CN108101821A - Naphthalene sulfonamide amino acid derivativges, preparation method and its medical usage - Google Patents

Naphthalene sulfonamide amino acid derivativges, preparation method and its medical usage Download PDF

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CN108101821A
CN108101821A CN201711361239.1A CN201711361239A CN108101821A CN 108101821 A CN108101821 A CN 108101821A CN 201711361239 A CN201711361239 A CN 201711361239A CN 108101821 A CN108101821 A CN 108101821A
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amino acid
naphthalene
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sulfonamido
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CN108101821B (en
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尤启冬
姜正羽
谭世界
陆朦辰
吴沣
周海山
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China Pharmaceutical University
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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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
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    • C07B2200/07—Optical isomers

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Abstract

The invention discloses naphthalene sulfonamide amino acid derivativges, preparation method and its medical usage, naphthalene sulfonamide amino acid derivativges R3Substituent group represents a kind of substituent group with amino acid structure, and the amino acid structure refers to the substituent group and at least contains there are one carboxyl and a secondary amine or tertiary amine, and the substituent group is connected to by secondary amine or tertiary amine on above-mentioned parent nucleus.Naphthalene sulfonamide amino acid derivativges provided by the invention can disturb Keap1 Nrf2 to combine, and activate Nrf2, so as to mitigate inflammatory damage, improve inflammatory microenvironment, have potential anti-inflammatory activity.Those skilled in the art will know that, Nrf2 activator can be used for the inflammatory reaction for inhibiting disease, therefore, the compounds of this invention can be used for being prepared into treatment of the anti-inflammatory drug for inflammation related disease, including Chronic Obstructive Pulmonary Disease, Alzheimer's disease, Parkinson, atherosclerosis, chronic renal disease, diabetes, intestines inflammation, rheumatoid arthritis etc..

Description

Naphthalene sulfonamide amino acid derivativges, preparation method and its medical usage
Technical field
The invention belongs to medicinal chemistry arts, and in particular to one kind have anti-inflammatory activity using naphthalene sulfonamide amino acids as The compound of basic framework, the preparation method for further relating to these compounds and the medical usage in anti-inflammatory field.
Background technology
The anti-inflammatory treatment drug being commonly used is broadly divided into steroidal anti-inflammatory drugs, mainly corticoid and non-steroid Body anti-inflammatory agent is mainly cyclooxygenase-2 inhibitor.The chemical constitution of non-steroidal anti-inflammatory drugs is although different, but passes through suppression mostly The synthesis of prostaglandin processed plays its antipyretic, analgesia, antiinflammation.These anti-inflammatory drugs of Clinical practice pass through at present Inhibit inflammatory reaction and generate anti-inflammatory drug effect, can not or seldom can improve the cause of disease for forming inflammation.It fundamentally to control Treating inflammation needs to improve the microenvironment for forming inflammation and activates in vivo anti-inflammatory systems.Inflammatory reaction and oxidative stress have important Internal association.Oxidative stress can cause albumen, nucleic acid and lipid molecule damage, and so as to cause inflammatory damage, activation is scorching Inflammation factor, induction and aggravation inflammatory reaction, this inflammation and tumour are angiocardiopathy, Parkinson, alzheimer's disease, chronic The occurrence and development of the diseases such as nephrosis are closely related；And antioxygen stress relevant albumen can with Scavenger of ROS, accelerate foreign matter generation It thanks and raises internal anti-oxidant protein content and treat inflammation [bibliography so as to improve inflammatory microenvironment：Trends Biochem Sci 2009；34(4):176-188；Annu Rev Pharmacol Toxicol 2007；47:89-116；J Biochem Mol Biol 2004；37(2):139-143；Genes Cells 2011；16(2):123-140].
Nrf2 is to be accredited for the first time in the red system K562 cells of ferroheme induction out for 1994, and participating in regulation and control oxidation should Sharp key transcription factor.Nrf2 belongs to leucine zipper nuclear transcription factor sub-family and drosophila CNC families are homologous, mankind Nrf2 With 2 subunit's p45 very high homologies of nuclear factor Hong Xi.The relevant most of antioxidant genes of oxidative stress all include Antioxidation reaction Element (ARE), Nrf2 play transcription initiation activity by combining ARE.The consensus of ARE is 5 '-RTGAYnnnGCR-3 ' (wherein R=A or G, Y=C orT).Keap1 is the main negative regulation albumen of intracellular Nrf2, and major function is normal In the case of keep intracellular relatively low Nrf2 horizontal；It is released under stress situation and the negative regulation of Nrf2 is acted on, raise Nrf2's It is horizontal.Nrf2 levels can effectively be raised to the negative regulation effect of Nrf2 by inhibiting Keap1, internal antioxidant system is activated, subtract Light inflammatory damage improves inflammatory microenvironment, so as to have the function that fundamentally to alleviate and treat inflammation.
At present, Nrf2 activator has been used for treating inflammatory related disorders.As dimethyl fumarate has ratified use by FDA In treatment multiple sclerosis, the second phase that CDDO-Me is carrying out treatment pulmonary hypertension (PAH) is clinical.Other has The natural products and class natural products of anti-inflammatory activity also have been found that Nrf2 can be activated, such as curcumin, resveratrol and chalcone Deng.
These Nrf2 activator have the how unsaturated structure that can be combined with Keap1 sulfydryls more, it is considered to be covalent modification The Nrf2 activator of type.And recently it has been reported that competitive interference Keap1-Nrf2 interactions also can be released effectively Keap1 acts on the negative regulation of Nrf2 and activates Nrf2.The mode of such activation Nrf2 has competitive, specificity, invertibity And the characteristics of highly selective, the genotoxic potential of covalent modification activation Nrf2 is avoided, is current research Nrf2 activated form inflammatory diseases The hot spot of sick medicine.
The content of the invention
It is an object of the invention to provide a kind of compound containing amino acid and single sulfonamide structure and preparation method thereof and Purposes.Preliminary active testing proves that the compound of this class formation can disturb Keap1-Nrf2 to combine, and activates Nrf2, so as to Mitigate inflammatory damage, improve inflammatory microenvironment, there is potential anti-inflammatory activity, numerous inflammation are used for available for anti-inflammatory drug is prepared into The inflammatory damage of disease relevant disease, these diseases include Chronic Obstructive Pulmonary Disease (COPD), Alzheimer's disease, Parkinson, Atherosclerosis, chronic renal disease (CKD), diabetes, intestines inflammation, rheumatoid arthritis etc..
The above-mentioned purpose of the present invention is achieved by following technical solution：
A kind of naphthalene sulfonamide amino acid derivativges as shown in structure formula (I)：
Wherein：R1Represent 4- trifluoromethyls, 4- trifluoromethoxies, 4- nitros, 4- hydroxyls, 4- methylols, 4- cyano or 4- Amino；Single, double or trisubstituted H, halogen, C1-C3 alkyl, C1-C3 alkoxies, C1-C3 alkylaminos or C1-C3 acylamino-s；
R2Represent H ,-CH2COOH、Or-CH2CONH2；
R3Represent a kind of substituent group with amino acid structure, the amino acid structure refers to there are one the substituent group at least contains Carboxyl and a secondary amine or tertiary amine, and the substituent group is connected to by secondary amine or tertiary amine on above-mentioned parent nucleus.
Preferably, R3Represent following substituent group：
Wherein：X represents H, O or S；R4Represent methyl, ethyl, tertiary butyl, phenyl, 4- anisyls or benzyl.
It is highly preferred that the chemical structural formula of the naphthalene sulfonamide amino acid derivativges is as follows：
Preferably, R3Represent following substituent group：
Wherein：
R5Represent H, methyl, isopropyl, sec-butyl, isobutyl group, tertiary butyl, cyclopenta, cyclohexyl methyl, methylol, uncle Fourth oxygen methyl, benzyloxymethyl, phenyl, benzyl, phenethyl, 4- luorobenzyls, 4- chlorobenzyls, 4- hydroxybenzyls, 4- methoxy-benzyls, 4- benzyloxy-benzyls, 2- indole methyls, 4- aminobutyls, 1- menaphthyls, carboxymethyl, carboxyethyl, methylthio ethyl, first sulfoxide second Base, methyl sulfone ethyl,
N values 0 or 1.
It is highly preferred that the chemical structural formula of the naphthalene sulfonamide amino acid derivativges is as follows：
Or chemical structural formula is as follows：
Or chemical structural formula is as follows：
Or chemical structural formula is as follows：
The preparation method of the naphthalene sulfonamide amino acid derivativges includes the following steps, wherein R2Represent H ,-CH2COOH Or
Wherein, compound (1) using tert-butyl hydroperoxide as raw material, is adopted into the synthesis step of compound (2) The preferred dimethyl sulfoxide of solvent and water, volume ratio preferably 4:1, compound (1) and reactant tert-butyl hydroperoxide (t- BuOOH) the amount of substance preferably 1:3.5~1:4.0；Compound (2) into the synthesis step of compound (3), compound (2) with it is anti- Answer the amount ratio preferably 1 of object Tf2O substances:1.5~1:2, the preferred triethylamine of used alkali, DIPEA.
For compound (3) into the synthesis step of compound (4), the preferred cesium carbonate of used alkali and DIPEA, catalyst are excellent Select Pd2(dba)3、Pd(dea)2, ligand preferred BINAP, RuPhos, in the preferred toluene of solvent, Isosorbide-5-Nitrae-dioxane, the tert-butyl alcohol It is one or more of.
Compound (4) is reduced, the used preferred first of solvent into the synthesis step of compound (5) using hydrogen palladium carbon Alcohol and tetrahydrofuran, the preferred 10%mol of palladium carbon inventory.
Compound (5) is into the synthesis step of compound (6), the preferred potassium carbonate of used alkali, saleratus, carbonic acid Sodium, sodium acid carbonate, pyridine, triethylamine, DIPEA, preferably in following solvent reaction：Tetrahydrofuran, toluene, 1,4- dioxane.
Compound (6) arrives compound (7), compound (6) and the weight ratio preferably 1 of methyl bromoacetate:2~1:3, it is used The preferred potassium carbonate of alkali, saleratus, sodium carbonate, sodium acid carbonate, pyridine, triethylamine, preferably reacted in following solvent： Dimethyl sulfoxide, N,N-dimethylformamide, 1,4- dioxane, acetonitrile.Reaction temperature is in room temperature.
Compound (7) arrives compound (8), and lithium hydroxide inventory is preferred, and making lithium hydroxide, concentration is 1- in the solution 3mol/L, dicyandiamide solution are methanol/water system or ethanol/water system, react room temperature.
Compound (6) is preferred to compound (9) lithium hydroxide inventory, and making lithium hydroxide, concentration is 1- in the solution 3mol/L, dicyandiamide solution are methanol/water system or ethanol/water system, react room temperature.
Compound (7) arrives compound (10), and lithium hydroxide inventory is preferred, and making lithium hydroxide, concentration is 1- in the solution 3mol/L, dicyandiamide solution are methanol/water system or ethanol/water system, react room temperature.
The preparation method of the naphthalene sulfonamide amino acid derivativges includes the following steps, wherein R2It represents
The synthetic method of compound (1) to compound (6) leads to R in formula (I) with working as3For-CH2It is identical when COOH ,-H.
Compound (6) is to compound (11), the preferred potassium carbonate of used alkali, saleratus, sodium carbonate, sodium acid carbonate, It is preferred that it is reacted in following solvent：Dimethyl sulfoxide, n,N-Dimethylformamide, Isosorbide-5-Nitrae-dioxane, acetonitrile, raw material 6 with The rate of charge (the amount ratio of substance) of bromoacetonitrile is 1:1-1:4, reaction temperature is in room temperature.
Compound (11) is to compound (12), ammonium chloride inventory (the amount ratio of substance) 1:4-1:8, preferably in following solvent In reacted：N,N-Dimethylformamide, Isosorbide-5-Nitrae-dioxane are one or more of, are heated to back flow reaction.
For compound (12) to target compound (13), lithium hydroxide inventory is preferred, makes lithium hydroxide concentration in the solution For 1-3mol/L, dicyandiamide solution is methanol/water system or ethanol/water system, reacts room temperature.
The pharmaceutically acceptable salt of above-mentioned naphthalene sulfonamide amino acid derivativges.
Naphthalene sulfonamide amino acid derivativges and its pharmaceutically acceptable salt is used to prepare Nrf2 activator Purposes.
The naphthalene sulfonamide amino acid derivativges and its pharmaceutically acceptable salt are used to prepare treatment or alleviate disease The purposes of the drug of the inflammation of disease, the disease is Chronic Obstructive Pulmonary Disease, Alzheimer's disease, Parkinson, artery are athero- Hardening, chronic renal disease, diabetes, intestines inflammation or rheumatoid arthritis.
Advantages of the present invention：
Compound provided by the invention containing amino acid and single sulfonamide structure can disturb Keap1-Nrf2 to combine, and activate Nrf2 so as to mitigate inflammatory damage, improves inflammatory microenvironment, has potential anti-inflammatory activity, available for being prepared into anti-inflammatory drug For the inflammatory damage of numerous inflammation related diseases, these diseases include Chronic Obstructive Pulmonary Disease (COPD), Alzheimer Disease, Parkinson, atherosclerosis, chronic renal disease (CKD), diabetes, intestines inflammation, rheumatoid arthritis etc..
Specific embodiment
Essentiality content of the present invention is specifically introduced with reference to embodiment, but the protection model of the present invention is not limited with this It encloses.
