• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Fluorine-containing pharmaceuticals approved by the FDA in 2020:Synthesis and biological activity

    2021-02-23 09:05:34YingjieYuAiyoLiuGgnDhwnHiboMeiWeiZhngKunisukeIzwVimSoloshonokJinlinHn
    Chinese Chemical Letters 2021年11期

    Yingjie Yu,Aiyo Liu,Ggn Dhwn,Hibo Mei,Wei Zhng,Kunisuke Izw,Vim A.Soloshonok,Jinlin Hn,*

    a Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,International Innovation Center for Forest Chemicals and Materials,College of Chemical Engineering,Nanjing Forestry University,Nanjing 210037,China

    b Department of Biomedical Science,Acharya Narendra Dev College,University of Delhi,India

    c Department of Chemistry,University of Massachusetts Boston,100 Morrissey Boulevard,Boston,MA 02125,United States

    d Hamari Chemical Ltd.,1-4-29 Kunijima,Higashi-Yodogawa-ku,Osaka 533-0024,Japan

    e Department of Organic Chemistry I,Faculty of Chemistry,University of the Basque Country UPV/EHU,Paseo Manuel Lardizábal 3,20018 San Sebastián,Spain

    f IKERBASQUE,Basque Foundation for Science,María Díaz de Haro 3,Plaza Bizkaia,48013 Bilbao,Spain

    ABSTRACT Thirteen new fluorine-containing drugs,which have been granted approval by the US Food and Drug Administration(FDA)in 2020,are profiled in this review.Therapeutic areas of these new fluorinated pharmaceuticals include medicines and diagnostic agents for Cushing’s disease,neurofibromatosis,migraine,Alzheimer’s disease,myelodysplastic syndromes,hereditary angioedema attacks,and various cancers.Molecules of these approved drugs feature aromatic fluorine(Ar-F)(11 compounds),aromatic Ar-CF3(1),aliphatic CHF(1)and CF2(1)groups.For each compound,we provide a spectrum of biological activity,medicinal chemistry discovery,and synthetic approaches.

    Keywords:Fluorine and compounds Blockbuster drugs Modern pharmaceuticals Synthesis Drug design and development Asymmetric synthesis

    1.Introduction

    Due to the growing impact of fluorinated compounds on the progress of energy[1],food[2],and health[3]related industries,organofluorine chemistry has become a multidisciplinary research area of general scientific interest.Indeed,virtually every organic chemistry research group has a certain interest in either synthesis or application of fluorinated molecules.Consequently,there has been an upsurge in covering the wealth of fluorine chemistry by critical thematic reviews focusing on various facets of fluorine,including new reagents[4],synthesis[5],biological properties and applications[6].Of particular interest to the practitioners is the application of fluorinated compounds in the design of modern pharmaceuticals[3,7].This multidisciplinary area of fluorine chemistry is constantly undergoing rapid development requiring timely updates to properly disseminate the new results,ideas,and methodological breakthroughs.To address this critical information need,we have initiated a series of mini-review focusing on the very recent entries of fluorine-containing drugs to the pharmaceutical market.The reviews covering fluorine-containing drugs approved by the US FDA in 2018[8]and 2019[9]were highly appreciated by the readers,as it follows from the number of downloads and citations.In the present review,we profile 13 new fluorinated drugs approved by the FDA last year(2020)for commercial use.The compounds discussed in the present work include(Fig.1)AyvakitTM(1),IsturisaTM(2),KoselugoTM(3),PemazyreTM(4),TabrectaTM(5),QinlockTM(6),Nurtec ODTTM(7),CeriannaTM(8),TauvidTM(9),InqoviTM(10),PralsebinibTM(11),OrladeyoTM(12),OrgovyxTM(13).Most of the compounds were developed to treat various cancers(1,4-6,8,11,13).Other therapeutic areas include Cushing’s disease(2),neurofibromatosis(3),migraine(7),Alzheimer’s disease(9),myelodysplastic syndromes(10),and hereditary angioedema(11).For each compound,we discuss the medicinal chemistry discovery,and biological activity,emphasizing synthesis and introduction of fluorine.

    Fig.1.Fluorine-containing drugs approved by the US FDA in 2020.

    Fig.2.Structures of 1A,1B and 1C.

    2.Avapritinib(BLU-285,AyvakitTM)

    Avapritinib(1),also named BLU-285,was developed by Blueprint Medicines as a potent type I inhibitor of KIT and plateletderived growth factor receptor alpha(PDGFRA)activation loop mutants.It is a chiral compound containing one(S)-configuration quaternary carbon center and a mono-fluorinated phenyl moiety(Fig.1).The structure-activity relationship(SAR)study by Blueprint Medicines disclosed that avapritinib(1)showed the best activity[10]with PDGFRA D842V(half maximal inhibitory concentration,IC50= 0.24 nmol/L),and KIT exon 11(IC500.6 nmol/L).Structural variations,such as opposite configuration(1A),non-fluoro substituent(1B)and introduction of two fluoro atom(1C),led to the decreased activities(Fig.2).Furthermore,avapritinib(1)was a highly selective inhibitor of KIT and PDGFRA activation loop mutant comparing with other compounds,such as imatinib,sunitinib and regorafenib with IC50value(PDGFRA exon 18)of 759 nmol/L,120 nmol/L,and 810 nmol/L,respectively[11].Avapritinib was approved in the USA in January 2020,with the trade name AyvakitTM,which was used to treat gastrointestinal stromal tumor(GIST)harboring a PDGFRA exon 18 mutation,including PDGFRA D842V mutations[12].

    The methods for the synthesis of avapritinib(1)usually rely on the reaction between amine 19 and aryl chloride 20.In 2015,Blueprint Medicines patented a related method for making racemic 1 as the product,which needed separationviachiral supercritical fluid chromatogram(SFC)[10].In 2020,an asymmetric catalytic method with bis[(2,3,5,6-η)-(1R,4R)-2,5-2,5-bis(4-trifluoromethylphenyl)bicyclo[2.2.2]octane-2-diene]bisμ-rhodium chloride(16)as catalyst was developed(Scheme 1)[13].First,condensation reaction between 4-fluoroacetophenone andp-toluenesulfonamide under reflux for 24 h generated imine 14.Imine 14 was subjected to Rh-catalyzed asymmetric addition reaction[14]of potassium 2-(1-piperazinyl)pyrimidine-5-trifluoroborate(15)in the presence of toluene-4-sulfonic acid to give the chiral sulfonamide 17.Deprotection of tosyl group of sulfonamide 17viatreatment with thiophenol and potassium carbonate(K2CO3)afforded the free amine 18,which was protected by Boc-group to produce the compound 19[15].Then,substitution reaction between compound 19 and 4-chloro-6-(1-methyl-1Hpyrazol-4-yl)pyrrolo[1,2-f][1,2,4]triazine(20)in the presence of DIPEA at room temperature for 5 h gave the intermediate 21.Finally,intermediate 21 was treated with 4 mol/L HCl in dioxane at room temperature for 1 h to provide the target product avapritinib(1)[13,15].

    The synthesis of intermediate aryl chloride 20 is shown in Scheme 2[16].In the presence of NaH,an amino group was introduced into methyl 4-bromo-1H-pyrrole-2-carboxylate(22)withO-(diphenylphosphoryl)hydroxylamine as the amine source.The resulted intermediate 23 was heated with formamide at 180 °C to give cyclic intermediate 24,which underwent the Suzuki coupling reaction with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole at 110 °C for 12 h.The obtained triazin-4(3H)-one intermediate 25 was chlorinated by treating with POCl3to afford the key intermediate 20.

    Scheme 1.Synthesis of avapritinib(1).

    Scheme 2.Synthesis of intermediate 20.

    3.Osilodrostat(IsturisaTM)

    Fig.3.Structures of 2A and 2B.

    Osilodrostat(2)was developed by Novartis as a potent small-molecule inhibitor of aldosterone synthase(CYP11B2)and 11β-hydroxylase(CYP11B1).Osilodrostat(2)is an asymmetric imidazole-derived compound featuring an essential monofluorinated phenyl moiety(Fig.1)[17].It was reported that compound FAD286 was a potent CYP11B2 inhibitor[18].Based on this understanding,Novartis started their SAR investigation and modified the FAD286(2A)scaffoldviavariations on the ring size and the substituents on the phenyl group(Fig.3).Careful SAR study led to the discovery of osilodrostat(2)with an IC50value of 9 nmol/L against CYP11B2.Fluoro group is also essential for bioactivity.Changing the fluoro group to others,such as chloro(2B),methoxyl,and bromo,decreased the potency against CYP19[17].Osilodrostat(2)received its first approval in January 2020 in the European Union(EU)and was approved by US FDA in March with the trade name IsturisaTMfor the treatment of Cushing’s disease[19].

