyl -3- pyrrolidines alcohol radical, The fluoro- 3- hydroxypyrrole alkyl of trans- -4-, 3- methyl -3- azetidin alcohol radical, 4- (methylol) pyrrolidines -3- alcohol radical, N, N- bis- Methyl ethylenediamine base, 3- hydroxypyrrole alkyl, 2- methylalanine base, 3- hydroxyazetidinium base, R2It is hydrogen, 1,4- dioxy six Ring group.
2. a kind of resorcinol methyl ether derivative containing substituted biphenyl according to claim 1, which is characterized in that described A kind of resorcinol methyl ether derivative containing substituted biphenyl is one of following compounds:
Work as R1It is amion acetic acid base, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure is
Work as R1It is (R)-pyrrolidines -3- formyl, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is (R) -3- pyrrolidines alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether containing substituted biphenyl spreads out Biology chemical structure be
Work as R1It is (S)-pyrrolidines -3- formyl, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is (S) -3- pyrrolidines alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether containing substituted biphenyl spreads out Biology chemical structure be
Work as R1It is azetidine -3- carboxylic acid group, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is (3R, 5S) -5- hydroxymethyl -3- pyrrolidines alcohol radical, R2It is described to contain substituted biphenyl when being Isosorbide-5-Nitrae-dioxane The chemical structure of resorcinol methyl ether derivative be
Work as R1It is the fluoro- 3- hydroxypyrrole alkyl of trans- -4-, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is 3- methyl -3- azetidin alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol containing substituted biphenyl The chemical structure of methyl ether derivative is
Work as R1It is 4- (methylol) pyrrolidines -3- alcohol radical, R2When being Isosorbide-5-Nitrae-dioxane, the isophthalic two containing substituted biphenyl The chemical structure of phenol methyl ether derivative is
Work as R1It is 3- hydroxypyrrole alkyl, R2When being Isosorbide-5-Nitrae-dioxane, the resorcinol methyl ether containing substituted biphenyl is derivative The chemical structure of object is
Work as R1It is amion acetic acid base, R2When being hydrogen, the chemical structure of the resorcinol methyl ether derivative containing substituted biphenyl is
Work as R1It is (S)-pyrrolidines -3- formyl, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is (R) -3- pyrrolidines alcohol radical, R2When being hydrogen, the chemistry knot of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
Work as R1It is (R)-pyrrolidines -3- formyl, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is (S) -3- pyrrolidines alcohol radical, R2When being hydrogen, the chemistry knot of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
Work as R1It is azetidine -3- carboxylic acid group, R2When being hydrogen, the change of the resorcinol methyl ether derivative containing substituted biphenyl Learning structure is
Work as R1It is 2- methylalanine base, R2When being hydrogen, the chemical structure of the resorcinol methyl ether derivative containing substituted biphenyl For
Work as R1It is N, N- dimethyl-ethylenediamine base, R2When being hydrogen, the chemistry of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
Work as R1It is (3R, 5S) -5- hydroxymethyl -3- pyrrolidines alcohol radical, R2When being hydrogen, the resorcinol first containing substituted biphenyl The chemical structure of ether derivant is
Work as R1It is the fluoro- 3- hydroxypyrrole alkyl of trans- -4-, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure be
Work as R1It is 3- methyl -3- azetidin alcohol radical, R2When being hydrogen, the resorcinol methyl ether derivative containing substituted biphenyl Chemical structure is
Work as R1It is 3- hydroxyazetidinium base, R2When being hydrogen, the chemistry knot of the resorcinol methyl ether derivative containing substituted biphenyl Structure is
Work as R1It is 3- hydroxypyrrole alkyl, R2When being hydrogen, the chemical structure of the resorcinol methyl ether derivative containing substituted biphenyl For
3. a kind of resorcinol methyl ether derivative containing substituted biphenyl described in claims 1 or 2 is in preparation PD-1/PD-L1 Application in inhibitor.
4. application according to claim 3, which is characterized in that the PD-1/PD-L1 inhibitor is by claim 1 institute A kind of resorcinol methyl ether derivative and medically acceptable auxiliary material composition containing substituted biphenyl stated.
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