Embodiment 1：
(4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-1)
(1) 4- nitros -1- naphthols (1-1)
1- nitronaphthalenes (8.5g, 49.1mmol) are dissolved in 20.0mL DMSO (dimethyl sulfoxide (DMSO)), then by potassium hydroxide (11.0g, 196.3mmol) is dissolved in 10.0mL water, and reaction system is added dropwise under ice bath, finally will be dissolved with tert-Butanol peroxide The 10.0mLDMSO solution of (9.8mL, 98.2mmol) instills reaction system.Rear stir about 10.0min is added dropwise, removes ice Bath, reacts at room temperature.4h is reacted, adds in Na2S2O3(1.5g, 9.3mmol) stirs 1.0h, adds 200.0mL water afterwards, with dilute salt Acid for adjusting pH with EA (ethyl acetate) 30mL extractions three times, merges organic layer, is washed 3 times with saturated nacl aqueous solution, used to 4 4M sodium hydroxides adjust pH to 10, and water layer is washed 3 times with EA, and dilute hydrochloric acid solution adjusts water layer pH to 4, there is yellow solid precipitation, It filters, drying obtains bright yellow solid 5.2g, yield 55.4%, m.p.156-159 DEG C of1H-NMR(300MHz,DMSO-d6)δ: 11.98 (br, 1H), 8.68 (d, 1H, J=8.79Hz), 8.42 (d, 1H, J=8.70Hz), 8.33 (d, 1H, J=8.34Hz), 7.78-7.83 (m, 1H), 7.61-7.66 (m, 1H), 6.98 (d, 1H, J=8.70Hz)；EI-MS m/z：190[M+H]+。
(2) 4- nitronaphthalenes -1- bases triflate (1-2)
4- nitro -1- naphthols (1-1) (2.0g, 10.6mmol) is dissolved in 20ml DCM, is successively added under condition of ice bath Enter Et3N (4.4ml, 31.9mmol) and Tf2(reaction system is placed in room temperature after charging and stirred O by (2.7ml, 16.3mmol) Mixing 2.0h to TLC monitorings, the reaction was complete.Reaction solution saturation NaHCO3(20ml) is neutralized, and organic phase washs two with water (20ml) It is secondary, then washed twice with saturation NaCl (20ml).Finally use anhydrous Na2SO4It is dry, it is spin-dried for organic solvent and is obtained again through column chromatography 2.0g faint yellow solids, yield 56%, m.p.59-61 DEG C；EI-MS m/z：322[M+H]+。
(3) (4- nitronaphthalene -1- bases)-L-PROLINE methyl esters (1-3)
Compound (1-2) (1g, 3.11mmol) and L-PROLINE methyl ester hydrochloride are added in dry reaction bulb (0.62g, 3.7mmol), then rapidly joins Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol) and Pd2(dba)3(0.14g, 0.16mmol), adds in DIPEA (1.1ml, 6.22mmol) and dioxane (10ml) in time, and nitrogen is protected Protect lower 100 DEG C of reactions 20h.It is cooled to room temperature, diatomite drainage, is spin-dried for system sand, column chromatography obtains 0.47g yellow oily liquids, produces Rate 51%.1H-NMR(300MHz,CDCl3) δ 8.84 (ddd, J=8.8,1.3,0.6Hz, 1H), 8.31 (d, J=8.8Hz, 1H), 8.25-8.18 (m, 1H), 7.69-7.61 (m, 1H), 7.48 (ddd, J=8.4,6.9,1.3Hz, 1H), 6.75 (d, J= 8.9Hz, 1H), 4.69 (t, J=7.3Hz, 1H), 4.12 (td, J=9.7,6.2Hz, 1H), 3.62 (s, 3H), 3.61-3.53 (m,1H),2.61-2.49(m,1H),2.25-2.11(m,2H),2.02-1.88(m,1H)；EI-MS m/z：301[M+H]+。
(4) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE ester methyl ester (1-4)
Compound (1-3) (470mg, 1.57mmol) is dissolved in 50mlTHF, 5% palladium carbon of timely addition (33mg, 0.31mmol), H in load2Ball makes it in H250 DEG C of heating reactions in environment.The reaction was complete (5h) for TLC monitorings, through diatomite drainage Palladium carbon is removed, 4- Methoxybenzenesulfonyl chlorides (390mg, 1.89mmol), pyridine (380 μ L, 4.71mmol), N are added in into filtrate2 80 DEG C of reaction 4h of heating under protection, TLC, which monitors to depressurize after the reaction was complete, boils off THF, EA is added in being completely dissolved, with 1M dilute hydrochloric acid (20ml) solution washs three times, is washed 2 times with saturation NaCl (20ml) solution, and anhydrous sodium sulfate drying boils off EA, column chromatography obtains 500mg white solids, yield 72%, m.p.120-123 DEG C of1H-NMR(300MHz,CDCl3) δ 8.18 (dd, J=6.9, 2.7Hz,1H),7.94-7.80(m,1H),7.72-7.62(m,2H),7.50-7.35(m,2H),7.20-7.10(m,1H), 6.93 (dt, J=8.1,1.7Hz, 1H), 6.88-6.74 (m, 3H), 4.47 (s, 1H), 3.93 (q, J=8.3,7.6Hz, 1H), 3.85-3.75 (m, 3H), 3.57-3.46 (m, 3H), 3.16 (q, J=8.7,6.0Hz, 1H), 2.54-2.37 (m, 1H), 2.15 (q, J=7.4Hz, 2H), 2.04 (d, J=13.5Hz, 1H)；EI-MS m/z：441[M+H]+。
(5) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-1)
Compound (1-4) (200.0mg, 454.0 μm of ol) is dissolved in 5.0mL methanol, adds in 5.0mL water, is finally added Enter LiOHH2O (191mg, 4.54mmol) is stirred overnight at room temperature.Next day filters out insoluble matter in reaction solution, adds into filtrate 50ml water, then pH to 4-5 is adjusted with hydrochloric acid solution, precipitation, the pale solid 120.0mg of filtering, yield is gradually precipitated in solution For 62%, m.p.130-133 DEG C of1H-NMR(300MHz,DMSO-d6)δ9.80(br,1H),8.17-8.07(m,1H),7.95 (dd, J=7.4,2.2Hz, 1H), 7.65-7.53 (m, 2H), 7.40 (tt, J=7.3,5.3Hz, 2H), 7.06-6.97 (m, 2H), 6.90 (d, J=1.3Hz, 2H), 4.38 (m, 1H), 3.82-3.86 (m, 1H), 3.78 (s, 3H), 3.01 (s, 1H), 2.34 (q, J=8.4Hz, 1H), 2.00-1.96 (m, 2H), 1.92-1.88 (m, 1H)；EI-MS m/z：427[M+H]+。
Embodiment 2：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-2)
The synthesis of 1-4 is same as Example 1
(1) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- dried meat Propylhomoserin methyl esters (2-1)
Compound (1-4) (200.0mg, 454 μm of ol) is dissolved in 5.0mLDMF, addition potassium carbonate (280.0mg, 2.0mmol), methyl bromoacetate (83.0mg, 545 μm of ol) is eventually adding to stir at room temperature.4h is reacted, water is added in into solution It is precipitated to solid, with EA (30ml) extractions three times, merges organic phase, then washed three times with saturation NACl aqueous solutions (30ml), then Organic phase anhydrous Na2SO4Dry, system is husky, and pale yellow oil 190mg, yield 82%. are obtained through column chromatography1H-NMR (300MHz,CDCl3) δ 8.22 (d, J=8.8Hz, 1H), 8.08-7.94 (m, 1H), 7.69 (ddd, J=11.1,8.8, 2.5Hz, 2H), 7.46 (s, 2H), 7.21-7.07 (m, 1H), 6.92 (t, J=7.9Hz, 3H), 4.72 (t, J=17.4Hz, 1H), 4.49 (d, J=8.4Hz, 1H), 4.20 (d, J=19.9Hz, 1H), 4.00 (dd, J=18.6,8.9Hz, 1H), 3.88 (dt, J=3.8,1.9Hz, 3H), 3.74-3.63 (m, 3H), 3.62-3.53 (m, 3H), 3.23 (s, 1H), 2.46 (d, J= 9.0Hz,1H),2.16(s,2H),2.00(s,1H)；EI-MS m/z：513[M+H]+。
(2) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-2)
It is identical with the synthetic method of compound (I-a-1), with compound (2-1) (180.0mg, 351.2 μm of ol), LiOH H2O (295.0g, 7.0mmol) is raw material, and white solid 110.0mg, yield 65%, m.p.75-78 DEG C of is obtained by the reaction1H- NMR (300MHz, DMSO-d6) δ 12.45 (br, 2H), 8.16 (d, J=6.9Hz, 1H), 8.08-7.94 (m, 1H), 7.60 (t, J =7.4Hz, 2H), 7.45 (q, J=4.6Hz, 2H), 7.06 (t, J=7.5Hz, 3H), 6.86 (dd, J=11.5,8.2Hz, 1H), 4.49-4.37 (m, 2H), 4.24 (dd, J=17.7,11.6Hz, 1H), 3.92 (t, J=7.8Hz, 1H), 3.84 (s, 3H),3.10(s,1H),2.44-2.35(m,1H),2.45-2.02(m,2H),1.99-1.89(m,1H)；EI-MS m/z：485 [M+H]+。
Embodiment 3：
(4- ((4- acetylamino phenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-3)
The synthesis of 1-3 is same as Example 1
(1) (4- ((4- acetylamino phenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE methyl esters (3-1)
It is identical with the synthetic method of compound (1-4), after compound (1-3) (500mg, 1.67mmol) hydrogenolysis with 4- acetyl Amino phenyl sulfonyl acyl chlorides (468mg, 2mmol), pyridine (404 μ L, 5.01mmol) are raw material, obtain 258mg white solids, yield is 33%, m.p.109-112 DEG C of1H-NMR (300MHz, C) δ 8.17 (d, J=7.8Hz, 1H), 7.84 (d, J=7.8Hz, 1H), 7.62 (d, J=8.5Hz, 2H), 7.56 (s, 1H), 7.48 (d, J=8.6Hz, 2H), 7.39 (s, 2H), 7.11 (d, J= 8.3Hz, 2H), 6.90 (d, J=8.2Hz, 1H), 6.74 (s, 1H), 4.47 (s, 1H), 3.91 (d, J=8.7Hz, 1H), 3.54 (s, 3H), 3.15 (s, 1H), 2.45 (d, J=10.8Hz, 1H), 2.15 (s, 5H), 2.01 (s, 3H)；EI-MS m/z：468[M+ H]+。
(2) (4- ((4- acetylamino phenyls) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-3)
Same compound (I-a-1), with compound (3-1) (120.0mg, 257.0 μm of ol) and LiOHH2O (108.0mg, It is 2.57mmol) raw material, obtains white solid 80.0mg, yield 69%, m.p.122-124 DEG C of1H-NMR(300MHz,DMSO-d6) δ 10.24 (s, 1H), 9.79 (s, 1H), 8.11 (d, J=8.0Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 7.66 (d, J= 8.6Hz, 2H), 7.58 (d, J=8.6Hz, 2H), 7.42 (p, J=6.7Hz, 2H), 6.92 (t, J=6.3Hz, 2H), 4.48 (s, 1H), 3.79 (q, J=7.5Hz, 1H), 3.04 (s, 1H), 2.39 (q, J=8.2Hz, 1H), 2.02 (d, J=22.9Hz, 3H)； EI-MS m/z：454[M+H]+。
Embodiment 4：
(4- ((4- acetylaminohydroxyphenylarsonic acids N- (carboxymethyl) phenyl) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-4)
The synthesis of 1-3 and embodiment 1 are completely the same
(1) (4- ((4- acetamidos-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- dried meat Propylhomoserin methyl esters (4-1)
It is identical with the synthetic method of compound (2-1), with compound (3-1) (120.0mg, 257 μm of ol), potassium carbonate (107.0mg, 0.77mmol) and methyl bromoacetate (47.2mg, 308 μm of ol) are raw material, obtain pale yellow oil 113mg, yield For 82%.1H-NMR (300MHz, C) δ 8.15 (d, J=7.8Hz, 1H), 7.80 (d, J=7.8Hz, 1H), 7.64 (d, J= 8.6Hz, 2H), 7.53 (s, 1H), 7.50 (d, J=8.6Hz, 2H), 7.39 (s, 2H), 7.11 (d, J=8.3Hz, 2H), 6.90 (d, J=8.2Hz, 1H), 6.72 (s, 1H), 4.45 (s, 1H), 4.23 (m, 2H), 3.90 (d, J=8.7Hz, 1H), 3.50 (s, 3H), 3.20 (s, 1H), 2.44 (d, J=10.8Hz, 1H), 2.17 (s, 5H), 2.00 (s, 3H)；EI-MS m/z：540[M+H ]+。
(2) (4- ((4- acetylaminohydroxyphenylarsonic acids N- (carboxymethyl) phenyl) sulfonamido) naphthalene -1- bases)-L-PROLINE (I-a-4)
It is identical with the synthetic method of compound (I-a-1), with compound (4-1) (113.0mg, 210 μm of ol), LiOH H2O (176.4g, 4.2mmol) is raw material, and white solid 90.0mg, yield 73%, m.p.137-141 DEG C of is obtained by the reaction1H- NMR(300MHz,DMSO-d6) δ 12.45 (br, 2H), 8.15 (d, J=7.7Hz, 2H), 7.45 (d, J=7.2Hz, 2H), 7.28 (d, J=7.4Hz, 2H), 7.02 (d, J=6.2Hz, 1H), 6.88 (t, J=9.2Hz, 1H), 6.57 (d, J=8.5Hz, 2H), 6.03 (s, 1H), 4.41 (d, J=8.1Hz, 1H), 4.26 (m, 2H), 3.91 (s, 1H), 3.11 (d, J=14.0Hz, 1H), 2.41(s,1H),2.00(m,3H)；EI-MS m/z：512[M+H]+。
Embodiment 5：
(2S, 4R) -4- (benzyloxy) -1- (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) pyrrolidines -2- formic acid (I-a-6)
The synthesis of 1-2 is same as Example 1
(1) (2S, 4R) -4- (benzyloxy) -1- (4- nitronaphthalene -1- bases) pyrrolidines -2- carboxylate methyl esters (5-1)
Same compound (1-3) synthetic method, with compound (1-2) (1g, 3.11mmol), O- benzyl-trans -4- hydroxyls - L-PROLINE methyl ester hydrochloride (1.01g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol)、Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.80g yellow oils Shape liquid, yield 63%.1H NMR(300MHz,CDCl3) δ 8.84 (ddd, J=8.8,1.3,0.6Hz, 1H), 8.31 (d, J= 8.8Hz, 1H), 8.25-8.18 (m, 1H), 7.69-7.61 (m, 1H), 7.48 (ddd, J=8.4,6.9,1.3Hz, 1H), 6.75 (d, J=8.9Hz, 1H), 4.69 (t, J=7.3Hz, 1H), 4.12 (td, J=9.7,6.2Hz, 1H), 3.62 (s, 3H), 3.61- 3.53(m,1H),2.61-2.49(m,1H),2.25-2.11(m,2H),2.02-1.88(m,1H)；EI-MS m/z：407[M+H ]+。