    The synthesis of osilodrostat(2)is accessed as showed in Scheme 3[20].Treatment of 3-fluoro-4-methylbenzonitrile byNbromosuccinimide(NBS)in the presence of benzoyl peroxide(BPO)in tetrachloride provided the benzyl bromide intermediate 21.On the other hand,2-(1H-imidazol-4-yl)acetic acid was protected by trityl groupviareaction with trityl chloride in the presence of pyridine,affording the intermediate 23.Then,the carboxylic group of intermediate 23 was reduced by BH3/THF to give alcohol 24 which was protected with butyldimethylsilyl generating intermediate 25.Substitution reaction between benzyl bromide intermediate 21 and intermediate 25 with triethylamine as a base at room temperature for 48 h provided intermediate 26.Deprotonation of intermediate 26 with LiHMDS and followed by reaction with methyl chloroformate in THF at -78 °C gave ester 27.Changing theO-protecting group from TBS to methanesulfonyl(Ms)resulted in compound 28,which underwent intramolecular cyclization reaction with the aid of K2CO3and NaI.Under the microwave heating conditions,decarboxylation of the intermediate 29 at 140 °C gave racemic-2,which was separated by chiral HPLC affording the desired osilodrostat(2).

    Scheme 3.Synthesis of osilodrostat(2).

    Scheme 4.Synthesis of selumetinib(3).

    Osilodrostat(2)and avapritinib(1)are chiral compounds.Selfdisproportionation of enantiomers(SDE)phenomenon may exist during their work-up and isolation procedures in the synthesis,influencing the stereochemical outcome[21].In this regard,we would like to recommend SDE-tests for accurate determination of stereoselectivity for their asymmetric synthesis by subject-ing enantiomerically enriched mixtures into physicochemical processes,such as achiral chromatography[22],evaporation[23],distillation[24]and sublimation[25].

    Fig.4.Structure of benzimidazole derived MEK inhibitor 30.

    4.Selumetinib(KoselugoTM)

    Selumetinib(3,AZD6244,ARRY-142886)was developed by AstraZeneca and Merck as an inhibitor of mitogen-activated protein kinase 1 and 2(MEK1/2)for the treatment of a rare genetic disease called neurofibromatosis,which emerges in early childhood and causes small tumors to grow all over a person’s nerves[26–28].Selumetinib(3)is anN-alkylated benzimidazole derivative(Fig.1),which was discovered by Array Biopharma in 2003 as a MEK inhibitor.Based on theN-alkylated benzimidazole precursor,Array Biopharma screened many related compounds 30 with modifications on the substituents at different positions(Fig.4).They chose a dozen of promising compounds exhibiting IC50(MEK1)value of less than 50 mmol/L[27].All these selected compounds containing a fluoro substituent at 4-position of benzimidazole clearly indicate the key role of the fluorine atom for the inhibitory activity.Selumetinib(3)was approved by the US FDA in April 2020 under the trade name KoselugoTMfor the treatment of tumors associated with neurofibromatosis and various cancers[26].

    The synthesis of selumetinib(3)is shown in Scheme 4[27],which was reported by Array Biopharma using methyl 4-amino-2,3-difluoro-5-nitrobenzoate(31)as the starting material.Intermolecular substitution reaction of fluorinated benzene 31 with 2-chloro aniline in xylenes under the nitrogen atmosphere at 140 °C for 6 days generated intermediate 32 which was subjected to reduction reaction with the use of zinc dust in the presence of acetic acid and diamine 33 was obtained.Cyclization reaction of 33 with formamidine acetate under reflux for 16 h gave benzimidazole intermediate 34.The treatment of benzimidazole intermediate 34 with NBS in the presence of TsOH gave brominated intermediate 35.Subsequently,N-methylation of benzimidazoleviathe reaction with iodomethane in the presence of K2CO3resulted in intermediate 36,which was subjected to the hydrolysis reaction to give acid 37.The condensation reaction of acid 37 withO-(2-vinyloxyethyl)-hydroxylamine was conducted using 1-hydroxybenzotriazole(HOBt)and EDCI in DMF at room temperature for 48 h to give amide 38 in excellent yield(90%).Finally,the desired compound 3 was prepared by deprotection with 1.0 mol/L HCl in ethanol.

    Scheme 5.Synthesis of pemigatinib(4).

    Scheme 6.Synthesis of capmatinib(5).

    In 2007,Array Biopharma also reported an alternative method for the preparation of intermediate 36,which was obtained by bromination and chlorination reaction of methyl 4-fluoro-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate[29].

    5.Pemigatinib(PemazyreTM)

    Pemigatinib(4,INCB054828),developed by Incyte,is a selective fibroblast growth factor receptor(FGFR)inhibitor,which has inhibitory effects on FGFR1(IC500.4 nmol/L),FGFR2(IC500.5 nmol/L),and FGFR3(IC501.0 nmol/L).Pemigatinib(4)shows a weaker inhibitory activity against FGFR4 with an IC50value of 30 nmol/L.Pemigatinib takes advantage of a hydrophobic selectivity pocket,often using a functionalized dimethoxyphenyl ring to gain FGFR selectivity and enhance the binders’ overall potency[30].Pemigatinib(4)contains tricyclic precursor,1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one,and a difluoro phenyl moiety(Fig.1).Incyte also conducted a careful SAR study through the variation of substituents on the phenyl group leading to the discovery of pemigatinib[31].Pemigatinib was approved by the US FDA in April 2020 under the trade name Pemazyre.It is used for the treatment of locally advanced or metastatic cholangiocarcinoma patients who have received FGFR2 fusion or rearrangement[32].

    The preparation of pemigatinib(4)developed by Incyte is shown in Scheme 5[31,33],which started from a substitution reaction to introduce ethylamino group to 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(39).The generated aldehyde intermediate 40 underwent condensation reaction with 2,6-difluoro-3,5-dimethoxyaniline for 2 days to give imine 42,which was subsequently reduced by LiAlH4,affording the amine intermediate 43.Then,the amine intermediate 43 reacted with triphosgene in THF resulting in the cyclization intermediate 44 after 6 h at room temperature.Deprotonation of the intermediate 44 by NaH in DMF followed by reaction with benzenesulfonyl chloride afforded the intermediate 45.Then,formylation of intermediate 45 with the use of LDA and DMF generated aldehyde 46.Reductive amination of aldehyde 46 with morpholine by use sodium triacetoxyborohydride as a reductant,finally,the sulfonyl protecting group was removedviathe treatment with tetrabutylammonium fluoride in THF to give pemigatinib(4).

    6.Capmatinib(TabrectaTM)

    Capmatinib(5,INCB 28060)was discovered by Incyte Corporation and developed by Novartis in 2009.Capmatinib is a highly selective and potent inhibitor of the MET receptor tyrosine kinase and has demonstrated clinically meaningful efficacy and a manageable safety profile in patients with advanced non–small-cell lung cancer harboring MET exon 14–skipping mutations[34].The chemical structure of capmatinib is shown in Fig.1,which contains an imidazo[1,2-b][1,2,4]triazine key moiety and a mono-fluorinated phenyl group.SAR study by Incyte was mainly based on the two key structural units[35,36].Based on results from Phase II,capmatinib was approved by the US FDA in May 2020 under the trade name TabrectaTMfor the treatment of metastatic non-small cell lung cancer(NSCLC)[37].