(2) (2S, 4R) -4- (benzyloxy) -1- (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) pyrrolidines -2- Methyl formate (5-2)
It is identical with the synthetic method of compound (1-4), after compound (5-1) (800mg, 1.97mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (489mg, 2.36mmol), pyridine (476 μ L, 5.91mmol) are raw material, obtain 450mg white solids, yield For 42%, m.p.102-103 DEG C of1H-NMR(300MHz,CDCl3)δ8.17-8.06(m,1H),7.80-7.71(m,1H), 7.63-7.52 (m, 2H), 7.27-7.18 (m, 5H), 7.07 (d, J=8.1Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 6.80- 6.69 (m, 2H), 6.44 (s, 1H), 4.61 (t, J=7.7Hz, 1H), 4.42 (d, J=2.7Hz, 2H), 4.26 (s, 1H), 4.06 (dd, J=10.7,4.7Hz, 1H), 3.72 (s, 3H), 3.46 (s, 3H), 3.24-3.12 (m, 1H), 2.49 (dd, J=13.2, 7.1Hz, 1H), 2.27 (ddd, J=13.4,8.3,5.5Hz, 1H)；EI-MS m/z：547[M+H]+。
(3) (2S, 4R) -4- (benzyloxy) -1- (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) pyrrolidines -2- Formic acid (I-a-5)
It is identical with the synthetic method of compound (I-a-1), with compound (5-2) (200.0mg, 366.0 μm of ol) and LiOH·H2O (154.0mg, 3.66mmol) is raw material, obtains white solid 150.0mg, yield 77%, m.p.100-102 ℃.1H-NMR (300MHz, DMSO-d6) δ 12.41 (br, 1H), 9.76 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 7.96 (d, J=7.9Hz, 1H), 7.60 (d, J=8.5Hz, 2H), 7.40 (d, J=6.8Hz, 2H), 7.27 (d, J=2.1Hz, 5H), 7.00 (d, J=8.8Hz, 2H), 6.91 (q, J=8.2Hz, 2H), 4.58-4.39 (m, 3H), 4.29 (s, 1H), 4.14 (dd, J= 10.6,4.5Hz, 1H), 3.31 (s, 2H), 3.11 (d, J=10.6Hz, 1H), 2.26-2.17 (m, 2H)；EI-MS m/z：533 [M+H]+。
Embodiment 6：
(2S, 4R) -4- (benzyloxy) -1- (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) pyrrole Cough up alkane -2- formic acid (I-a-6)
The synthesis of 5-2 and embodiment 5 are completely the same
(1) (2S, 4R) -4- (benzyloxy) -1- (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulphurs Acylamino-) naphthalene -1- bases) pyrrolidines -2- methyl formates (6-1)
It is identical with the synthetic method of compound (2-1), with compound (5-2) (200.0mg, 366 μm of ol), potassium carbonate (152.0mg, 1.1mmol) and methyl bromoacetate (67.2mg, 439 μm of ol) are raw material, obtain pale yellow oil 183mg, yield For 81%.1H-NMR (300MHz, CDCl3) δ 8.20 (dd, J=9.0,4.5Hz, 1H), 8.12-7.96 (m, 1H), 7.75- 7.65 (m, 2H), 7.54-7.43 (m, 2H), 7.32 (ddd, J=10.5,8.1,2.9Hz, 5H), 7.15 (dd, J=20.3, 8.1Hz, 1H), 6.97-6.83 (m, 3H), 4.78-4.65 (m, 2H), 4.50 (d, J=8.3Hz, 2H), 4.36-4.30 (m, 1H), 4.27-4.15 (m, 2H), 3.87 (s, 3H), 3.67 (d, J=4.4Hz, 3H), 3.60 (d, J=5.1Hz, 3H), 3.35 (dd, J=11.8,9.8Hz, 1H), 2.58 (dd, J=13.0,7.4Hz, 1H), 2.34 (ddd, J=13.0,9.0,5.3Hz, 1H)；EI-MS m/z：619[M+H]+。
(2S, 4R) -4- (benzyloxy) -1- (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) pyrrole Cough up alkane -2- formic acid (I-a-6)
Same compound (I-a-1) method, with compound (6-1) (180.0mg, 295.8 μm of ol), LiOHH2O (248.5g, 5.9mmol) is raw material, reacts to obtain white solid 130.0mg, yield 7%, m.p.107-111 DEG C of1H-NMR (300MHz, DMSO-d6) δ 12.62 (br, 2H), 8.14 (td, J=6.2,5.4,3.3Hz, 1H), 8.08-7.96 (m, 1H), 7.68-7.56 (m, 2H), 7.51-7.41 (m, 2H), 7.27 (dtd, J=18.3,6.2,5.5,3.1Hz, 5H), 7.11-7.02 (m, 3H), 6.85 (t, J=8.2Hz, 1H), 4.60 (d, J=2.8Hz, 1H), 4.53-4.45 (m, 2H), 4.45-4.40 (m, 1H), 4.34-4.24 (m, 2H), 4.24-4.14 (m, 1H), 3.84 (d, J=2.6Hz, 3H), 3.27-3.15 (m, 1H), 2.29- 2.15(m,1H)；EI-MS m/z:591[M+H]+。
Embodiment 7：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-1)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-L-phenylalanine methyl esters (7-1)
Same compound (1-3) method, with compound (1-2) (1g, 3.11mmol), L-phenylalanine methyl ester hydrochloride (0.81g, 3.73mmol), Cs2CO3(2g,6.22mmol)、(±)-BINAP(0.29g,0.47mmol)、Pd2(dba)3 (0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.55g yellow oily liquids, yield 51% .1HNMR(300MHz,CDCl3) δ 8.86 (d, J=8.8Hz, 1H), 8.32 (d, J=8.8Hz, 1H), 7.69 (d, J=8.5Hz, 1H), 7.59-7.50 (m, 1H), 7.38-7.27 (m, 4H), 7.22-7.14 (m, 2H), 6.34 (d, J=8.9Hz, 1H), 6.03 (d, J=7.5Hz, 1H), 4.62 (q, J=6.3Hz, 1H), 3.82 (s, 3H), 3.34 (qd, J=13.7,5.9Hz, 2H)；EI- MS m/z：351[M+H]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine ester methyl ester (7-2)
Same compound (1-4) method, after compound (7-1) (550.0mg, 1.57mmol) hydrogenolysis with 4- methoxybenzene sulphonyl Chlorine (390mg, 1.88mmol), pyridine (380 μ L, 4.71mmol) are raw material, obtain 312mg white solids, yield 41%, m.p.105-108℃.1H-NMR(300MHz,CDCl3) δ 7.91-7.82 (m, 1H), 7.73 (d, J=7.6Hz, 1H), 7.67- 7.58 (m, 2H), 7.47-7.38 (m, 2H), 7.29 (d, J=12.3Hz, 3H), 7.23-7.14 (m, 2H), 7.05 (d, J= 8.1Hz, 1H), 6.89-6.79 (m, 2H), 6.39 (d, J=8.9Hz, 2H), 4.99 (d, J=8.1Hz, 1H), 4.51 (d, J= 7.4Hz, 1H), 3.81 (d, J=3.6Hz, 3H), 3.72 (s, 3H), 3.27 (dd, J=10.4,6.0Hz, 2H)；EI-MS m/z： 491[M+H]+。
(3) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- phenylpropyl alcohols Propylhomoserin methyl esters (7-3)
Same compound (2-1), with compound (7-2) (212.0mg, 432 μm of ol), potassium carbonate (180.0mg, 1.3mmol) It is raw material with methyl bromoacetate (80.0mg, 518 μm of ol), obtains pale yellow oil 110mg, yield 45%.1H-NMR (300MHz,CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 5H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 2H), 6.41-6.28 (m, 1H), 4.72 (d, J=17.3Hz, 1H), 4.50 (d, J=7.9Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.88 (d, J =3.3Hz, 3H), 3.73 (dt, J=13.7,1.7Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.33-3.18 (m, 2H)；EI- MS m/z:563[M+H]+。
(4) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-1)
It is identical with the synthetic method of compound (I-a-1), with compound (7-3) (110.0mg, 195.4 μm of ol), LiOH H2O (380.0g, 9.0mmol) is raw material, and white solid 96.0mg, yield 96%, m.p.120-122 DEG C of is obtained by the reaction1H- NMR (300MHz, DMSO-d6) δ 12.74 (br, 2H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J=17.2,8.4Hz, 2H), 7.40 (dd, J=17.9,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7,7.2Hz, 3H), 7.04 (t, J= 8.1Hz, 2H), 6.93 (dd, J=18.2,8.2Hz, 1H), 6.25 (dd, J=11.8,8.4Hz, 1H), 4.39 (d, J= 17.8Hz, 1H), 4.28-4.08 (m, 2H), 3.82 (d, J=4.5Hz, 3H), 3.27-3.18 (m, 2H)；EI-MS m/z：535 [M+H]+。
Embodiment 8：
(4- ((N- (carboxymethyl) -4- acetylphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-2)
The synthesis of 7-1 is same as Example 7
(1) (4- ((4- acetylphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine ester methyl ester (8-1)
It is identical with the synthetic method of compound (7-2), after compound (7-1) (550.0mg, 1.57mmol) hydrogenolysis with 4- second Acylamino- benzene sulfonyl chloride (390mg, 1.88mmol), pyridine (380 μ L, 4.71mmol) are raw material, obtain 312mg white solids, Yield is 41%, m.p.115-118 DEG C of1H-NMR (300MHz, CDCl3) δ 7.91-7.82 (m, 1H), 7.73 (d, J= 7.8Hz, 1H), 7.67-7.58 (m, 2H), 7.47-7.38 (m, 2H), 7.29 (d, J=12.5Hz, 3H), 7.23-7.14 (m, 2H), 7.05 (d, J=8.1Hz, 1H), 6.89-6.79 (m, 2H), 6.39 (d, J=8.9Hz, 2H), 4.99 (d, J=8.1Hz, 1H), 4.51 (d, J=7.4Hz, 1H), 3.72 (s, 3H), 3.27 (dd, J=10.4,6.0Hz, 2H), 2.02 (s, 3H)；EI-MS m/z：506[M+H]+。
(2) (4- ((4- acetylaminohydroxyphenylarsonic acids N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- benzene Methyl lactamine (8-2)
Same compound (2-1), with compound (8-1) (212.0mg, 412 μm of ol), potassium carbonate (180.0mg, 1.3mmol) It is raw material with methyl bromoacetate (80.0mg, 518 μm of ol), obtains pale yellow oil 160mg, yield 65%.1H-NMR (300MHz, CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 5H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 2H), 6.41-6.28 (m, 1H), 4.72 (d, J=17.3Hz, 1H), 4.50 (d, J=7.9Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.88 (d, J =3.3Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.33-3.18 (m, 2H), 2.00 (s, 3H)；EI-MS m/z：578[M+H ]+。
(3) (4- ((N- (carboxymethyl) -4- acetylamino phenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-2)
It is identical with the synthetic method of compound (I-a-1), with compound (8-2) (110.0mg, 185.4 μm of ol), LiOH H2O (370.0g, 8.7mmol) is raw material, and white solid 96.0mg, yield 94%, m.p.125-128 DEG C of is obtained by the reaction1H- NMR (300MHz, DMSO-d6) δ 12.74 (br, 2H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J=17.2,8.4Hz, 2H), 7.40 (dd, J=17.9,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7,7.2Hz, 3H), 7.04 (t, J= 8.1Hz, 2H), 6.93 (dd, J=18.2,8.2Hz, 1H), 6.25 (dd, J=11.8,8.4Hz, 1H), 4.39 (d, J= 17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.00(s,3H)；EI-MS m/z：550[M+H]+。
Embodiment 9：
(4- ((N- (carboxymethyl) -4- aminomethyl phenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-3)
The synthesis of 7-1 is same as Example 7
(1) (4- ((4- aminomethyl phenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine ester methyl ester (9-1)
It is identical with the synthetic method of compound (7-2), after compound (7-1) (550.0mg, 1.57mmol) hydrogenolysis with 4- first Base benzene sulfonyl chloride (385mg, 1.93mmol), pyridine (395 μ L, 4.88mmol) are raw material, obtain 332mg white solids, yield For 45%, m.p.111-114 DEG C of1H-NMR (300MHz, CDCl3) δ 7.91-7.82 (m, 1H), 7.73 (d, J=7.8Hz, 1H), 7.67-7.58 (m, 2H), 7.47-7.38 (m, 2H), 7.29 (d, J=12.5Hz, 3H), 7.23-7.14 (m, 2H), 7.05 (d, J=8.1Hz, 1H), 6.89-6.79 (m, 2H), 6.39 (d, J=8.9Hz, 2H), 4.99 (d, J=8.1Hz, 1H), 4.51 (d, J=7.4Hz, 1H), 3.72 (s, 3H), 3.27 (dd, J=10.4,6.0Hz, 2H), 2.42 (s, 3H)；EI-MS m/z：475 [M+H]+。
(2) (4- ((4- methyl-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- phenylpropyl alcohol ammonia Sour methyl esters (9-2)
Same compound (2-1) synthetic method, with compound (9-1) (212.0mg, 412 μm of ol), potassium carbonate (180.0mg, 1.3mmol) and methyl bromoacetate (80.0mg, 518 μm of ol) be raw material, give light yellow oil 165mg, yield 65%.1H- NMR (300MHz, CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 5H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 2H), 6.41- 6.28 (m, 1H), 4.72 (d, J=17.3Hz, 1H), 4.50 (d, J=7.9Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.88 (d, J=3.3Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.33-3.18 (m, 2H), 2.40 (s, 3H)；EI-MS m/z:547 [M+H]+。
(3) (4- ((N- (carboxymethyl) -4- aminomethyl phenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-3)
It is identical with the synthetic method of compound (I-a-1), with compound (9-2) (110.0mg, 185.4 μm of ol), LiOH H2O (370.0g, 8.9mmol) is raw material, and white solid 90.0mg, yield 94%, m.p.127-130 DEG C of is obtained by the reaction1H- NMR (300MHz, DMSO-d6) δ 12.74 (br, 2H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J=17.2,8.4Hz, 2H), 7.40 (dd, J=17.9,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7,7.2Hz, 3H), 7.04 (t, J= 8.1Hz, 2H), 6.93 (dd, J=18.2,8.2Hz, 1H), 6.25 (dd, J=11.8,8.4Hz, 1H), 4.39 (d, J= 17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.40(s,3H)；EI-MS m/z：519[M+H]+。
Embodiment 10：
(4- ((N- (carboxymethyl) -2,4,6- trimethylphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b-4)
The synthesis of 7-1 is same as Example 7
(1) (4- ((2,4,6- trimethylphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine ester methyl ester (10-1)
Same compound (7-2) synthetic method, with 2 after compound (7-1) (550.0mg, 1.57mmol) hydrogenolysis, 4,6- front threes Base benzene sulfonyl chloride (395mg, 1.90mmol), pyridine (385 μ L, 4.78mmol) are raw material, obtain 342mg white solids, yield is 44%, m.p.109-112 DEG C of1H-NMR (300MHz, CDCl3) δ 7.91-7.82 (m, 1H), 7.73 (d, J=7.8Hz, 1H), 7.67-7.58 (m, 2H), 7.47-7.38 (m, 2H), 7.29 (d, J=12.0Hz, 1H), 7.23-7.14 (m, 2H), 7.05 (d, J =8.1Hz, 1H), 6.89-6.79 (m, 2H), 6.39 (d, J=8.9Hz, 1H), 4.99 (d, J=8.1Hz, 1H), 4.51 (d, J =7.4Hz, 1H), 3.72 (s, 3H), 3.27 (dd, J=10.4,6.0Hz, 2H), 2.62 (s, 6H), 2.22 (s, 3H)；EI-MS m/z：503[M+H]+。
(2) (4- ((2,4,6- trimethyls-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- Phenyalanine methyl ester (10-2)
Same compound (2-1) synthetic method, with compound (9-1) (212.0mg, 412 μm of ol), potassium carbonate (180.0mg, 1.3mmol) and methyl bromoacetate (80.0mg, 518 μm of ol) be raw material, give light yellow oil 165mg, yield 65%.1H- NMR (300MHz, CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 4H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 1H), 6.41- 6.28 (m, 1H), 4.72 (d, J=17.3Hz, 1H), 4.50 (d, J=7.9Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.88 (d, J=3.3Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.33-3.18 (m, 2H), 2.62 (s, 6H), 2.22 (s, 3H)；EI- MS m/z：575[M+H]+。
(3) (4- ((N- (carboxymethyl) -2,4,6- trimethylphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-b- 4)
It is identical with the synthetic method of compound (I-a-1), with compound (10-2) (110.0mg, 175.6 μm of ol), LiOH·H2O (370.0g, 8.8mmol) is raw material, and white solid 96.0mg, yield 94%, m.p.117-120 is obtained by the reaction ℃.1H-NMR (300MHz, DMSO-d6) δ 12.74 (br, 2H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J=17.2, 8.4Hz, 2H), 7.40 (dd, J=17.9,7.4Hz, 3H), 7.22 (ddt, J=21.4,13.7,7.2Hz, 3H), 7.04 (t, J =8.1Hz, 1H), 6.93 (dd, J=18.2,8.2Hz, 1H), 6.25 (dd, J=11.8,8.4Hz, 1H), 4.39 (d, J= 17.8Hz,1H),4.28-4.08(m,2H),3.27-3.18(m,2H),2.62(s,6H),2.22(s,3H)；EI-MS m/z： 547[M+H]+。
Embodiment 11：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Valine (I-c-1)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-Valine methyl esters (11-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), L-phenylalanine methyl esters Hydrochloride (0.63g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2 (dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.42g yellow oils, yield 45%,1H NMR (300MHz, CDCl3) δ 8.99 (dd, J=8.8,1.2Hz, 1H), 8.43 (d, J=8.9Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 7.73 (ddd, J=8.7,6.9,1.3Hz, 1H), 7.58 (ddd, J=8.3,6.9,1.3Hz, 1H), 6.47 (d, J=8.9Hz, 1H), 5.84 (d, J=8.1Hz, 1H), 4.22 (dd, J=8.1,5.4Hz, 1H), 3.82 (s, 3H), 2.35 (pd, J=6.9,5.4Hz, 1H), 1.18 (d, J=6.9Hz, 3H), 1.08 (d, J=6.8Hz, 3H)；EI-MS m/z： 303[M+H]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Valine ester methyl ester (11-2)
Same compound (1-4) synthetic method, after compound (11-1) (420.0mg, 1.39mmol) hydrogenolysis with 4- methoxyl groups Benzene sulfonyl chloride (345mg, 1.67mmol), pyridine (336 μ L, 4.17mmol) are raw material, obtain 320mg white solids, yield 52%, M.p.95-98 DEG C,1H-NMR (300MHz, CDCl3) δ 7.87 (dt, J=8.2,1.9Hz, 2H), 7.69-7.58 (m, 2H), 7.49-7.36 (m, 2H), 7.04 (dd, J=8.1,1.8Hz, 1H), 6.84 (dt, J=8.9,2.6Hz, 2H), 6.48-6.33 (m, 2H), 4.98 (d, J=8.8Hz, 1H), 4.01 (ddd, J=8.4,5.8,1.9Hz, 1H), 3.82 (d, J=1.9Hz, 3H), 3.75 (d, J=1.9Hz, 3H), 2.33-2.19 (m, 1H), 1.15 (dd, J=6.8,1.9Hz, 3H), 1.07 (dd, J=6.8, 1.9Hz,3H)；EI-MS m/z：442[M+H]+。
(3) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- figured silk fabrics ammonia Sour methyl esters (11-3)
It is identical with the synthetic method of compound (2-1), with compound (11-2) (160.0mg, 362 μm of ol), potassium carbonate (150.0mg, 1.1mmol) and methyl bromoacetate (66.0mg, 518 μm of ol) are raw material, obtain pale yellow oil 120mg, yield For 59%,1H-NMR (300MHz, CDCl3) δ 8.09-7.97 (m, 1H), 7.89 (dt, J=6.4,2.3Hz, 1H), 7.74- 7.64 (m, 2H), 7.55-7.44 (m, 2H), 7.10 (dd, J=13.9,8.2Hz, 1H), 6.92 (ddd, J=8.9,4.8, 2.6Hz, 2H), 6.34 (t, J=7.9Hz, 1H), 5.07 (dd, J=26.6,8.6Hz, 1H), 4.71 (dd, J=17.8, 2.7Hz, 1H), 4.23 (d, J=17.8Hz, 1H), 4.02 (ddd, J=11.0,8.6,5.7Hz, 1H), 3.87 (d, J= 1.8Hz, 3H), 3.76 (d, J=16.4Hz, 3H), 3.66 (s, 3H), 1.11 (ddd, J=26.3,11.7,6.8Hz, 6H)；EI- MS m/z：563[M+H]+。
(4) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Valine (I-c-1)
It is identical with the synthetic method of compound (I-a-1), with compound (12-3) (120.0mg, 247.0 μm of ol), LiOH·H2O (207.0mg, 4.9mmol) is raw material, and white solid 98.0mg, yield 82%, m.p.199- is obtained by the reaction 201℃.1H-NMR (300MHz, DMSO-d6) δ 12.63 (br, 2H), 8.32 (dt, J=7.3,3.6Hz, 1H), 7.97 (ddd, J =17.8,6.6,3.6Hz, 1H), 7.66-7.56 (m, 2H), 7.45 (dq, J=6.6,3.6,2.6Hz, 2H), 7.06 (d, J= 8.5Hz, 2H), 6.95 (dd, J=13.8,8.5Hz, 1H), 6.31 (t, J=9.0Hz, 1H), 6.23 (t, J=9.0Hz, 1H), 4.40 (dd, J=17.7,5.1Hz, 1H), 4.21 (dd, J=17.7,9.1Hz, 1H), 3.83 (s, 3H), 3.75-3.67 (m, 1H), 2.28 (q, J=7.2,6.7Hz, 1H), 1.14-0.97 (m, 6H)；EI-MS m/z：459[M+H]+。
Embodiment 12：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Isoleucine (I-c-1)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-l-Isoleucine methyl esters (12-1)
Same compound (1-3) method, with compound (1-2) (1g, 3.11mmol), L-Leu methyl ester hydrochloride (0.68g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2(dba)3 (0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.66g yellow oily liquids, yield 67%,1H NMR (300MHz, CDCl3) δ 9.00 (d, J=8.8Hz, 1H), 8.44 (d, J=8.9Hz, 1H), 7.94 (d, J=8.5Hz, 1H), 7.74 (ddd, J=8.6,7.0,1.3Hz, 1H), 7.59 (ddd, J=8.3,6.9,1.4Hz, 1H), 6.47 (d, J= 8.9Hz, 1H), 5.88 (d, J=8.0Hz, 1H), 4.31 (dd, J=7.9,5.3Hz, 1H), 3.82 (s, 3H), 2.10 (s, 1H), 1.73 (ddd, J=13.0,7.5,5.3Hz, 1H), 1.45 (dt, J=14.7,7.6Hz, 1H), 1.16-0.96 (m, 6H)；EI- MS m/z：317[M+H]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Isoleucine ester methyl ester (12-2)
It is identical with the synthetic method of compound (1-4), after compound (12-1) (660.0mg, 2.09mmol) hydrogenolysis with 4- Methoxybenzenesulfonyl chloride (519mg, 2.51mmol), pyridine (505 μ L, 6.27mmol) are raw material, obtain 465mg white solids, Yield is 49%, m.p.105-107 DEG C,1H NMR(300MHz,CDCl3)δ7.89-7.82(m,2H),7.67-7.61(m, 2H), 7.43 (ddd, J=7.3,4.9,1.7Hz, 2H), 7.07-7.02 (m, 1H), 6.88-6.80 (m, 2H), 6.44-6.35 (m, 2H), 5.01 (s, 1H), 4.11 (d, J=5.9Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.03 (q, J=6.9Hz, 2H), 1.73 (ddd, J=12.4,7.4,4.7Hz, 1H), 1.47-1.38 (m, 1H), 1.06-0.97 (m, 6H)；EI-MS m/z： 457[M+H]+。
(3) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- is different bright Propylhomoserin methyl esters (12-3)
Same compound (2-1) method, with compound (12-2) (300.0mg, 568 μm of ol), potassium carbonate (218.0mg, 1.7mmol) and methyl bromoacetate (104.3mg, 682 μm of ol) is raw material, obtains faint yellow solid 300mg, yield 84%, M.p.124-127 DEG C,1H NMR(300MHz,CDCl3)δ8.07-7.97(m,1H),7.89-7.80(m,1H),7.74-7.64 (m, 2H), 7.49 (dt, J=6.9,3.1Hz, 2H), 7.10 (dd, J=11.4,8.2Hz, 1H), 6.98-6.86 (m, 2H), 6.34 (dd, J=8.3,5.4Hz, 1H), 5.10 (d, J=27.8Hz, 1H), 4.71 (dd, J=17.8,3.5Hz, 1H), 4.23 (d, J=17.8Hz, 1H), 4.11 (s, 1H), 3.87 (d, J=1.9Hz, 3H), 3.76 (d, J=16.3Hz, 3H), 3.67 (s, 3H), 2.01 (s, 1H), 1.81-1.67 (m, 1H), 1.41 (dd, J=14.6,7.3Hz, 1H), 1.02 (ddt, J=12.4, 7.5,3.9Hz,6H)；EI-MS m/z：528[M+H]+。
(4) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Isoleucine (I-c-1)
Same compound (I-a-1) synthetic method, with compound (12-3) (300.0mg, 600.0 μm of ol), LiOHH2O (504.0mg, 12.0mmol) is raw material, reacts to obtain white solid 230.0mg, yield 73%, m.p.>250℃.1HNMR (300MHz, DMSO-d6) δ 12.65 (br, 2H), 8.43-8.26 (m, 1H), 8.04-7.89 (m, 1H), 7.60 (dt, J=8.8, 6.6Hz, 2H), 7.49-7.34 (m, 2H), 7.12-7.02 (m, 2H), 6.97 (t, J=8.6Hz, 1H), 6.45 (dd, J= 10.5,7.5Hz, 1H), 6.24 (dd, J=8.5,4.6Hz, 1H), 4.41 (dd, J=17.6,4.0Hz, 1H), 4.28-4.14 (m,1H),4.02(s,1H),3.83(s,3H),2.06-1.75(m,2H),1.73-1.52(m,1H),1.09-0.71(m,6H) .EI-MS m/z：501[M+H]+。
Embodiment 13：
(S) -2- ((4- ((N- (naphthalene -1- bases carboxymethyl) -4- methoxyphenyls) sulfonamido)) amino) -3- (4- chlorobenzenes Base) propionic acid (I-c-3)
The synthesis of 1-2 is same as Example 1
(1) (S) -3- (4- chlorphenyls) -2- ((4- nitronaphthalene -1- bases) amino) methyl propionate (13-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), (S) -2- amino -3- (4- chlorphenyls) propionate hydrochloride (0.93g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol)、Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 1.0g yellow oils Shape liquid, yield 84%.1H-NMR (300MHz, CDCl3) δ 8.95 (d, J=8.7Hz, 1H), 8.40 (d, J=8.8Hz, 1H), 7.77 (d, J=8.5Hz, 1H), 7.70 (t, J=7.8Hz, 1H), 7.52 (t, J=7.7Hz, 1H), 7.24 (s, 2H), 7.04 (d, J=7.9Hz, 2H), 6.45 (d, J=8.8Hz, 1H), 5.86 (d, J=7.3Hz, 1H), 4.67 (q, J=5.9Hz, 1H), 3.82 (s, 3H), 3.30 (qd, J=13.9,5.4Hz, 2H)；EI-MS m/z：385[M+H]+。
(2) (S) -3- (4- chlorphenyls) -2- ((4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) propionic acid first Ester (13-2)
It is identical with the synthetic method of compound (1-4), after compound (13-1) (1.0g, 2.60mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (646mg, 3.12mmol), pyridine (628 μ L, 7.8mmol) are raw material, obtain 550mg white solids, yield 40%, m.p.104-108 DEG C of1H-NMR (300MHz, CDCl3) δ 7.87 (dt, J=7.7,2.6Hz, 1H), 7.73 (dt, J= 7.9,2.7Hz, 1H), 7.67-7.58 (m, 2H), 7.46-7.38 (m, 2H), 7.26 (dd, J=7.2,1.4Hz, 2H), 7.13- 7.01 (m, 3H), 6.88-6.77 (m, 2H), 6.50 (s, 1H), 6.39 (d, J=8.2Hz, 1H), 5.01 (d, J=7.8Hz, 1H), 4.51 (q, J=6.3Hz, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.23 (qd, J=13.7,5.7Hz, 2H)；EI-MS m/z：525[M+H]+。
(3) (S) -3- (4- chlorphenyls) -2- ((4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulphonyl Amino) naphthalene -1- bases) amino) methyl propionate (13-3)
It is identical with the synthetic method of compound (2-1), with compound (13-2) (330.0mg, 629 μm of ol), potassium carbonate (260.8mg, 1.89mmol) and methyl bromoacetate (115.5mg, 755 μm of ol) are raw material, obtain pale yellow oil 300mg, are produced Rate is 80%.1H-NMR(300MHz,CDCl3)δ8.10-7.97(m,1H),7.79-7.74(m,1H),7.73-7.63(m, 2H), 7.55-7.44 (m, 2H), 7.30 (d, J=8.3Hz, 1H), 7.24 (d, J=8.4Hz, 1H), 7.18-7.04 (m, 3H), 6.95-6.87 (m, 2H), 6.41-6.29 (m, 1H), 5.09 (s, 1H), 4.72 (dd, J=17.8,6.4Hz, 1H), 4.50 (dt, J=12.1,5.7Hz, 1H), 4.24 (dd, J=17.8,3.8Hz, 1H), 3.87 (d, J=4.0Hz, 3H), 3.77-3.70 (m, 3H), 3.67 (d, J=6.5Hz, 3H), 3.31-3.16 (m, 2H)；EI-MS m/z：597[M+H]+。