    The synthesis of capmatinib(5)is illustrated in Scheme 6[35,36],which was developed by Incyte.First,a key intermediate,2-chloro-3-(quinolin-6-yl)propanal(49)was synthesized from the chlorination of 3-(quinolin-6-yl)propanal(48)with NCS.On the other hand,4-bromo-3-fluoro-Nmethoxy-N-methylbenzamide(51)was prepared from 4-bromo-3-fluorobenzoic acidviathe formation of acyl chloride and amidation reaction withN,O-dimethylhydroxylamine.Compound 51 was converted into methyl ketone 52viathe reaction with methylmagnesium chloride in THF,which was further treated with HBr and followed by ethyl orthoformate under reflux to afford intermediate 53.Intermediate 53 underwent a cyclization reaction with aminoguanidine bicarbonate in potassium hydroxide(KOH)under reflux resulting in 1,2,4-trizazin-3-amine 54.Then,a second cyclization reaction was conducted,and 1,2,4-trizazin-3-amine 54 was converted to heterocyclic intermediate 55.Under microwave heating conditions,the Pd-catalyzed coupling reaction between intermediate 55 and zinc cyanide in the presence ofN,N,N’,N’-tetramethylethylenediamine(TMPDA)gave nitrile intermediate 56,which was transferred into the final capmatinib(5)viahydrolysis under acidic conditions and followed by amidation with methylamine.

    Fig.5.Structures of 6A.

    Scheme 7.Synthesis of ripretinib(6).

    7.Ripretinib(QinlockTM)

    Ripretinib(6,DCC-2618)was developed by Deciphera Pharmaceuticals as a tyrosine kinase inhibitor that inhibits KIT protooncogene receptor tyrosine kinase and platelet-derived growth factor receptor A(PDGFRA)kinase.Ripretinib(6)also contains a mono-fluoro substituent on phenyl group,which has been demonstrated to be very important for the inhibitory activityviaSAR study(Fig.1).For example,the IC50(GIST430)value of ripretinib(6)is less than 10 nmol/L,and ripretinib also shows high activity against GIST48,GIST T1,and GIST882.However,non-fluorinated analog 6A displaces less efficiency against GIST430 with IC50between 100 nmol/L and 10 nmol/L(Fig.5),even no inhibitory activity was observed against GIST48,GIST T1,and GIST882[38,39].Ripretinib(6)got its first approval by the US FDA in May 2020 under the trade name QinlockTMfor the treatment of adult patients with advanced gastrointestinal stromal tumors(GISTs)[40].

    Fig.6.Structure of 7A.

    One synthetic method for the preparation of ripretinib(6)developed by Deciphera Pharmaceuticals is shown in Scheme 7[38].First,an aldehyde intermediate 61 was prepared,starting from ethyl 4,6-dichloronicotinate(58).Amination substitution reaction of 4-chloro of ethyl 4,6-dichloronicotinate(58)using 65% ethylamine in water at room temperature gave the intermediate 59,which was reduced by LiAlH4at 0 °C to give alcohol 60.Oxidation of alcohol 60 with MnO2at room temperature provided the aldehyde intermediate 61.On the other hand,the addition of iron powder and saturated ammonium chloride to ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate(62)and heating at 55 °C for 1 h afforded amine 63.Then,the mixture of amine 63 and aldehyde intermediate 61 was sonicated in the presence of KF on alumina(40%)to give the cyclic compound 64.Next,compound 64 was treated with methylamine in a sealed tube and heated to 100° C.resulting in the amination compound 65.Finally,reaction of compound 65 with phenyl isocyanate in the presence of triethylamine at room temperature for 4 h to form the desired product 6[38].

    8.Rimegepant(Nurtec ODTTM)

    Rimegepant(7,BMS-927711)was discovered by Bristol-Myers Squibb in 2011,which was used as an oral calcitonin gene-related peptide(CGRP)antagonist for treating migraine in clinical trials.Rimegepant is a chiral compound featuring three chiral carbon centers and contains a cyclohepta[b]pyridine core,a bisdifluorinated phenyl moiety,and aβ-alanine derived cyclic moiety(Fig.1)[41,42].Previously,Bristol-Myers Squibb developed BMS-846372(7A)as an oral CGRP receptor antagonist with a Ki value of 0.070 nmol/L(Fig.6)[43].Further SAR investigation based on the key difluorophenyl substituted cyclohepta[b]pyridine unit led to the discovery of rimegepant(7,BMS-927711)with the hCGRP Ki value of 0.027 nmol/L[41,43].In 2016,Biohaven Pharmaceutical entered into the development and commercialization of rimegepant.In February 2020,rimegepat received its first FDA approval for the acute treatment of migraine with or without aura in adults[44].

    The synthetic route developed by Bristol-Myers Squibb for the preparation of rimegepant(7)is shown in Scheme 8[41,45].Chiral alcohol 67 was generatedviaa Rh-catalyzed chemo- and enantioselective reduction of 7,8-dihydro-5H-cyclohepta[b]pyridine-5,9-dione(66)with 99%ee,which was protected by triisopropylsilyl triflate(TIPSOTf)to give compound 68[46].Then,compound 68 was subjected to theα-arylation reaction with 1-bromo-2,3-difluorobenzene resulting in the ketone 69.Enantiomerically pure alcohol 70 could be easily obtained from dynamic resolution and diastereoselective reduction of ketone 69 with the use of Li(BuO)3AlH as a reductant in methyltert-butyl ether(MTBE)[46].Then,the treatment of alcohol 70 with NCS in the presence of triphenylphosphine in THF for 5 h affording chloride intermediate 71 with inversion of the chiral center.Substitution reaction of chloride intermediate 71 with sodium azide in DMF resulted in the azide 72 with the second inversion of the chiral center.Removal of triisopropylsilyl(TIPS)protecting group with TBAF in THF gave free alcohol 73,which was subjected to the substitution reaction to give the ester 75.The generated azide intermediate 75 was treated with trimethylphosphine in THF at room temperature for 2 h and followed by stirred with water for 3 h resulting in the desired rimegepant(7).

    Scheme 8.Synthesis of rimegepant(7).

    Scheme 9.Radioactive synthesis of fluoroestradiol F–18(8).

    9.Fluoroestradiol F-18(CeriannaTM)

    Estrogen receptors(ER)are important prognostic biomarkers to visualize tumor progression/regression and targeted hormone treatment.The radioactive fluorine18F molecules can accumulate in cancerous tissues expressing estrogen receptor,thus providing contrast agents for diagnosis.They can also be used for the assessment of heterogeneity in ER expression evading the requirement of biopsy[47].A wide range of18F radiopharmaceuticals used in PET has been reported in the literature[48].The introduction of a small and highly electronegative fluorine atom as a hydrogen mimic may improve both pharmacokinetic and physicochemical properties,including binding affinity,metabolic stability and bioavailability.To develop high-affinity estrogen receptor-targeted diagnostic agents having the ability to cross the blood-brain barrier led to the synthesis of radioactive fluoroestradiols.These molecules have a high binding affinity for estrogen receptors and have high tissue permeability,including the blood-brain barrier[49].

    Fluoroestradiol F-18(8,also known as[18F]16α-fluoroestradiol)was developed by Zionexa USA and commercialized through Petnet Solutions,Zionexa USA’s manufacture and exclusive distributor in the USA.The US FDA approved Fluoroestradiol F-18 on May 20,2020,as a radioactive diagnostic agent for the non-invasive visual monitoring of ER-positive lesions during PET scan of patients with recurrent or metastatic breast cancer(Fig.1).The agent provides enough contrast in PET scan images and helps diagnose multiple tumor sites without patient discomfort.The FDA approval was based primarily on the data from two published clinical trials[50,51].All the patients with recurrent or metastatic ER-positive breast cancer received radioactive fluoroestradiol before PET scan,and the results were compared to tissue biopsy data.

    Kiesewetteret al.reported the first synthetic procedures for the preparation of18F-labeled estrogens[52].Other research groups[53]later reported the synthesis of fluoroestradiols.18F fluorine required for synthesizing the fluoroestrogens was made from18OH2O by the18O(p,n)18F reaction[52].The18F was eluted with a solution of 100μL of 0.25 mol/L K2CO3and 900μL of K2.2.2(15 mg/mL in MeCN)into the reaction vial.Compound 3-Omethoxymethyl-16,17-O-sulphuryl-16-epiestriol(MMSE,76)in anhydrous MeCN was added to azeotropically dried kryptofix-2.2.2(K2.2.2)/K18F,and the mixture was heated at 110 °C for 15 min to provide intermediate 77.After18F fluorination,the solution was quenched by heating the reaction mixture with 2.0 mol/L HCl(0.6 mL)for 10 min at 120 °C and then neutralized by adding 2.0 mL of 4.2% NaHCO3.The crude product 8 was purified by semipreparative HPLC with 50% ethanol(Scheme 9)[54].The radiochemical yield(decay corrected)based on re-solubilized18F fluoride activity was 29-43%.

    10.Flortaucipir F-18(TauvidTM)

    Alzheimer’s disease(AD)is a progressive neurodegenerative disorder wherein neurofibrillary tangles(NFTs)are formed due to hyperphosphorylation of microtubule stabilizing tau protein leading to its abnormal accumulation in the patients’brains[55–57].Although no cure exists,early intervention is required to delay the symptoms with proper medication and disease management.Usually,the disorder is diagnosed based on the patient’s medical history of memory loss and cognitive functions.Various tau-specific ligands have been reported in the literature[58].

    Flortaucipir F-18(9,also known as18F-AV1451 or18F-T807)was developed by Avid Radiopharmaceuticals,a wholly-owned subsidiary of Lilly.Approved by US FDA on May 28,2020,flortaucipir F-18 is the first radioactive diagnostic agent to visually detect the density and differential distribution of these tau deposits in the brain of suspected patients using positron emission tomography(PET).Flortaucipir F-18 administered intravenously,crosses the blood-brain barrier,and interacts with the misfolded tau protein in the brain.It can be easily identified with a PET scan and helps diagnose the tau associated pathology(Fig.1)[59].

    In addition to a synthetic route reported by Holt’s group[60],Frey,Scott and co-workers reported an updated route for fortaucipir F-18(Scheme 10).A solution ofN-Boc nitro-precursor of tauvid 78 in DMSO(0.5 mg in 500μL)was added to a solution of dried18F-fluoride(produced from18F-fluoride with K2CO3(3.5 mg in 500 μL of H2O)and kryptofix-2.2.2(K2.2.2)(15 mg in 1 mL of EtOH).The mixture was heated to 130 °C for 10 min with constant stirring.After the completion of the reaction,the reaction mixture was cooled to 50 °C,and purified by semi-preparative HPLC.The fluoro derivative 79 was eluted with 0.5 mL of EtOH followed by thermal deprotection to get flortaucipir F-18(9)[61].The radiochemical yield(non-corrected)of flortaucipir F-18 prepared using this method was 14% based on starting18F-fluoride.

    Fig.7.Structures of decitabine,cedazuridine,and tetrahydrouridine(THU).

    Scheme 10.Radioactive synthesis of flortaucipir F-18(9).

    11.Decitabine/cedazuridine(InqoviTM)

    Inqovi is a fixed-dose combination of decitabine/cedazuridine developed by Astex Pharmaceuticals Inc.,a subsidiary of Otsuka Pharmaceuticals.The US FDA approved it on July 7,2020,for the treatment of myelodysplastic syndromes and chronic myelomonocytic leukaemia.

    Decitabine(10a)is a hypomethylating nucleoside metabolic inhibitor,also known as cytidine antimetabolite,that after metabolism incorporates itself into DNA and inhibit DNA methyltransferase 1(DNMT1)in proliferating cancer cells leading to reactivation of silenced tumor suppressor genes and apoptosis of cancerous cells restoring normal cellular differentiation and proliferation(Fig.7)[62].The oral bioavailability of this compound is limiting owing to its first-pass metabolism by the enzyme cytidine deaminase present in the gut,kidney and liver.Therefore,to facilitate its oral bioavailability and reduce high dose decitabineassociated gastrointestinal toxicity,its co-administration with cytidine deaminase(CDA)inhibitor-tetrahydrouridine(THU)(80)is suggested,and the patent was granted to Otsuka Pharmaceutical Co.,Ltd.[63].Poor aqueous solubility of THU and its isomerization at low pH reduce its potency in primates.

    Both cytidine and deoxycytidine are being acted upon by CDA,proving that the 2′-hydroxy group of cytidine has no specific role in binding[64].This has further been proved by the co-crystal structure of mouse CDA with THU,which shows that only the 3′-OH and 5′-OH groups of sugar form critical hydrogen bonds with the specific amino acid residues in the active site[65].Later,2′-deoxytetrahydrouridine was reported to be more potent than THU[66].To improve the acid stability and increase the systemic exposure,Ferrariset al.described 2′-fluorinated tetrahydrouridine derivatives such as cedazuridine(10b)as new generation CDA inhibitors that prevent the breakdown and efficacy of decitabine in primates[67].The acid-stable CDA inhibitor cedazuridine(10b)showed improved acid stability and better oral bioavailability in rhesus monkeys than tetrahydrouridine and its other analogs.Further,its co-administration with a CDA substrate decitabine showed increased plasma levels of decitabine in primates[67,68].The orientation of a 4-hydroxyl group of THU plays a critical role in the mechanism of inhibition of CDA,explaining the difference in potency of its two isomers.A similar binding mode/interaction with the active site zinc atom is observed for fluorinated analogs.

    The US FDA approved Cedazuridine to combine with decitabine for sale by Astex Pharmaceuticals Inc.under the name Inqovi.The approval is based on phase III studies that compared systemic exposure to decitabine from Inqovi and assessed its safety and effi-cacy[69].

    The fluorinated THU analogs were prepared using the procedures reported by the Sturla group for the synthesis of 2′-deoxytetrahydrouridine[70].The synthesis of cedazuridine(10b)was published with the details of its development and pharmacological evaluation.As illustrated in Scheme 11,the key intermediate,gemcitabine(87)was prepared with chiral difluoro ester 81 as the starting reagent[70b].Intramolecular cyclization reaction of compound 81 generated intermediate 82 in 100% yield,which was protected by 3-fluorobenzoyl group to give compound 83.Reduction of this lactone 83 by lithium tri-tert-butoxyaluminohydride at 20 °C,followed by treatment with methanesulfonyl chloride in the presence of trimethylamine,resulting in the intermediate 85.Substitution reaction of intermediate 85 by cytosine in the presence of ammonium sulfate and 1,1,1,3,3,3-hexamethyldisilazane(HMDS)afforded the intermediate 86,which was treated by 30% ammonia to give gemcitabine(87).Then,rhodium-catalyzed hydrogenation of compound 87 formed 2-deoxy-2,2-difluorodihydrouridine(88).This was followed by the reduction of intermediate 88 with NaBH4to give a mixture of difluorinated tetrahydrouridine epimers(10b)and(89)that differ in hydroxyl group stereochemistry at the position-4 along with 4-deoxy by-product 90.The preparative HPLC separated two epimers 10b and 89,and also removed the by-product 90.

    Scheme 11.Synthesis of cedazuridine(10b).

    Scheme 12.Synthesis of pralsetinib(11).

    12.Pralsetinib(BLU-667,GavretoTM)

    First-generation kinase inhibitors for kinase-driven cancers like BCR-ABL fusions(imatinib),EGFR mutations(erlotinib and gefitinib),and ALK rearrangements(crizotinib)have been reported in the literature[71].However,due to drug resistance development,search for next-generation kinase inhibitors with more potency and selectivity is desired[72].Rearranged during transfection(RET)fusions have a receptor tyrosine kinase domain that is implicated in various cancers,including non-small cell lung cancer(NSCLC),medullary thyroid cancer(MTC),and papillary thyroid cancer[73].In normal conditions,RET fusions are involved in kidney morphogenesis and embryonic development[74].However,oncogenic RET kinase activation leads to tumorigenesisviapoint mutations and gene rearrangements[75,76].RET fusion proteins and specific activating point mutations lead to hyperactivation of downstream signaling cascades responsible for uncontrolled cell proliferation.The compounds like cabozantinib,vandetanib,sorafenib,regorafenib are active against the wild-type RET but are much less active against the mutated forms.

    Subbiahet al.describe pralsetinib(11,also known as BLU-667)as an orally active,highly potent,and selective RET inhibitor for the treatment of metastatic RET fusion-positive non-small cell lung cancer(NSCLC)caused by abnormal RET(receptor tyrosine kinase rearranged during transfection)genes(Fig.1)[77,78].More than 60 chemical scaffolds were tested and optimized to identify leads with improved RET potency and selectivity against other human kinases leading to the synthesis of pralsetinib.The efficacy of pralsetinib was evaluated in patients with RET fusion-positive metastatic NSCLC,and the compound showed increased RET selectivity and potency compared to multi-kinase inhibitors.The US FDA granted its approval to Blueprint Medicines on September 4,2020.