(4) (S) -2- ((4- ((N- (naphthalene -1- bases carboxymethyl) -4- methoxyphenyls) sulfonamido)) amino) -3- (4- chlorine Phenyl) propionic acid (I-c-3)
It is identical with the synthetic method of compound (I-a-1), with compound (13-3) (300.0mg, 503.2 μm of ol), LiOH·H2O (422.7mg, 10.1mmol) is raw material, and white solid 270.0mg, yield 94%, m.p.131- is obtained by the reaction 133℃.1H-NMR (300MHz, DMSO-d6) δ 12.77 (s, 2H), 8.26 (q, J=5.5Hz, 1H), 7.94 (ddd, J= 14.3,6.7,2.7Hz, 1H), 7.65-7.53 (m, 2H), 7.43 (ddd, J=12.1,9.3,7.5Hz, 4H), 7.36-7.25 (m, 2H), 7.08-7.00 (m, 2H), 6.93 (dd, J=17.4,8.3Hz, 1H), 6.59 (t, J=9.8Hz, 1H), 6.26 (dd, J=11.7,8.5Hz, 1H), 4.39 (dd, J=17.7,2.1Hz, 1H), 4.20 (dt, J=20.8,13.0Hz, 2H), 3.83 (d, J=4.1Hz, 3H), 3.23 (dq, J=14.6,9.2,7.5Hz, 2H)；EI-MS m/z：569[M+H]+。
Embodiment 14：
(S) -2- ((4- ((N- (naphthalene -1- bases carboxymethyl) -4- methoxyphenyls) sulfonamido)) amino) -3- (4- methoxies Base phenyl) propionic acid (I-c-4)
The synthesis of 1-2 is same as Example 1
(1) (S) -3- (4- methoxyphenyls) -2- ((4- nitronaphthalene -1- bases) amino) methyl propionate (14-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), (S) -2- amino -3- (4- methoxyphenyls) propionate hydrochloride (0.92g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, are obtained 1.0g yellow oily liquids, yield 85%.1H-NMR (300MHz, CDCl3) δ 8.99 (dd, J=8.9,1.2Hz, 1H), 8.43 (d, J=8.8Hz, 1H), 7.80 (d, J=8.5Hz, 1H), 7.73 (ddd, J=8.5,6.8,1.3Hz, 1H), 7.56 (ddd, J=8.5,5.3,1.5Hz, 1H), 7.07-7.02 (m, 2H), 6.86-6.82 (m, 2H), 6.46 (d, J=8.8Hz, 1H), 5.81 (d, J=7.1Hz, 1H), 4.65 (dt, J=7.5,5.5Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.36- 3.29(m,1H),3.27-3.20(m,1H)；EI-MS m/z：381[M+H]+。
(2) (S) -3- (4- methoxyphenyls) -2- ((4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) third Sour methyl esters (14-2)
The synthetic method of same compound (1-4), after compound (14-1) (1.0g, 2.63mmol) hydrogenolysis with 4- methoxybenzenes Sulfonic acid chloride (653mg, 3.16mmol), pyridine (636 μ L, 7.89mmol) are raw material, obtain 800mg white solids, yield 58%, m.p.82-85℃.1H-NMR (300MHz, CDCl3) δ 7.89-7.83 (m, 1H), 7.73 (dt, J=5.1,3.3Hz, 1H), 7.65-7.60 (m, 2H), 7.44-7.39 (m, 2H), 7.12-7.08 (m, 2H), 7.04 (d, J=8.1Hz, 1H), 6.85 (d, J =2.5Hz, 2H), 6.82 (d, J=2.8Hz, 2H), 6.44-6.36 (m, 2H), 4.98 (d, J=7.7Hz, 1H), 4.47 (t, J =6.5Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H), 3.21 (dd, J=10.6,5.8Hz, 2H)；EI-MS m/z：521[M+H]+。
(3) (S) -2- ((4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases) Amino) -3- (4- methoxyphenyls) methyl propionate (14-3)
It is identical with the synthetic method of compound (2-1), with compound (14-2) (600.0mg, 1154 μm of ol), potassium carbonate (180.0mg, 3.46mmol) and methyl bromoacetate 211.8mg, 1385 μm of ol) it is raw material, pale yellow oil 600mg is obtained, is produced Rate is 92%.1H-NMR (300MHz, CDCl3) δ 8.09-7.96 (m, 1H), 7.77-7.72 (m, 1H), 7.67 (dd, J=8.8, 5.5Hz, 2H), 7.54-7.42 (m, 2H), 7.16-7.04 (m, 3H), 6.95-6.80 (m, 4H), 6.34 (dd, J=17.6, 8.2Hz, 1H), 4.71 (dd, J=17.8,5.3Hz, 1H), 4.46 (dt, J=11.2,5.8Hz, 1H), 4.24 (dd, J= 17.8,2.8Hz, 1H), 3.87 (d, J=4.1Hz, 3H), 3.80 (d, J=8.1Hz, 3H), 3.73 (d, J=13.0Hz, 3H), 3.67 (d, J=5.2Hz, 3H), 3.27-3.15 (m, 2H)；EI-MS m/z：563[M+H]+。
(4) (S) -2- ((4- ((N- (naphthalene -1- bases carboxymethyl) -4- methoxyphenyls) sulfonamido)) amino) -3- (4- first Phenyl) propionic acid (I-c-4)
It is identical with the synthetic method of compound (I-a-1), with compound (14-3) (120.0mg, 213.1 μm of ol), LiOH·H2O (179.0g, 4.3mmol) is raw material, and white solid 100.0mg, yield 83%, m.p. is obtained by the reaction>250 ℃.1H-NMR(300MHz,DMSO-d6)δ12.74(br,2H),8.26(s,1H),7.96(s,1H),7.66-7.52(m,2H), 7.43 (dd, J=6.9,2.9Hz, 2H), 7.39-7.24 (m, 2H), 7.04 (t, J=8.4Hz, 2H), 6.98-6.76 (m, 3H), 6.54 (s, 1H), 6.23 (dd, J=13.2,8.5Hz, 1H), 4.38 (dd, J=17.8,2.2Hz, 1H), 4.17 (dd, J= 21.2,17.7Hz, 2H), 3.82 (d, J=4.4Hz, 3H), 3.73-3.63 (m, 3H), 3.16 (s, 2H)；EI-MS m/z：565 [M+H]+。
Embodiment 15：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-methionine (I-c-5)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-l-methionine methyl esters (15-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), l-methionine methyl esters Hydrochloride (0.75g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2 (dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.48g yellow oily liquids, yield 46%,1H-NMR(300MHz,CDCl3) δ 8.94 (dd, J=8.7,1.2Hz, 1H), 8.40 (d, J=8.8Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.69 (ddd, J=8.6,6.9,1.2Hz, 1H), 7.53 (ddd, J=8.3,6.8,1.2Hz, 1H), 6.51 (d, J=8.9Hz, 1H), 6.13 (d, J=7.6Hz, 1H), 4.59 (q, J=6.5Hz, 1H), 3.85 (s, 3H), 2.68 (td, J =6.8,2.5Hz, 2H), 2.31 (ddq, J=21.2,14.3,7.2Hz, 2H), 2.14 (s, 3H)；EI-MS m/z：335[M+H ]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-methionine ester methyl ester (15-2)
Same compound (1-4) synthetic method, after compound (15-1) (480.0mg, 1.44mmol) hydrogenolysis with 4- methoxyl groups Benzene sulfonyl chloride (357mg, 1.72mmol), pyridine (348 μ L, 4.32mmol) are raw material, obtain 220mg white solids, yield 30%, m.p.98-101℃.1H-NMR(300MHz,CDCl3) δ 7.88 (td, J=7.2,3.2Hz, 2H), 7.63 (d, J=2.1Hz, 1H), 7.61 (d, J=2.1Hz, 1H), 7.44-7.36 (m, 2H), 7.01 (d, J=8.1Hz, 1H), 6.82 (d, J=3.8Hz, 2H), 6.79 (d, J=2.1Hz, 1H), 6.39 (d, J=8.2Hz, 1H), 5.17 (d, J=7.9Hz, 1H), 4.39 (q, J= 6.8Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 2.68 (t, J=7.1Hz, 2H), 2.29-2.15 (m, 2H), 2.11 (s, 3H)；EI-MS m/z：475[M+H]+。
(3) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- first sulphur Propylhomoserin methyl esters (15-3)
Same compound (2-1), with compound (15-2) (110.0mg, 230 μm of ol), potassium carbonate (95.4mg, 0.69mmol) It is raw material with methyl bromoacetate (42.2mg, 276 μm of ol), obtains pale yellow oil 100mg, yield 80%.1H-NMR (300MHz,CDCl3) δ 8.96 (dd, J=8.7,1.2Hz, 1H), 8.42 (d, J=8.8Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.69 (ddd, J=8.7,6.9,1.2Hz, 1H), 7.53 (ddd, J=8.3,6.8,1.2Hz, 1H), 6.55 (d, J= 8.8Hz, 1H), 6.23 (d, J=7.6Hz, 1H), 4.45 (dd, J=17.7,3.8Hz, 1H), 4.19 (dd, J=17.7, 12.0Hz, 2H), 3.81 (s, 3H), 2.68 (td, J=6.8,2.5Hz, 2H), 2.31 (ddq, J=21.4,14.5,7.2Hz, 2H),2.14(s,3H)；EI-MS m/z：547[M+H]+。
(4) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-methionine (I-c-5)
Same compound (I-a-1) method, with compound (15-3) (100.0mg, 183.0 μm of ol), LiOHH2O (153.0mg, 3.7mmol) is raw material, reacts to obtain white solid 75.0mg, yield 79%, m.p.95-98 DEG C,1H-NMR (300MHz, DMSO-d6) δ 12.72 (br, 2H), 8.37-8.24 (m, 1H), 7.97 (ddd, J=16.3,7.0,3.6Hz, 1H), 7.61 (dd, J=9.7,7.9Hz, 2H), 7.45 (dt, J=6.6,3.6Hz, 2H), 7.11-7.02 (m, 2H), 6.96 (dd, J= 12.8,8.2Hz, 1H), 6.51 (d, J=8.2Hz, 1H), 6.26 (q, J=8.4Hz, 1H), 4.41 (dd, J=17.7,3.8Hz, 1H), 4.21 (dd, J=17.7,12.0Hz, 2H), 3.84 (s, 3H), 2.74-2.56 (m, 2H), 2.33-2.07 (m, 2H), 2.06 (d, J=10.0Hz, 3H)；EI-MS m/z：519[M+H]+。
Embodiment 16：
(S) -2- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -4- (first sulfo group) Butyric acid (I-c-6)
The synthesis of 15-3 is identical with embodiment 15
(S) -2- ((4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases) ammonia Base) -4- (methyl sulfo group) methyl butyrate (16-1)
Compound (15-3) (400.0mg, 0.8mmol) is dissolved in dichloromethane dropwise addition m-chloro peroxide benzene first under condition of ice bath The dichloromethane dilution of sour (152mg, 0.88mmol), TlC are monitored after reaction, and white solid is obtained through column chromatography 0.2g, yield 43%.1H-NMR (300MHz, CDCl3) δ 8.96 (dd, J=8.7,1.2Hz, 1H), 8.42 (d, J= 8.8Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.69 (ddd, J=8.7,6.9,1.2Hz, 1H), 7.53 (ddd, J=8.3, 6.8,1.2Hz, 1H), 6.55 (d, J=8.8Hz, 1H), 6.23 (d, J=7.6Hz, 1H), 5.23 (m, 1H), 4.66 (dd, J= 17.7,3.8Hz, 1H), 4.43 (m, 1H) 4.19 (dd, J=17.7,12.0Hz, 1H), 3.81-3.64 (m, 9H), 3.22 (m, 2H), 2.88-2.95 (m, 3H), 2.38 (ddq, J=21.4,14.5,7.2Hz, 2H)；EI-MS m/z：579[M+H]+。
(2) (S) -2- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -4- (first sulphurs Base) butyric acid (I-c-6)
It is identical with the synthetic method of compound (I-a-1), with compound (16-1) (200.0mg, 346 μm of ol), LiOH H2O (290.0mg, 6.9mmol) is raw material, is obtained by the reaction white solid 125.0mg, yield 52%, m.p.98-102 DEG C,1H- NMR (300MHz, DMSO-d6) δ 12.72 (br, 2H), 8.37-8.24 (m, 1H), 7.97 (ddd, J=16.3,7.0,3.6Hz, 1H), 7.61 (dd, J=9.7,7.9Hz, 2H), 7.45 (dt, J=6.6,3.6Hz, 2H), 7.11-7.02 (m, 2H), 6.96 (dd, J=12.8,8.2Hz, 1H), 6.51 (d, J=8.2Hz, 1H), 6.26 (q, J=8.4Hz, 1H), 4.41 (dd, J= 17.7,3.8Hz, 1H), 4.21 (dd, J=17.7,12.0Hz, 2H), 3.84 (s, 3H), 3.32 (m, 2H), 2.95 (m, 3H), 2.38 (ddq, J=21.4,14.5,7.2Hz, 2H)；EI-MS m/z：551[M+H]+。
Embodiment 17：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Serine (I-c-7)
The synthesis of 1-2 is same as Example 1
(1) O- benzyls-N- (4- nitronaphthalene -1- bases)-Serine methyl esters (17-1)
It is identical with the synthetic method of compound (1-3), with-L- compound (1-2) (2g, 6.22mmol), O- benzyls ammonia Acid methyl ester hydrochloride salt (1.54g, 7.46mmol), Cs2CO3(4g, 12.44mmol), (±)-BINAP (0.58g, 0.94mmol), Pd2(dba)3(0.28g, 0.32mmol), DIPEA (2.2ml, 12.44mmol) are raw material, obtain 1.40g yellow oily liquids, Yield is 59%,1H-NMR (300MHz, CDCl3) δ 8.98 (d, J=8.8Hz, 1H), 8.38 (d, J=8.8Hz, 1H), 7.90 (d, J=8.5Hz, 1H), 7.73 (ddd, J=8.6,6.9,1.3Hz, 1H), 7.57 (ddd, J=8.4,6.9,1.4Hz, 1H), 7.36-7.27 (m, 5H), 6.35 (d, J=8.8Hz, 1H), 6.15 (d, J=7.7Hz, 1H), 4.61 (d, J=1.4Hz, 2H), 4.50 (dt, J=7.5,3.6Hz, 1H), 4.08-3.93 (m, 2H), 3.82 (s, 3H)；EI-MS m/z：381[M+H]+。
(2) O- benzyls-N- (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Serine methyl esters (17-2)
It is identical with the synthetic method of compound (1-4), after compound (24-1) (1.4g, 3.68mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (914mg, 4.42mmol), pyridine (889 μ L, 11.04mmol) are raw material, obtain 1.2g gray solids, yield For 63%, m.p.94-97 DEG C,1H-NMR (300MHz, CDCl3) δ 7.86 (ddd, J=9.8,7.1,2.2Hz, 2H), 7.65- 7.58 (m, 2H), 7.45-7.37 (m, 2H), 7.37-7.30 (m, 5H), 7.02 (d, J=8.1Hz, 1H), 6.83-6.77 (m, 2H), 6.74 (s, 1H), 6.30 (d, J=8.2Hz, 1H), 5.37 (d, J=7.4Hz, 1H), 4.60 (d, J=3.1Hz, 2H), 4.37 (p, J=3.9Hz, 1H), 3.95 (qd, J=9.4,3.9Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H)；EI-MS m/z： 521[M+H]+。
(3) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Serine methyl esters (17-3)