    The synthesis of pralsetinib was reported in a patent(Scheme 12)[79].2,4-Dichloro-6-methylpyrimidine(91)was treated with MeSNa in THF to provide methylthiolated pyrimidine 92.Methyl 4-iodo-1-methoxycyclohexanecarboxylate(93)dissolved in dimethylacetamide is treated with Rieke Zinc and compound 92 followed by addition of PdCl2dppf to coupling product 94.Oxidation of sulfide in 94 withmCPBA afforded methylsulfonylpyrimidine 95,which was treated with acetic acid to afford 4-hydroxypyrimidine compound 96.Chlorination of 96 with POCl3for 97 followed by chlorine-displacement with 3-methyl-1-pyrazol-5-amine(98)in the presence of Pd2(dba)3andt-BuXPhos under heating gave compound 99.At the last step,the ester of compound 99 was hydrolyzed to acid,followed by benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP)-promoted amide coupling with compound 100 gave a mixture of diastereomers,and pralsetinib(11)was isolated by SFC as white solids.

    Fig.8.Structures of BCX4161 and compound 102.

    Scheme 13.Synthesis of berotralstat(12).

    13.Berotralstat(OrladeyoTM)

    Hereditary angioedema is a life-threatening rare genetic disorder caused by mutations in the regulatory regions of gene encoding a serine protease-C1 esterase inhibitor[80].This inhibitor covalently binds and inactivates plasma kallikrein(PKal)- a protease responsible for cleaving a biologic peptide-kininogen,thereby preventing uncontrolled contact activation and release of a potent vasodilator,bradykinin.Due to over activation of the kallikrein–bradykinin cascade,either a deficiency(type I)or dysfunction(type II)of C1 esterase inhibitor is observed that leads to an uncontrolled increase of bradykinin,leading to increased vascular permeability and episodic swelling and pain[81].

    The drugs available for oral prophylaxis against angioedema attacks are attenuated androgens,such as danazol and tranexamic acid.Due to various undesirable adverse androgenic hormonal effects and contraindications of these drugs,their clinical use is limited.Various groups have reported SAR studies of PKal inhibitors having different scaffolds like amino acid trimers,1H-pyrazole-4-carboxamide/1H-imidazole-4-carboxamide,3-(trifluoromethyl)-1H-pyrazole-5-carboxamide,7H-purin-6-amine,nicotinamide,pyrrolidine-2-carboxamide,benzylamine.Many peptide-based PKal inhibitors having different scaffolds and selectivity have been developed,and a few of them have reached clinical trials or market[82].Only two small-molecule non-peptidic pKal inhibitors were reported,BCX4161(101)[83]and compound 102(Fig.8)[84].BCX4161 failed in Phase 2 clinical trials due to its poor pharmacokinetics and efficacy.An orally bioavailable non-peptidic C1 inhibitor-BCX7353(orladeyo)developed by BioCryst Pharmaceuticals Inc.,is a potent oral small-molecule inhibitor of plasma kallikrein that performs its function by inhibiting its proteolytic activity and reducing bradykinin formation[85].This inhibitor is the first oral non-steroidal medication approved by the US FDA on December 3,2020,for the prophylactic treatment of hereditary angioedema that may help prevent angioedema attacks.

    The synthetic route for berotralstat is shown in Scheme 13[86].The reaction of 3-formylbenzonitrile(103)and Grignard reagent 104 gave aniline derivative 105,which was used for PyBrOpromoted amide coupling with acid 106 to afford amide 107.The reaction of 107 with cyclopropylmethanamine in the presence of SOCl2gave compound 108,which then converted to berotralstat(12)after de-Boc with HCl and chiral resolution.

    14.Relugolix(OrgovyxTM)

    Gonadotropin-releasing hormones(GnRH)are produced in the hypothalamus and released into the pituitary.These hormones interact with the GnRH receptor and activate the biosynthesis of luteinizing hormone(LH)and follicle-stimulating hormone(FSH).The secretion of these hormones is controlled by feedback regulation from the hypothalamus[87].

    GnRH antagonists bind competitively to GnRH receptors and decrease the release of LH and FSH from the anterior pituitary gland and,ultimately,decreases testosterone production in males and estrogen in females.Various peptidic GnRH antagonists,including GnRH-derived linear peptides[88],a cyclic hexapeptide derivative[89],a bicyclic peptide derivative[90]and so on,are reported in the literature.The problems associated with peptide-based compounds like metabolic stability and oral bioavailability created the strong need for a non-peptide based oral GnRH antagonist for sexhormone-dependent cancers,e.g.,prostatic cancer,endometriosis,etc.

    To overcome this issue of poor metabolic stability and a short half-life of peptide-based drugs,orally active non-peptidic small molecules are required to treat these hormone-based reproductive disorders[91].Various non-peptidic GnRH-antagonists[92]are reported to prevent or treat anterior pituitary hormone-dependent diseases.Abbott Laboratories reported the first non-peptide GnRH antagonist[93].

    Orally active thienopyrimidine based selective GnRH receptor antagonist was first described in 2004[94,95].Takeda Company developed a series of thienopyridine derivatives,including sufugolix and relugolix.Besides,various scaffolds of non-peptidic GnRH antagonists have been designed and tested[96].

    The US FDA approved Relugolix(also known as TAK-385)in December 2020 as the first oral medication for treating advanced prostate cancer.The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained a low testosterone level equal to castration[97].It was the second orally active GnRH antagonist to be introduced for clinical use after elagolix(Orilissa)developed by Neurocrine Biosciences[98].

    The bicyclic scaffold of thieno-[2,3-d]pyrimidine-2,4-dione core mimics a type IIβ-turn of the human GnRH receptor.The structure-activity relationship(SAR)studies led to the identification of the compound,sufugolix showing goodin vitroandin vivoGnRH antagonistic activities[99].To improvein vivoGnRH antagonistic activity,Miwaet al.synthesized various analogs by performing modification at the 5-position of the thieno[2,3-d]pyrimidine-2,4-dione ring scaffold[95].Further optimization was carried out by modification at 3- and 5-positions that resulted in relugolix(13)as a highly potent and orally active GnRH antagonist(Fig.1).Optimized the thienopyrimidine ring at positions 5 and 3 by introducing polar substituents to increase GnRH antagonistic activity and reduction in CYP3A4 inhibition reported with earlier analogs.Using molecular modeling strategy,they observed that the 2,6-difluorobenzyl group shows a hydrophobic interaction with Tyr283.The methoxyureido group interacts with both Gln106 and Asn102,and a tertiary amine forms a hydrogen bond with Asp302 of the GnRH receptor.Although substituting phenyl with pyridyl group leads to a decrease in logD,but CYP3A4 inhibition remained.The introduction of the hydroxymethyl group into the pyridyl ring and modifying the methylene linker could not reduce the CYP3A4 inhibitory activity.Further,no change was observed with the pyridyl ring’s modification with the triazolyl ring or cyclic carboxamide group.But replacement with alkylsulfamoyl or methoxyethyl group leads to a decrease of logD value and the reduction of CYP3A4 inhibition.The SAR data showed that the methoxy group’s introduction into the para position of a pyridine derivative leads to improved antagonistic activity with low CYP3A4 inhibitory activity.Further,to reduce the logD,the pyridine ring was replaced with a pyridazine ring.The derivative showed improved antagonistic activity with some CYP3A4 inhibition.To further reduce the logD,theN-methyl group was introduced in place of theN-2-methoxyethyl group.The dimethylaminomethyl pyridazine derivative showed potent antagonistic activities with no CYP3A4 inhibitory activity.

    The synthesis of relugolix is shown in Scheme 14[95].2-Aminothiophene derivative 109 was treated with ethoxycarbonychloride to form intermediate 110 followed by alkylation with 2,6-difluorobenzylchloride to giveN,N-disubstituted amine 111 which was brominated withN-bromosuccinimide(NBS)and 2,2′-azobis(isobutyronitrile)(AIBN)to afford bromomethyl derivative 112.The reaction of 112 withN-(2-methoxyethyl)methylamine gave tertiary amine 113 followed by a one-pot reduction of NO2to NH2and the treatment with 1,10-carbonyldiimidazole(CDI)andN-methoxyamine hydrochloride to give compound 114.Selective alkaline hydrolysis of ethyl ester yielded compound 115.The thiophene-3-carboxylic acid thus formed is condensed with various amines using diethyl phosphorocyanidate(DEPC)followed by cyclization under basic conditions using NaOEt provided the corresponding thieno[2,3-d]pyrimidine-2,4-dione derivatives 116.The reaction of 116 with 1-chloroethylchloroformate afforded the intermediary quaternary ammonium salts,and subsequent nucleophilic substitution with dimethylamine gave product relugolix(13).

    Scheme 14.Synthesis of relugolix(13).

    15.Conclusions and outlook

    One of the striking trends observed for the drugs approved in 2020 is an overwhelming dominance of aromatic fluorination.While it is not completely unexpected,due to the advances in synthetic methodology,one would expect an increasing number of compounds featuring aliphatic fluorine.Nevertheless,some new fluorination motifs represented by KoselugoTM(3),TauvidTM(9)and PralsebinibTM(11),bearing fluorine on a heteroaromatic moiety.Also of interest are compounds PemazyreTM(4),Nurtec ODTTM(7),and OrgovyxTM(13),featuring two fluorine atoms on a phenyl ring.In this line,we also can mention QinlockTM(6)as an example of the fluorination-halogenation(Br)motif.Another example of multiple fluorinations is OrladeyoTM(12),possessing aromatic fluorine in combination with heteroaromatic trifluoromethyl group.Other cases of aromatic fluorination represented by AyvakitTM(1),IsturisaTM(2)and TabrectaTM(5)correspond to a rather established pattern ofortho- orpara-substitution to increase the metabolic stability of a drug molecule.Examples of aliphatic fluorination are represented by CeriannaTM(8)(CHF)and InqoviTM(10)(CF2).In both cases,the fluorinated moiety is located next to a stereogenic center bearing hydroxy and amino functional groups,thus requiring an elaborated synthetic approach.As a manifestation of the growing importance of PET,functional imaging technique,is the approval of two new drugs CeriannaTM(8)and TauvidTM(9),bearing F18nucleus,representing aliphatic and heteroaromatic fluorination,respectively.Another striking trend observed for the new pharmaceuticals in 2020 is that over 50% of compounds were developed as anticancer drugs,including AyvakitTM(1),PemazyreTM(4),TabrectaTM(5),QinlockTM(6),CeriannaTM(8),PralsebinibTM(11),OrgovyxTM(13).Other therapeutic areas represented by IsturisaTM(2),developed against Cushing’s disease,KoselugoTM(3)to cure neurofibromatosis,Nurtec ODTTM(7)to treat migraine,TauvidTM(9)as a remedy for Alzheimer’s disease,InqoviTM(10)to address myelodysplastic syndromes and PralsebinibTM(11)to cure hereditary angioedema(11).Similar to the previous years,over 50% of new drugs approved in 2020 are chiral compounds represented by AyvakitTM(1),IsturisaTM(2),Nurtec ODTTM(7),CeriannaTM(8),InqoviTM(10),PralsebinibTM(11)and OrladeyoTM(12).In this regard,we would like to stress the necessity of conducting the corresponding SDEtests[25f]to ensure the accuracy of the reported values of the stereochemical outcome of catalytic enantioselective reactions.It is important to know that fluorine is an SDE-phoric substituent[6c],requiring a detailed study of the SDE properties of chiral fluorinated drugs to ensure their safe production storage and administration.Finally,we would like to point our recent concerns with fluoride overload in humans and the environment[3f].Fluorinecontaining drugs are considered as one of the sources of fluoride,calling for the necessity for more detailed and systematic studies of the metabolism of fluoro-organic products and the effect of fluoride on human health.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    Acknowledgments

    We gratefully acknowledge the financial support from the National Natural Science Foundation of China(No.21761132021)and IKERBASQUE,Basque Foundation for Science.