Compound (17-2) (0.8g, 1.58mmol) is dissolved in a small amount of THF, adds the methanol of 30ml, is added in time H in 10% palladium carbon (168mg, 0.16mol) load2Ball makes it in H250 DEG C of heating reactions in environment.The reaction was complete for TLC monitorings (10h) removes palladium carbon through diatomite drainage, directly system sand, and gray solid 0.5g is obtained through column chromatography, yield 77%, M.p.110-113 DEG C,1H-NMR(300MHz,CDCl3)δ7.92-7.82(m,2H),7.64-7.58(m,2H),7.44-7.35 (m, 2H), 6.99 (d, J=8.1Hz, 1H), 6.83-6.77 (m, 3H), 6.35 (d, J=8.2Hz, 1H), 5.42 (s, 1H), 4.31 (d, J=3.8Hz, 1H), 4.07 (d, J=3.8Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H)；EI-MS m/z：431[M +H]+。
(4) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- ammonia Sour methyl esters (17-4)
It is identical with the synthetic method of compound (2-1), with compound (17-3) (200.0mg, 465 μm of ol), potassium carbonate (193.0mg, 1.4mmol) and methyl bromoacetate (85.4mg, 558 μm of ol) are raw material, obtain pale yellow oil 190mg, yield For 81%,1H-NMR(300MHz,CDCl3) δ 8.03 (ddd, J=9.8,6.8,2.2Hz, 1H), 7.94 (dt, J=6.4, 2.1Hz, 1H), 7.67 (dd, J=9.0,2.9Hz, 2H), 7.54-7.45 (m, 2H), 7.13 (t, J=8.5Hz, 1H), 6.90 (dd, J=9.1,2.7Hz, 2H), 6.39 (t, J=7.8Hz, 1H), 5.52 (s, 1H), 4.71 (dd, J=17.8,1.9Hz, 1H), 4.35 (s, 1H), 4.24 (d, J=17.8Hz, 1H), 4.07 (d, J=10.3Hz, 2H), 3.87 (d, J=1.2Hz, 3H), 3.84 (d, J=13.0Hz, 3H), 3.66 (s, 3H)；EI-MS m/z：503[M+H]+。
(5) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-Serine (I-c-7)
It is identical with the synthetic method of compound (I-a-1), with compound (17-4) (190mg, 378.0 μm of ol), LiOH H2O (318.0mg, 7.6mmol) is raw material, is obtained by the reaction white solid 143.0mg, yield 80%, m.p.136-139 DEG C,1H-NMR(300MHz,DMSO-d6) δ 12.76 (s, 2H), 8.20 (s, 1H), 8.00 (d, J=16.9Hz, 1H), 7.69-7.54 (m, 2H), 7.47 (s, 2H), 7.07 (s, 2H), 7.01-6.88 (m, 1H), 6.29 (s, 1H), 6.21 (s, 1H), 4.42 (d, J= 18.5Hz, 1H), 4.26 (d, J=15.1Hz, 1H), 4.17 (s, 1H), 3.92 (s, 2H), 3.84 (s, 3H)；EI-MS m/z： 475[M+H]+。
Embodiment 18：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-Aspartic acid (I-c-8)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-L-Aspartic acid dimethyl ester (18-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), L-Aspartic acid diformazan Ester hydrochloride (0.74g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2 (dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.65g yellow oily liquids, yield For 63%,1H-NMR (300MHz, CDCl3) δ 9.01-8.91 (m, 1H), 8.41 (d, J=8.8Hz, 1H), 7.94 (d, J= 8.7Hz, 1H), 7.72 (ddd, J=8.6,6.9,1.3Hz, 1H), 7.57 (ddd, J=8.4,6.8,1.3Hz, 1H), 6.50 (d, J=8.9Hz, 1H), 6.39 (d, J=7.6Hz, 1H), 4.71 (dt, J=7.6,4.9Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.08 (qd, J=16.5,5.0Hz, 2H)；EI-MS m/z：333[M+H]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-Aspartic acid dimethyl ester (18-2)
It is identical with the synthetic method of compound (1-4), after compound (18-1) (650.0mg, 1.96mmol) hydrogenolysis with 4- Methoxybenzenesulfonyl chloride (487mg, 2.35mmol), pyridine (474 μ L, 5.88mmol) are raw material, obtain 230mg white solids, Yield is 25%, m.p.147-150 DEG C,1H-NMR(300MHz,CDCl3)δ7.90-7.84(m,2H),7.66-7.60(m, 2H), 7.42 (ddt, J=6.6,4.2,2.2Hz, 2H), 7.06 (d, J=8.1Hz, 1H), 6.83 (d, J=8.9Hz, 2H), 6.61 (s, 1H), 6.42 (d, J=8.2Hz, 1H), 5.46 (d, J=7.8Hz, 1H), 4.58 (dt, J=7.6,5.4Hz, 1H), 3.81(s,3H),3.80(s,3H),3.73(s,3H),3.07-2.93(m,2H)；EI-MS m/z：473[M+H]+。
(3) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-Aspartic acid (I-c-8)
It is identical with the synthetic method of compound (I-a-1), with compound (18-2) (100.0mg, 212.0 μm of ol) and LiOH·H2O (89.0mg, 2.12mmol) is raw material, obtains gray solid 81.0mg, yield 86%, m.p.160-163 DEG C,1H- NMR(300MHz,DMSO-d6) δ 12.55 (br, 1H), 9.47 (s, 1H), 8.04 (d, J=7.9Hz, 1H), 7.81 (d, J= 7.8Hz, 1H), 7.48 (d, J=8.5Hz, 2H), 7.30 (d, J=7.7Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 6.72 (d, J=8.2Hz, 1H), 6.26 (d, J=8.3Hz, 1H), 4.33 (s, 1H), 3.70 (s, 3H), 2.79 (d, J=6.4Hz, 2H)； EI-MS m/z：445[M+H]+。
(4) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- asparagus ferns Propylhomoserin dimethyl ester (18-3)
It is identical with the synthetic method of compound (2-1), with compound (18-3) (100.0mg, 250 μm of ol), potassium carbonate (103.7mg, 0.75mmol) and methyl bromoacetate (54.4mg, 300 μm of ol) are raw material, obtain pale yellow oil 100mg, yield For 84%,1H-NMR (300MHz, CDCl3) δ 8.03 (s, 1H), 7.88 (d, J=7.9Hz, 1H), 7.68 (dd, J=8.5, 6.0Hz, 2H), 7.54-7.47 (m, 2H), 7.13 (dd, J=8.1,5.0Hz, 1H), 6.92 (dd, J=9.0,4.6Hz, 3H), 6.44-6.36 (m, 1H), 4.71 (dd, J=17.6,2.3Hz, 1H), 4.59 (d, J=5.6Hz, 1H), 4.24 (d, J= 17.8Hz, 1H), 3.88 (d, J=2.3Hz, 3H), 3.81 (d, J=13.9Hz, 3H), 3.74 (d, J=12.6Hz, 3H), 3.67 (d, J=1.7Hz, 3H), 3.01 (s, 2H)；EI-MS m/z：545[M+H]+。
Embodiment 19：
(4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-d-1)
The synthesis of 7-2 and embodiment 7 are completely the same
(3) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-d-1)
It is identical with the synthetic method of compound (I-a-1), with compound (7-2) (100.0mg, 204.1 μm of ol) and LiOH·H2O (86.0mg, 2.04mmol) is raw material, obtains white solid 78.0mg, yield 90%, m.p.111-115 DEG C .1H-NMR (300MHz, DMSO-d6) δ 12.79 (br, 1H), 9.53 (s, 1H), 8.24-8.16 (m, 1H), 7.87 (dd, J= 7.7,2.0Hz, 1H), 7.59-7.51 (m, 2H), 7.44-7.33 (m, 4H), 7.26 (dd, J=8.2,6.6Hz, 2H), 7.21- 7.13 (m, 1H), 7.03-6.94 (m, 2H), 6.75 (d, J=8.2Hz, 1H), 6.38 (s, 1H), 6.24 (d, J=8.4Hz, 1H),4.21(s,1H),3.78(s,3H),3.24-3.15(m,2H)；EI-MS m/z：477[M+H]+。
Embodiment 20：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-d-2)
The synthesis of 7-2 and embodiment 7 are completely the same
(1) (4- ((N- (cyano methyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine methyl esters (20-1)
Same compound (2-1) synthetic method, with compound (7-2) (200.0mg, 408 μm of ol), potassium carbonate (166.0mg, 1.2mmol) and bromoacetonitrile (58.8mg, 490 μm of ol) is raw material, obtains grey grease 198mg, yield 92%.1H-NMR (300MHz, CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 5H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 2H), 6.41-6.28 (m, 1H), 4.92 (d, J=17.8Hz, 1H), 4.50 (d, J=7.9Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.88 (d, J =3.3Hz, 3H), 3.73 (dt, J=13.7,1.7Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.33-3.18 (m, 2H)；EI- MS m/z：530[M+H]+。
(2) (4- ((N- ((2H- tetrazolium -5- bases) methyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L- phenyl Alanine (I-d-2)
Compound (20-1) (198.0mg, 374 μm of ol) is dissolved in 5.0ml DMF, addition sodium azide (56mg, 1.1mmol), ammonium chloride (80.0mg, 1.5mmol) is eventually adding, is heated to flowing back.TLC monitorings the reaction was complete (about 5h), Xiang Rong Water is added in liquid, there is solid precipitation, is filtered, solid is dissolved with EA, is washed 3 times with 3mol/L sodium hydroxide solutions, separate water layer, Water layer is washed 2 times with a small amount of EA, with hydrochloric acid tune pH to 2, there is a solid precipitation, suction filtration dry light yellow solid 88mg, yield are 40%, m.p.>250℃.1H-NMR(300MHz,DMSO-d6)δ12.54(br,2H),8.26(s,1H),7.95(s,1H), 7.60 (dd, J=17.2,8.4Hz, 2H), 7.40 (dd, J=17.5,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7, 7.2Hz, 3H), 7.04 (t, J=8.1Hz, 2H), 6.93 (dd, J=18.2,8.2Hz, 1H), 6.25 (dd, J=11.8, 8.4Hz,1H),5.00-5.12(m,2H),4.28-4.08(m,1H),3.82(s,3H),3.25-3.20(m,2H)；EI-MS m/ z：559[M+H]+。
Embodiment 21：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-d-3)
The synthesis of 7-3 and embodiment 7 are completely the same
(1) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases)-L- phenylpropyl alcohols Propylhomoserin (I-d-3)
Compound (7-3) (500.0mg, 0.89mmol) is dissolved in 10ml methanol, in 5ml water, adds in hydroxylamine hydrochloride (68.4mg, 0.98mmol), the protection of sodium hydroxide (117.6mg, 2.84mmol) nitrogen is heated to flowing back, after reacting 5 hours Add water, adjust pH to 4-5, there is white solid precipitation, filter and dry to obtain product 400.0mg, yield 82%, m.p.203-206 DEG C .1H-NMR (300MHz, DMSO-d6) δ 12.98 (br, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J=17.2, 8.4Hz, 2H), 7.40 (dd, J=17.2,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7,7.2Hz, 3H), 7.06 (t, J =8.1Hz, 2H), 6.95 (dd, J=18.2,8.4Hz, 1H), 6.25 (dd, J=11.6,8.4Hz, 1H), 4.81-5.01 (m, 2H),4.18-4.08(m,1H),3.80(s,3H),3.27-3.18(m,2H)；EI-MS m/z：550[M+H]+。
Embodiment 22：
(4- ((N- (2- amino -2- oxoethyls) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-phenylalanine (I-d-4)
The synthesis of 9-2 and embodiment 9 are completely the same
(1) (4- ((N- (2- amino -2- oxoethyls) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L- phenylpropyl alcohol ammonia Sour methyl esters (22-1)
Same compound (2-1) synthetic method, with compound (7-2) (200.0mg, 408 μm of ol), potassium carbonate (166.0mg, 1.1mmol) and acetbromamide (68.0mg, 490 μm of ol) is raw material, obtains brown oil 180mg, yield 81%.1H-NMR (300MHz,CDCl3) δ 8.03 (dd, J=20.4,8.1Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.71-7.64 (m, 2H), 7.54-7.43 (m, 2H), 7.37-7.22 (m, 5H), 7.19-7.05 (m, 2H), 6.91 (t, J=7.3Hz, 2H), 6.41-6.28 (m, 1H), 4.62 (d, J=17.3Hz, 1H), 4.40 (d, J=7.9Hz, 1H), 4.14 (d, J=17.8Hz, 1H), 3.90 (d, J =3.3Hz, 3H), 3.76 (dt, J=13.5,1.7Hz, 3H), 3.67 (t, J=3.2Hz, 3H), 3.32-3.15 (m, 2H)；EI- MS m/z：548[M+H]+。
(2) (4- ((N- (2- amino -2- oxoethyls) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L- phenylpropyl alcohol ammonia Sour (I-d-4)
It is identical with the synthetic method of compound (I-a-1), with compound (22-1) (180.0mg, 329.0 μm of ol), LiOH·H2O (138.6g, 3.3mmol) is raw material, and gray solid 148.0mg, yield 68%, m.p.146- is obtained by the reaction 149℃.1H-NMR (300MHz, DMSO-d6) δ 12.74 (br, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J= 17.2,8.4Hz, 2H), 7.40 (dd, J=17.3,7.4Hz, 4H), 7.22 (ddt, J=21.4,13.7,7.4Hz, 3H), 7.04 (t, J=8.1Hz, 2H), 6.93 (dd, J=17.2,8.2Hz, 1H), 6.25 (dd, J=11.8,8.4Hz, 1H), 4.59 (d, J =17.8Hz, 1H), 4.28-4.08 (m, 2H), 3.82 (s, 3H), 3.30-3.19 (m, 2H)；EI-MS m/z：534[M+H]+。
Embodiment 23：
(4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-methionine (I-d-5)
The synthesis of 15-2 and embodiment 15 are completely the same
(1) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-methionine (I-c-5)
It is identical with the synthetic method of compound (I-a-1), with compound (15-2) (100.0mg, 210.0 μm of ol) and LiOH·H2O (89.0mg, 2.10mmol) is raw material, obtains white solid 70.0mg, yield 72%, m.p.113-116 DEG C .1H-NMR (300MHz, DMSO-d6) δ 9.57 (d, J=3.2Hz, 1H), 8.34-8.25 (m, 1H), 7.97-7.89 (m, 1H), 7.63-7.56 (m, 2H), 7.42 (td, J=7.0,6.2,3.8Hz, 2H), 7.03 (dq, J=9.8,3.0Hz, 2H), 6.82 (d, J=8.2Hz, 1H), 6.27 (dd, J=8.4,6.5Hz, 1H), 4.17 (d, J=4.9Hz, 1H), 3.81 (s, 3H), 2.67 (td, J=13.4,7.0Hz, 2H), 2.29-2.11 (m, 2H), 2.04 (d, J=21.8Hz, 3H)；EI-MS m/z：461[M+H]+。
Embodiment 24：
(4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-Aspartic acid (I-c-20)