    国产主播在线观看一区二区| 精品福利观看| 黑人欧美特级aaaaaa片| 免费看日本二区| 精品无人区乱码1区二区| 性欧美人与动物交配| 成人18禁在线播放| 国产精品一区二区免费欧美| 成人一区二区视频在线观看| 国产亚洲精品一区二区www| 欧美激情久久久久久爽电影| 一级a爱视频在线免费观看| 2021天堂中文幕一二区在线观 | 俺也久久电影网| 三级毛片av免费| 老司机福利观看| 精品第一国产精品| 99国产精品一区二区三区| 亚洲中文字幕一区二区三区有码在线看 | videosex国产| 1024视频免费在线观看| 精品无人区乱码1区二区| 成人18禁高潮啪啪吃奶动态图| netflix在线观看网站| 国产黄片美女视频| 国产av在哪里看| 一a级毛片在线观看| 啦啦啦 在线观看视频| 国产成人精品无人区| 国产精品美女特级片免费视频播放器 | 韩国精品一区二区三区| 亚洲男人天堂网一区| 制服丝袜大香蕉在线| 久久精品国产亚洲av高清一级| 麻豆国产av国片精品| 亚洲欧美激情综合另类| 夜夜躁狠狠躁天天躁| 精品少妇一区二区三区视频日本电影| 日韩成人在线观看一区二区三区| 亚洲狠狠婷婷综合久久图片| 啪啪无遮挡十八禁网站| 热99re8久久精品国产| 制服人妻中文乱码| 国产黄片美女视频| 国内揄拍国产精品人妻在线 | 日日干狠狠操夜夜爽| 麻豆成人午夜福利视频| 男女那种视频在线观看| 午夜激情av网站| 自线自在国产av| 久久人妻av系列| 精品久久久久久久久久免费视频| 在线观看66精品国产| 亚洲欧美日韩无卡精品| 男女床上黄色一级片免费看| 国产精华一区二区三区| 亚洲第一电影网av| 国产精品国产高清国产av| 久久久久久九九精品二区国产 | 男人舔女人下体高潮全视频| a级毛片a级免费在线| 十八禁人妻一区二区| 免费在线观看黄色视频的| 色尼玛亚洲综合影院| 搞女人的毛片| 一进一出抽搐gif免费好疼| 国内揄拍国产精品人妻在线 | 99热这里只有精品一区 | 女性被躁到高潮视频| 日韩欧美国产一区二区入口| 男女床上黄色一级片免费看| 高清毛片免费观看视频网站| 日韩欧美在线二视频| 一本综合久久免费| 美女大奶头视频| or卡值多少钱| 精品无人区乱码1区二区| 精品第一国产精品| 免费无遮挡裸体视频| 91成人精品电影| 88av欧美| 禁无遮挡网站| 日韩大尺度精品在线看网址| 中文亚洲av片在线观看爽| 巨乳人妻的诱惑在线观看| 亚洲国产精品999在线| 久久精品影院6| a级毛片a级免费在线| 一级作爱视频免费观看| 精品久久久久久成人av| 成人永久免费在线观看视频| 午夜影院日韩av| 久久香蕉国产精品| 18禁黄网站禁片午夜丰满| 级片在线观看| 亚洲人成网站在线播放欧美日韩| 一进一出好大好爽视频| 99国产精品一区二区蜜桃av| 最新在线观看一区二区三区| 可以在线观看毛片的网站| 一边摸一边做爽爽视频免费| 日韩欧美一区二区三区在线观看| 亚洲精品中文字幕一二三四区| 一进一出抽搐动态| 成人精品一区二区免费| 身体一侧抽搐| 男女床上黄色一级片免费看| 午夜精品久久久久久毛片777| 黄色丝袜av网址大全| 在线十欧美十亚洲十日本专区| 亚洲精品在线观看二区| 丝袜美腿诱惑在线| 老司机午夜福利在线观看视频| 亚洲国产日韩欧美精品在线观看 | 国产欧美日韩精品亚洲av| 国产黄色小视频在线观看| 一进一出抽搐动态| 99久久99久久久精品蜜桃| 国产精品综合久久久久久久免费| 啦啦啦 在线观看视频| 日韩有码中文字幕| 久久精品亚洲精品国产色婷小说| 午夜免费观看网址| 免费在线观看成人毛片| 欧美绝顶高潮抽搐喷水| 丰满的人妻完整版| 香蕉国产在线看| 国产1区2区3区精品| 精品人妻1区二区| 欧美zozozo另类| 国产亚洲欧美精品永久| 婷婷精品国产亚洲av| 欧美在线黄色| 一进一出好大好爽视频| 国产精品免费视频内射| 18禁观看日本| 在线视频色国产色| 亚洲久久久国产精品| 黄频高清免费视频| 麻豆国产av国片精品| 中文在线观看免费www的网站 | 看片在线看免费视频| 亚洲成人免费电影在线观看| 国产精品久久久av美女十八| 亚洲av成人av| 久久精品91无色码中文字幕| 精品久久蜜臀av无| 国产精品野战在线观看| 午夜两性在线视频| 欧美精品啪啪一区二区三区| 日韩欧美 国产精品| 丝袜在线中文字幕| 美女午夜性视频免费| 欧美成人性av电影在线观看| 桃色一区二区三区在线观看| 色综合婷婷激情| 老熟妇仑乱视频hdxx| 午夜福利一区二区在线看| 黄色 视频免费看| 精品一区二区三区视频在线观看免费| 久久亚洲精品不卡| 99国产精品一区二区蜜桃av| 首页视频小说图片口味搜索| 久久青草综合色| 国产精品亚洲一级av第二区| 亚洲精品久久成人aⅴ小说| 亚洲片人在线观看| 久久99热这里只有精品18| 99国产综合亚洲精品| 男人的好看免费观看在线视频 | 久久亚洲真实| 久久久精品国产亚洲av高清涩受| 精品一区二区三区av网在线观看| 一级a爱视频在线免费观看| 在线观看一区二区三区| 久久中文字幕人妻熟女| 亚洲人成伊人成综合网2020| 免费一级毛片在线播放高清视频| 国产视频一区二区在线看| 午夜福利一区二区在线看| 亚洲aⅴ乱码一区二区在线播放 | 老司机福利观看| 99国产精品一区二区三区| 亚洲中文字幕一区二区三区有码在线看 | 亚洲色图av天堂| 一二三四社区在线视频社区8| 国产视频内射| 日本黄色视频三级网站网址| а√天堂www在线а√下载| 最近最新中文字幕大全电影3 | 香蕉国产在线看| 一本综合久久免费| 啦啦啦 在线观看视频| 欧美成人免费av一区二区三区| 亚洲国产高清在线一区二区三 | 国产精品电影一区二区三区| 国产又爽黄色视频| 热99re8久久精品国产| 国产乱人伦免费视频| 天堂√8在线中文| 国产欧美日韩一区二区精品| 天堂影院成人在线观看| 国产伦一二天堂av在线观看| 国产成人欧美| 亚洲成av片中文字幕在线观看| 一级片免费观看大全| 十分钟在线观看高清视频www| 热re99久久国产66热| 天天躁夜夜躁狠狠躁躁| 成人免费观看视频高清| 18禁黄网站禁片午夜丰满| xxx96com| 婷婷亚洲欧美| 日韩成人在线观看一区二区三区| 亚洲人成77777在线视频| 亚洲人成电影免费在线| 怎么达到女性高潮| 少妇粗大呻吟视频| www.999成人在线观看| 91国产中文字幕| 天堂影院成人在线观看| 日本黄色视频三级网站网址| 亚洲成人国产一区在线观看| 十八禁人妻一区二区| 亚洲天堂国产精品一区在线| 久热爱精品视频在线9| 午夜福利一区二区在线看| 免费看十八禁软件| 一本精品99久久精品77| 久久久久久免费高清国产稀缺| 欧美黑人欧美精品刺激| 1024手机看黄色片| 色综合欧美亚洲国产小说| 日日摸夜夜添夜夜添小说| 日本黄色视频三级网站网址| 亚洲精品色激情综合| 欧美乱妇无乱码| 久久青草综合色| 伊人久久大香线蕉亚洲五| 90打野战视频偷拍视频| av片东京热男人的天堂| 91九色精品人成在线观看| 亚洲欧美日韩无卡精品| 听说在线观看完整版免费高清| 在线看三级毛片| 亚洲自偷自拍图片 自拍| 久久国产乱子伦精品免费另类| 日日干狠狠操夜夜爽| 午夜久久久在线观看| 欧美不卡视频在线免费观看 | 国内揄拍国产精品人妻在线 | 热99re8久久精品国产| 亚洲中文字幕日韩| 午夜a级毛片| 禁无遮挡网站| 9191精品国产免费久久| 精华霜和精华液先用哪个| 99久久无色码亚洲精品果冻| 怎么达到女性高潮| 最好的美女福利视频网| 色精品久久人妻99蜜桃| 久久国产亚洲av麻豆专区| 午夜福利在线在线| 黄频高清免费视频| 伦理电影免费视频| 色哟哟哟哟哟哟| videosex国产| 狂野欧美激情性xxxx| 黑人巨大精品欧美一区二区mp4| videosex国产| 亚洲av电影不卡..在线观看| 亚洲国产欧美日韩在线播放| 国产精品av久久久久免费| 午夜成年电影在线免费观看| 久久精品91蜜桃| 88av欧美| www国产在线视频色| 丝袜在线中文字幕| 欧美在线一区亚洲| 最近最新中文字幕大全电影3 | 国产高清激情床上av| 欧美性猛交黑人性爽| 国内揄拍国产精品人妻在线 | 日日干狠狠操夜夜爽| 欧美色欧美亚洲另类二区| 好看av亚洲va欧美ⅴa在| avwww免费| 精品欧美国产一区二区三| 最近最新免费中文字幕在线| 美女高潮喷水抽搐中文字幕| 久久久国产成人免费| 好看av亚洲va欧美ⅴa在| 国产主播在线观看一区二区| 又大又爽又粗| 亚洲在线自拍视频| 国产成人欧美| 91成年电影在线观看| 成熟少妇高潮喷水视频| 成人特级黄色片久久久久久久| 亚洲精品国产精品久久久不卡| 久久久久久亚洲精品国产蜜桃av| 一级a爱视频在线免费观看| 亚洲中文av在线| 久久久久国产一级毛片高清牌| 国产精品1区2区在线观看.