The synthesis of 18-2 is identical with embodiment 18
(1) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-L-Aspartic acid (I-c-20)
It is identical with the synthetic method of compound (I-a-1), with compound (18-2) (100.0mg, 212.0 μm of ol) and LiOH·H2O (89.0mg, 2.12mmol) is raw material, obtains gray solid 81.0mg, yield 86%, m.p.160-163 DEG C,1H- NMR(300MHz,DMSO-d6) δ 12.55 (br, 1H), 9.47 (s, 1H), 8.04 (d, J=7.9Hz, 1H), 7.81 (d, J= 7.8Hz, 1H), 7.48 (d, J=8.5Hz, 2H), 7.30 (d, J=7.7Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 6.72 (d, J=8.2Hz, 1H), 6.26 (d, J=8.3Hz, 1H), 4.33 (s, 1H), 3.70 (s, 3H), 2.79 (d, J=6.4Hz, 2H)； EI-MS m/z：445[M+H]+。
Embodiment 25：
(4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Alanine (I-e-1)
The synthesis of 1-2 is same as Example 1
(1) (4- nitronaphthalene -1- bases)-l-Alanine methyl esters (25-1)
Same compound (1-3) synthesis, with compound (1-2) (1g, 3.11mmol), l-Alanine methyl ester hydrochloride (0.52g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2(dba)3 (0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.40g yellow oily liquids, yield 47%.1H- NMR(300MHz,CDCl3) δ 8.99 (d, J=8.7Hz, 1H), 8.43 (d, J=8.7Hz, 1H), 7.93 (d, J=8.5Hz, 1H), 7.78-7.67 (m, 1H), 7.56 (dd, J=11.0,4.7Hz, 1H), 6.43 (d, J=8.8Hz, 1H), 5.93 (d, J= 6.7Hz, 1H), 4.44 (p, J=6.7Hz, 1H), 3.95-3.77 (m, 3H), 1.71-1.60 (m, 3H)；EI-MS m/z：275[M +H]+。
(2) (4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Alanine methyl esters (25-2)
It is identical with the synthetic method of compound (1-4), after compound (25-1) (400.0mg, 1.46mmol) hydrogenolysis with 4- Methoxybenzenesulfonyl chloride (363mg, 1.75mmol), pyridine (353 μ L, 4.38mmol) are raw material, obtain 200mg white solids, Yield is 33%, m.p.124-127 DEG C of1H-NMR (300MHz, CDCl3) δ 7.89 (dt, J=7.9,1.5Hz, 2H), 7.66 (dd, J=9.4,2.5Hz, 2H), 7.51-7.43 (m, 2H), 7.09 (d, J=8.1Hz, 1H), 6.87 (dd, J=9.3, 2.4Hz, 2H), 6.46 (s, 1H), 6.39 (d, J=8.2Hz, 1H), 5.06 (s, 1H), 4.32 (d, J=6.9Hz, 1H), 3.85 (s, 3H), 3.82 (d, J=1.9Hz, 3H), 1.65 (s, 3H)；EI-MS m/z：415[M+H]+。
(3) (4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases) the third ammonia of-L- Sour methyl esters (25-3)
It is identical with the synthetic method of compound (2-1), with compound (25-2) (100.0mg, 250 μm of ol), potassium carbonate (103.7mg, 0.75mmol) and methyl bromoacetate (104.3mg, 682 μm of ol) are raw material, obtain pale yellow oil 100mg, are produced Rate is 84%.1H-NMR (300MHz, CDCl3) δ 8.02 (s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.72-7.64 (m, 2H), 7.53-7.42 (m, 2H), 7.11 (dd, J=9.9,8.2Hz, 1H), 6.96-6.86 (m, 2H), 6.31 (t, J=8.0Hz, 1H), 5.13 (s, 1H), 4.71 (d, J=17.8Hz, 1H), 4.32-4.20 (m, 2H), 3.87 (d, J=1.4Hz, 3H), 3.79 (d, J =13.7Hz, 3H), 3.71-3.63 (m, 3H), 1.63-1.57 (m, 3H)；EI-MS m/z：487[M+H]+。
(4) (4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases)-l-Alanine (I-d-1)
It is identical with the synthetic method of compound (I-a-1), with compound (25-3) (100.0mg, 206.0 μm of ol), LiOH·H2O (173.0mg, 4.1mmol) is raw material, and white solid 73.0mg, yield 77%, m.p. is obtained by the reaction>250 ℃.1H-NMR (300MHz, DMSO-d6) δ 12.68 (br, 2H), 8.31 (d, J=7.3Hz, 1H), 8.00 (dd, J=19.9, 7.5Hz, 1H), 7.73-7.57 (m, 2H), 7.46 (d, J=7.9Hz, 2H), 7.08 (d, J=8.8Hz, 2H), 6.99 (dd, J= 15.3,8.6Hz, 1H), 6.54 (t, J=26.4Hz, 1H), 6.26 (t, J=8.9Hz, 1H), 4.45 (d, J=18.4Hz, 1H), 4.27 (d, J=13.9Hz, 1H), 4.21-4.13 (m, 1H), 3.86 (s, 3H), 1.65-1.51 (m, 3H)；EI-MS m/z：459 [M+H]+。
Embodiment 26：
(S) -3- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) butyric acid (I-e-2)
(1) (S) -3- ((4- nitronaphthalene -1- bases) amino) methyl butyrate (26-1)
The synthesis of 1-2 is same as Example 1
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), (S) -3- amino -3- Phenylpropionic acid methyl ester (0.58g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2 (dba) 3 (0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.8g yellow oily liquids, are produced Rate is 89%,1H-NMR (300MHz, CDCl3) δ 9.00 (dd, J=8.9,1.2Hz, 1H), 8.28 (d, J=8.9Hz, 1H), 8.06 (dd, J=8.5,1.2Hz, 1H), 7.73 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.61 (ddd, J=8.4,6.9, 1.3Hz, 1H), 6.94 (d, J=6.2Hz, 1H), 6.28 (d, J=8.9Hz, 1H), 5.08 (td, J=6.6,5.1Hz, 1H), 3.70 (s, 3H), 3.05 (qd, J=15.1,5.9Hz, 2H), 1.63-1.57 (m, 3H)；EI-MS m/z：289[M+H]+。
(2) (S) -3- ((4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) methyl butyrate (26-2)
It is identical with the synthetic method of compound (1-4), after compound (26-1) (0.8g, 2.78mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (690mg, 3.33mmol), pyridine (672 μ L, 8.34mmol) are raw material, obtain 520mg white solids, yield For 44%, m.p.111-114 DEG C,1H-NMR (300MHz, CDCl3) δ 7.94 (dt, J=7.7,1.7Hz, 2H), 7.60 (d, J= 8.9Hz, 2H), 7.47 (qd, J=7.0,1.5Hz, 2H), 7.37 (ddd, J=8.5,4.7,1.7Hz, 3H), 7.33-7.28 (m, 2H), 6.38 (s, 1H), 6.18 (d, J=8.3Hz, 1H), 5.75 (s, 1H), 4.94 (s, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 2.96 (dd, J=6.4,2.6Hz, 2H), 1.60-1.57 (m, 3H)；EI-MS m/z：429[M+H]+。
(3) (S) -3- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) methyl butyrate (26-3)
It is identical with the synthetic method of compound (2-1), with compound (26-2) (200.0mg, 468 μm of ol), potassium carbonate (193.5mg, 1.4mmol) and methyl bromoacetate (104.3mg, 562 μm of ol) are raw material, obtain faint yellow solid 200mg, yield is 85%, m.p.105-107 DEG C；1H NMR (300MHz, CDCl3) δ 8.02 (s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.72- 7.64 (m, 2H), 7.53-7.42 (m, 2H), 7.11 (dd, J=9.9,8.2Hz, 1H), 6.96-6.86 (m, 2H), 6.31 (t, J =8.0Hz, 1H), 5.13 (s, 1H), 4.71 (d, J=17.8Hz, 1H), 4.32-4.20 (m, 2H), 3.87 (d, J=1.4Hz, 3H), 3.79 (d, J=13.7Hz, 3H), 3.71-3.63 (m, 3H), 3.02 (m, 2H), 1.63-1.57 (m, 3H)；EI-MS m/ z：501[M+H]+。
(4) (S) -3- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) butyric acid (I- e-2)
It is identical with the synthetic method of compound (I-a-1), with compound (26-3) (200.0mg, 400.0 μm of ol), LiOH·H2O (336.0mg, 8.0mmol) is raw material, and white solid 167.0mg, yield 88%, m.p. is obtained by the reaction>250 ℃.1HNMR(300MHz,DMSO-d6)δ9.52(s,1H),8.25-8.19(m,1H),7.93-7.85(m,1H),7.78-7.72 (m, 1H), 7.58 (dq, J=9.8,2.9Hz, 2H), 7.39 (td, J=6.8,6.2,3.6Hz, 2H), 7.20 (s, 1H), 7.10- 7.05 (m, 1H), 7.05-6.97 (m, 2H), 6.78 (d, J=8.4Hz, 1H), 6.20 (d, J=8.3Hz, 1H), 4.11-4.04 (m, 1H), 3.79 (s, 3H), 2.98 (m, 2H), 1.51 (d, J=7.0Hz, 3H)；EI-MS m/z：473[M+H]+。
Embodiment 27：
(S) -2- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -2- phenylacetic acids (I-e-3)
The synthesis of 1-2 is same as Example 1
(1) (S) -2- ((4- nitronaphthalene -1- bases) amino) -2- phenylacetates (27-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), L- Phenylglycine methyl esters Hydrochloride (0.76g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2 (dba) 3 (0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 0.9g yellow oily liquids, yield is 83%,1HNMR (300MHz, CDCl3) δ 9.00 (dd, J=8.9,1.2Hz, 1H), 8.28 (d, J=8.9Hz, 1H), 8.06 (dd, J=8.5,1.2Hz, 1H), 7.73 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.61 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.42-7.29 (m, 5H), 6.94 (d, J=6.2Hz, 1H), 6.28 (d, J=8.9Hz, 1H), 5.38 (td, J=6.6, 5.1Hz,1H),3.70(s,3H)；EI-MS m/z：337[M+H]+。
(2) (S) -3- ((4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -3- phenylpropionic acid methyl esters (27-2)
It is identical with the synthetic method of compound (1-4), after compound (27-1) (0.9g, 2.57mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (640mg, 3.08mmol), pyridine (691 μ L, 8.58mmol) are raw material, obtain 400mg white solids, yield For 33%, m.p.98-102 DEG C,1H NMR (300MHz, CDCl3) δ 7.94 (dt, J=7.7,1.7Hz, 2H), 7.60 (d, J= 8.9Hz, 2H), 7.47 (qd, J=7.0,1.5Hz, 2H), 7.37 (ddd, J=8.5,4.7,1.7Hz, 3H), 7.33-7.28 (m, 2H), 6.82 (dd, J=8.4,5.3Hz, 3H), 6.38 (s, 1H), 6.18 (d, J=8.3Hz, 1H), 5.75 (s, 1H), 5.40 (s,1H),3.81(s,3H),3.68(s,3H)；EI-MS m/z：477[M+H]+。
(3) (S) -2- ((4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- bases) Amino) -2- phenylacetates (27-3)
It is identical with the synthetic method of compound (2-1), with compound (27-2) (200.0mg, 420 μm of ol), potassium carbonate (172.2mg, 1.26mmol) and methyl bromoacetate (77.1mg, 504 μm of ol) are raw material, obtain faint yellow solid 200mg, yield is 87%, EI-MS m/z：563[M+H]+。
(4) (S) -2- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -2- phenyl Acetic acid (I-e-3)
It is identical with the synthetic method of compound (I-a-1), with compound (27-3) (200.0mg, 364.0 μm of ol), LiOH·H2O (302.2mg, 7.2mmol) is raw material, and white solid 166.0mg, yield 88%, m.p. is obtained by the reaction>250 ℃.1HNMR(300MHz,DMSO-d6)δ12.53(br,2H),8.41-8.30(m,1H),8.01-7.84(m,1H),7.62- 7.55(m,1H),7.55-7.40(m,5H),7.36-7.12(m,3H),7.08-7.02(m,1H),6.97-6.91(m,1H), 6.83 (dd, J=23.5,8.3Hz, 1H), 6.22 (t, J=8.0Hz, 1H), 5.4 (d, J=7.1Hz, 1H), 4.36 (dd, J= 17.7,15.7Hz, 1H), 4.14 (dd, J=17.7,3.4Hz, 1H), 3.81 (d, J=12.5Hz, 3H), EI-MS m/z：521 [M+H]+。
Embodiment 28：
(R) -3- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -3- phenylpropionic acids (I-e-4)
The synthesis of 1-2 is same as Example 1
(1) (S) -3- ((4- nitronaphthalene -1- bases) amino) -3- phenylpropionic acid methyl esters (28-1)
It is identical with the synthetic method of compound (1-3), with compound (1-2) (1g, 3.11mmol), (R) -3- amino -3- Phenylpropionic acid methyl ester (0.52g, 3.73mmol), Cs2CO3(2g, 6.22mmol), (±)-BINAP (0.29g, 0.47mmol), Pd2(dba)3(0.14g, 0.16mmol), DIPEA (1.1ml, 6.22mmol) are raw material, obtain 1.0g yellow oily liquids, are produced Rate is 90%,1H-NMR (300MHz, CDCl3) δ 9.00 (dd, J=8.9,1.2Hz, 1H), 8.28 (d, J=8.9Hz, 1H), 8.06 (dd, J=8.5,1.2Hz, 1H), 7.73 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.61 (ddd, J=8.4,6.9, 1.3Hz, 1H), 7.42-7.29 (m, 5H), 6.94 (d, J=6.2Hz, 1H), 6.28 (d, J=8.9Hz, 1H), 5.08 (td, J= 6.6,5.1Hz, 1H), 3.70 (s, 3H), 3.05 (qd, J=15.1,5.9Hz, 2H)；EI-MS m/z：351[M+H]+。
(2) (S) -3- ((4- ((4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -3- phenylpropionic acid methyl esters (28-2)
It is identical with the synthetic method of compound (1-4), after compound (28-1) (1.0g, 2.86mmol) hydrogenolysis with 4- methoxies Base benzene sulfonyl chloride (710mg, 3.43mmol), pyridine (691 μ L, 8.58mmol) are raw material, obtain 700mg white solids, yield For 50%, m.p.107-110 DEG C,1H-NMR (300MHz, CDCl3) δ 7.94 (dt, J=7.7,1.7Hz, 2H), 7.60 (d, J= 8.9Hz, 2H), 7.47 (qd, J=7.0,1.5Hz, 2H), 7.37 (ddd, J=8.5,4.7,1.7Hz, 3H), 7.33-7.28 (m, 2H), 6.82 (dd, J=8.4,5.3Hz, 3H), 6.38 (s, 1H), 6.18 (d, J=8.3Hz, 1H), 5.75 (s, 1H), 4.94 (s, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 2.96 (dd, J=6.4,2.6Hz, 2H)；EI-MS m/z：491[M+H]+。
(3) (S) -3- ((4- ((4- methoxyl groups-N- (2- methoxyl group -2- oxoethyls) phenyl) sulfonamido) naphthalene -1- Base) amino) -3- phenylpropionic acid methyl esters (28-3)