| 欧美黑人欧美精品刺激| 99热6这里只有精品| 国产精品一区二区精品视频观看| 亚洲国产欧洲综合997久久, | 亚洲欧美精品综合一区二区三区| 久久中文看片网| 日韩一卡2卡3卡4卡2021年| av免费在线观看网站| 国产av不卡久久| 久久草成人影院| 国产乱人伦免费视频| 国产99白浆流出| 国产精品99久久99久久久不卡| 两个人免费观看高清视频| 亚洲五月婷婷丁香| 亚洲人成网站高清观看| 少妇粗大呻吟视频| 亚洲狠狠婷婷综合久久图片| 免费看日本二区| 中文字幕精品免费在线观看视频| 久久狼人影院| 午夜精品在线福利| av电影中文网址| 婷婷六月久久综合丁香| 久久久国产成人免费| 不卡av一区二区三区| www.999成人在线观看| 在线av久久热| 国产亚洲av高清不卡| 亚洲人成77777在线视频| 国产久久久一区二区三区| 午夜视频精品福利| 18禁美女被吸乳视频| 黑人欧美特级aaaaaa片| 久久人人精品亚洲av| 在线观看午夜福利视频| 亚洲国产欧美网| 国产精品久久久人人做人人爽| 日韩有码中文字幕| 免费无遮挡裸体视频| 国产亚洲欧美在线一区二区| 一卡2卡三卡四卡精品乱码亚洲| 12—13女人毛片做爰片一| 日本a在线网址| 一本精品99久久精品77| 欧美最黄视频在线播放免费| 不卡av一区二区三区| 亚洲第一青青草原| e午夜精品久久久久久久| av免费在线观看网站| 国产精品一区二区精品视频观看| 在线永久观看黄色视频| 狂野欧美激情性xxxx| 国产高清视频在线播放一区| 午夜亚洲福利在线播放| 免费高清视频大片| 色精品久久人妻99蜜桃| 国产精品久久电影中文字幕| 女人被狂操c到高潮| 一边摸一边做爽爽视频免费| 91av网站免费观看| 九色国产91popny在线| 午夜福利在线在线| 人成视频在线观看免费观看| 日日夜夜操网爽| 国产高清激情床上av| 国内精品久久久久久久电影| 久久香蕉精品热| 欧美激情高清一区二区三区| 黄片播放在线免费| 国产真人三级小视频在线观看| 1024手机看黄色片| 色老头精品视频在线观看| 女性生殖器流出的白浆| 国产精品永久免费网站| www.自偷自拍.com| 十八禁人妻一区二区| 99国产精品一区二区三区| 国产午夜精品久久久久久| 欧美中文综合在线视频| 神马国产精品三级电影在线观看 | 日日干狠狠操夜夜爽| 中文字幕av电影在线播放| 国产av一区二区精品久久| xxxwww97欧美| 变态另类成人亚洲欧美熟女| 久久国产精品影院| 99在线人妻在线中文字幕| 中出人妻视频一区二区| 国产精品亚洲一级av第二区| 黑丝袜美女国产一区| 午夜久久久久精精品| 欧美av亚洲av综合av国产av| 真人一进一出gif抽搐免费| 少妇熟女aⅴ在线视频| 久久久水蜜桃国产精品网| 国产激情久久老熟女| 国产av在哪里看| 久久久国产成人免费| 少妇 在线观看| 少妇裸体淫交视频免费看高清 | 国产欧美日韩一区二区精品| 777久久人妻少妇嫩草av网站| 天天添夜夜摸| 亚洲 欧美一区二区三区| 国产av一区二区精品久久| e午夜精品久久久久久久| 久久婷婷成人综合色麻豆| 久久精品91无色码中文字幕| 熟妇人妻久久中文字幕3abv| 女性生殖器流出的白浆| 国产区一区二久久| 免费在线观看日本一区| 亚洲 国产 在线| 亚洲九九香蕉| 精品久久蜜臀av无| 精品电影一区二区在线| 麻豆av在线久日| 欧美性长视频在线观看| 久久久国产精品麻豆| 亚洲在线自拍视频| 国内揄拍国产精品人妻在线 | 欧美 亚洲 国产 日韩一| 亚洲男人天堂网一区| 国产精品 欧美亚洲| 一级a爱片免费观看的视频| 三级毛片av免费| 亚洲一区二区三区色噜噜| 欧美成人一区二区免费高清观看 | 一级作爱视频免费观看| 欧美激情高清一区二区三区| 婷婷精品国产亚洲av| 一本久久中文字幕| 亚洲全国av大片| 久久久久久亚洲精品国产蜜桃av| 欧美黑人精品巨大| 欧美久久黑人一区二区| 90打野战视频偷拍视频| 色老头精品视频在线观看| 又大又爽又粗| 男人舔女人的私密视频| 欧美一级毛片孕妇| 久久天堂一区二区三区四区| 国产1区2区3区精品| 中文字幕另类日韩欧美亚洲嫩草| 在线观看66精品国产| 1024手机看黄色片| 国产亚洲精品第一综合不卡| 欧美国产日韩亚洲一区| 老汉色av国产亚洲站长工具| 在线av久久热| 亚洲专区国产一区二区| 免费搜索国产男女视频| 欧美性长视频在线观看| 免费高清在线观看日韩| 亚洲中文日韩欧美视频| 琪琪午夜伦伦电影理论片6080| 精品第一国产精品| 久久精品夜夜夜夜夜久久蜜豆 | 视频区欧美日本亚洲| 人妻丰满熟妇av一区二区三区| 国产欧美日韩一区二区三| 亚洲国产中文字幕在线视频| 美女免费视频网站| xxxwww97欧美| 久久欧美精品欧美久久欧美| 在线观看日韩欧美| 麻豆久久精品国产亚洲av| 国产伦人伦偷精品视频| 少妇裸体淫交视频免费看高清 | 国产伦人伦偷精品视频| 国产aⅴ精品一区二区三区波| 国产成人系列免费观看| 午夜激情福利司机影院| 免费在线观看影片大全网站| 又大又爽又粗| 淫妇啪啪啪对白视频| 成人永久免费在线观看视频| 1024香蕉在线观看| 中文字幕精品亚洲无线码一区 | 欧美又色又爽又黄视频| 精品熟女少妇八av免费久了| 国产一区二区三区视频了| 91国产中文字幕| 夜夜看夜夜爽夜夜摸| 亚洲精品久久国产高清桃花| av免费在线观看网站| 国产高清有码在线观看视频 | 欧美成人免费av一区二区三区| 欧美日韩黄片免| 欧美黑人巨大hd| 女性被躁到高潮视频| 美女午夜性视频免费| 女生性感内裤真人,穿戴方法视频| 免费在线观看亚洲国产| 日本成人三级电影网站| 满18在线观看网站| netflix在线观看网站| 19禁男女啪啪无遮挡网站| 日韩大尺度精品在线看网址| 国产精品一区二区三区四区久久 | 久久久久国产精品人妻aⅴ院| 成人午夜高清在线视频 | 国产伦人伦偷精品视频| 黄网站色视频无遮挡免费观看| 久久这里只有精品19| 日韩欧美一区视频在线观看| 欧美最黄视频在线播放免费| 最近最新中文字幕大全免费视频| 丝袜在线中文字幕| 精品午夜福利视频在线观看一区| 亚洲精品美女久久久久99蜜臀| 一本大道久久a久久精品| 亚洲精品久久国产高清桃花| 午夜免费成人在线视频| 级片在线观看| 99国产综合亚洲精品| 国产亚洲av高清不卡| 国内精品久久久久久久电影| 欧美午夜高清在线| 韩国av一区二区三区四区| 18美女黄网站色大片免费观看| 国产成人欧美| 人妻久久中文字幕网| АⅤ资源中文在线天堂| 岛国在线观看网站| 欧美日韩福利视频一区二区| 美女午夜性视频免费| 欧美最黄视频在线播放免费| 69av精品久久久久久| 久久久久久九九精品二区国产 | 变态另类成人亚洲欧美熟女| 很黄的视频免费| 一进一出好大好爽视频| 久久久久免费精品人妻一区二区 | 欧美日韩精品网址| av福利片在线| 国内揄拍国产精品人妻在线 | 黄片小视频在线播放| 亚洲一区二区三区不卡视频| 久久九九热精品免费| 久久久久久人人人人人| 制服诱惑二区| 精品高清国产在线一区| 日韩精品中文字幕看吧| 亚洲一码二码三码区别大吗| 国产99白浆流出| 亚洲欧美激情综合另类| www.自偷自拍.com| 亚洲免费av在线视频| 国产高清激情床上av| 黄片播放在线免费| 琪琪午夜伦伦电影理论片6080| 超碰成人久久| 一边摸一边抽搐一进一小说| 精品电影一区二区在线| 特大巨黑吊av在线直播 | 国产视频内射| 波多野结衣av一区二区av| 老司机福利观看| 色综合亚洲欧美另类图片| 日日摸夜夜添夜夜添小说| 国产伦人伦偷精品视频| 国产乱人伦免费视频| 禁无遮挡网站| 亚洲专区中文字幕在线| 女人被狂操c到高潮| 午夜免费观看网址| 窝窝影院91人妻| 午夜亚洲福利在线播放| 国产精品亚洲一级av第二区| 一进一出抽搐动态| 97人妻精品一区二区三区麻豆 | 天天躁夜夜躁狠狠躁躁| 久久久国产成人精品二区| 欧美午夜高清在线| 啦啦啦观看免费观看视频高清| 欧美性猛交╳xxx乱大交人| 一级a爱视频在线免费观看| 国产熟女午夜一区二区三区| 成人国产一区最新在线观看| 一卡2卡三卡四卡精品乱码亚洲| 88av欧美| 久久久久免费精品人妻一区二区 | 欧美日韩一级在线毛片| 亚洲成人精品中文字幕电影| 精品久久久久久久久久久久久 | 首页视频小说图片口味搜索| 精品国产美女av久久久久小说| 国产1区2区3区精品| 51午夜福利影视在线观看| 可以免费在线观看a视频的电影网站| 亚洲片人在线观看| 国产成人av激情在线播放| 日韩视频一区二区在线观看| 国产精品乱码一区二三区的特点| 久久久久国内视频| 老汉色∧v一级毛片| 亚洲免费av在线视频| 久久99热这里只有精品18| 亚洲aⅴ乱码一区二区在线播放 | 久久久久久人人人人人| 99精品久久久久人妻精品| 美女大奶头视频| 精品第一国产精品| 亚洲人成77777在线视频| 麻豆成人av在线观看| 无人区码免费观看不卡| 欧美在线黄色| 日日夜夜操网爽|