It is identical with the synthetic method of compound (2-1), with compound (28-2) (200.0mg, 408 μm of ol), potassium carbonate (169.2mg, 1.22mmol) and methyl bromoacetate (104.3mg, 682 μm of ol) are raw material, obtain pale yellow oil 200mg, are produced Rate is 87%,1H-NMR (300MHz, CDCl3) δ 7.98 (dt, J=7.7,1.7Hz, 2H), 7.62 (d, J=8.9Hz, 2H), 7.49 (qd, J=7.0,1.5Hz, 2H), 7.35 (ddd, J=8.5,4.7,1.7Hz, 3H), 7.35-7.24 (m, 2H), 6.80 (dd, J=8.4,5.3Hz, 3H), 6.37 (s, 1H), 6.18 (d, J=8.3Hz, 1H), 5.77 (s, 1H), 4.50 (s, 1H), 4.39 (d, J=5.6Hz, 1H), 4.24 (d, J=17.8Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H), 2.96 (dd, J=6.4,2.6Hz, 2H)；EI-MS m/z：563[M+H]+。
(4) (S) -3- ((4- ((N- (carboxymethyl) -4- methoxyphenyls) sulfonamido) naphthalene -1- bases) amino) -3- phenyl Propionic acid (I-e-4)
It is identical with the synthetic method of compound (I-a-1), with compound (28-3) (200.0mg, 356.0 μm of ol), LiOH·H2O (298.2mg, 7.1mmol) is raw material, and white solid 165.0mg, yield 87%, m.p. is obtained by the reaction>250 ℃.1H-NMR(300MHz,DMSO-d6)δ12.53(br,2H),8.41-8.30(m,1H),8.01-7.84(m,1H),7.62- 7.55(m,1H),7.55-7.40(m,5H),7.36-7.12(m,3H),7.08-7.02(m,1H),6.97-6.91(m,1H), 6.83 (dd, J=23.5,8.3Hz, 1H), 6.22 (t, J=8.0Hz, 1H), 4.94 (d, J=7.1Hz, 1H), 4.36 (dd, J= 17.7,15.7Hz, 1H), 4.14 (dd, J=17.7,3.4Hz, 1H), 3.81 (d, J=12.5Hz, 3H), 3.09 (dt, J= 17.2,8.9Hz, 1H), 2.72 (dt, J=15.7,4.8Hz, 2H)；EI-MS m/z：535[M+H]+。
Embodiment 29：Test examples
Activation effect of the naphthalene sulfonamide amino acid derivativges to Nrf2 of embodiment 1-28 preparations is measured respectively.
1st, the Keap1-Nrf2 protein-protein interactions Inhibition test based on fluorescence polarization (FP experiments)
Instrument used in FP experiments is SpectraMax Multi-Mode Microplate Reader (Molecular Devices), the exciting light of instrument and the wavelength of transmitting light are selected according to corresponding fluorophor.Use 3676384 holes of Corning Plate carries out experimental work.The reaction system of orifice plate is 40 μ L.Wherein the 4nM FITC-9merNrf2 polypeptides fluorescence comprising 10 μ L is visited The inhibitor of pin, the 12nM Keap1Kelch domain proteins solution of 10 μ L and 20 μ L respective concentrations.Positive control uses 20 μ L + 10 μ L protein solutions of+10 μ L probes of 100nM Nrf2 nonapeptides (Ac-LDEETGEFL-OH), negative control are+10 μ L of 10 μ L probes + 20 μ L HEPES buffer solutions of protein solution, blank control are+30 μ L HEPES buffer solutions of 10 μ L probes.Exist in advance before testing Mixing, incubation 30 minutes at room temperature.This experiment middle probe fluorophor is fluorescein, and a length of 485nm of excitation light wave emits light Wavelength is 535nm.In this research milli bias (mP) is calculated using fluorescence intensity (F ║ and F ┴) horizontally and vertically instead Answer the situation of change of polarised light.Inhibiting rate computational methods of the inhibitor under certain concentration are：
Inhibiting rate %=(1- (Pobs-Pmin)/(Pmax-Pmin))×100。
Pmax、PminAnd PobsRepresent respectively the polarization value of Keap1 and fluorescence probe hole, the polarization value in fluorescence probe hole and Polarization value containing inhibitor hole.The IC of compound is calculated using concentration-inhibiting rate curve of inhibitor50(result such as following table institute Show).
2nd, ARE luciferase reporter genes are tested
Cell culture invitro
The HepG2 cells containing ARE luciferase reporter plasmids will be transfected (using what is bought from QIAGEN Antioxidant Response Reporter plasmids, according to transfected to obtain to guide) with containing 10% hyclone RPMI-1640 culture mediums, in 37 DEG C, 5%CO2Under the conditions of cultivate.
(1) 0.25% pancreatin digestive juice of the HepG2-ARE-C8 cells in exponential phase is handled, concentration is made For 4 × 105Cell suspension.100 μ L overnight incubations are added in into 96 hole elisa Plates respectively.
(2) testing compound is configured to concentration needed for 2 times with culture medium, adds in 100 μ L into corresponding hole respectively, Tert-butyl hydroquinone (tBHQ) is positive control, and DMSO is negative control.To add 96 hole elisa Plates of compound as 37 DEG C, 5%CO212h is incubated under conditions of constant temperature, saturated humidity.
(3) the 5X lysates in Luciferase Assay Reagent box are configured to 1X lysates, it is spare.
(4) 96 hole elisa Plates are taken out, culture medium from hole is suctioned out, cell is washed with 1XPBS buffer solutions, after washing PBS buffer solution is suctioned out.The 1X cell pyrolysis liquids of 25 or 30 μ L are added in per hole, crack 15min on ice.Cracking finishes, and stands 3- 5min, the supernatant lysate for drawing 20 μ L are added in corresponding 96 hole white ELISA Plate.
(5) white ELISA Plate is put into Thermo Scientific LuminoskanAscent chemiluminescence micropore readings In instrument, 100 μ L Luciferase Assay Reagents are added in (by 1 bottle of luciferase in Luciferase Assay Reagent box to every hole before test Detection substrate and 1 bottle of luciferase assay buffer are uniformly mixed to prepare), it adds in after detection reagent and carries out reading within 1min.
The results are shown in table below.
Above-mentioned data explanation, compound provided by the invention have good Keap1-Nrf2 protein-protein interactions (PPI) inhibitory activity, so as to good Nrf2 excitations；In luciferase reporter gene experiment, the present invention provides Compound show good induced activity, be expected to exploitation into Nrf2 exciting agents for anti-inflammatory.
To sum up, the compound provided by the invention containing amino acid and single sulfonamide structure can disturb Keap1-Nrf2 to tie It closes, activates Nrf2, so as to mitigate inflammatory damage, improve inflammatory microenvironment, there is potential anti-inflammatory activity.Those skilled in the art Know, Nrf2 activator can be used for the inflammatory reaction (bibliography for inhibiting disease：Protections of the Nrf2 in inflammation related disease Effect, Pharmaceutical Biotechnology, the 4th phase in 2013), therefore, these compounds provided by the invention can be used for being prepared into anti-inflammatory agent Object be used for numerous inflammation related diseases treatment, these diseases include Chronic Obstructive Pulmonary Disease (COPD), Alzheimer's disease, Parkinson, atherosclerosis, chronic renal disease (CKD), diabetes, intestines inflammation, rheumatoid arthritis etc..
The effect of above-described embodiment is the essentiality content for specifically introducing the present invention, but those skilled in the art should know Protection scope of the present invention should not be confined to the specific embodiment by road.

Claims (10)

1. a kind of naphthalene sulfonamide amino acid derivativges as shown in structure formula (I)：
Wherein：R1Represent 4- trifluoromethyls, 4- trifluoromethoxies, 4- nitros, 4- hydroxyls, 4- methylols, 4- cyano or 4- amino； Single, double or trisubstituted H, halogen, C1-C3 alkyl, C1-C3 alkoxies, C1-C3 alkylaminos or C1-C3 acylamino-s；
R2Represent H ,-CH2COOH、Or-CH2CONH2；
R3A kind of substituent group with amino acid structure is represented, the amino acid structure refers to the substituent group at least containing there are one carboxyls With a secondary amine or tertiary amine, and the substituent group is connected to by secondary amine or tertiary amine on above-mentioned parent nucleus.
2. naphthalene sulfonamide amino acid derivativges according to claim 1, which is characterized in that R3Represent following substituent group：
Wherein：X represents H, O or S；R4Represent methyl, ethyl, tertiary butyl, phenyl, 4- anisyls or benzyl.
3. naphthalene sulfonamide amino acid derivativges according to claim 2, which is characterized in that chemical structural formula is as follows：
4. naphthalene sulfonamide amino acid derivativges according to claim 1, which is characterized in that R3Represent following substituent group：
Wherein：
R5Represent H, methyl, isopropyl, sec-butyl, isobutyl group, tertiary butyl, cyclopenta, cyclohexyl methyl, methylol, tertiary fourth oxygen first Base, benzyloxymethyl, phenyl, benzyl, phenethyl, 4- luorobenzyls, 4- chlorobenzyls, 4- hydroxybenzyls, 4- methoxy-benzyls, 4- benzyloxies Base benzyl, 2- indole methyls, 4- aminobutyls, 1- menaphthyls, carboxymethyl, carboxyethyl, methylthio ethyl, first sulfoxide ethyl, methyl sulfone Ethyl,
N values 0 or 1.
5. naphthalene sulfonamide amino acid derivativges according to claim 4, which is characterized in that chemical structural formula is as follows：
Or chemical structural formula is as follows：
Or chemical structural formula is as follows：
Or chemical structural formula is as follows：
6. the preparation method of any naphthalene sulfonamide amino acid derivativges of claim 1-5, R2Represent H ,-CH2COOH orIt is characterised in that it includes following steps：
7. the preparation method of any naphthalene sulfonamide amino acid derivativges of claim 1-5, R2It representsIt is special Sign is, includes the following steps：
8. the pharmaceutically acceptable salt of any naphthalene sulfonamide amino acid derivativges of claim 1-5.
9. any naphthalene sulfonamide amino acid derivativges of claim 1-5 and its pharmaceutically acceptable salt is used to prepare The purposes of Nrf2 activator.
10. any naphthalene sulfonamide amino acid derivativges of claim 1-5 and its pharmaceutically acceptable salt are used to make The purposes of the drug of the standby inflammation treated or alleviate disease, the disease is Chronic Obstructive Pulmonary Disease, Alzheimer's disease, pa Jin Sen, atherosclerosis, chronic renal disease, diabetes, intestines inflammation or rheumatoid arthritis.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108752245A (en) * 2018-07-16 2018-11-06 宁夏医科大学 Naphthalene sulfonylamide acetamides and its application and pharmaceutical composition
CN110256305A (en) * 2019-07-24 2019-09-20 中国药科大学 A kind of naphthalenesulfonamide compound, preparation method and application
CN110734439A (en) * 2019-11-07 2020-01-31 中国药科大学 pyrazolo [3,4-d ] pyrimidine compounds with mother nucleus and preparation method thereof
CN111362857A (en) * 2020-04-23 2020-07-03 中国药科大学 Compound with indoline skeleton, preparation method and medical application thereof
CN113861110A (en) * 2021-11-05 2021-12-31 中国药科大学 Polysubstituted sulfonamide compound, preparation method and medical application thereof
CN115925606A (en) * 2023-01-05 2023-04-07 宁夏医科大学 5- (3- (sulfonamido) phenyl) -1H-pyrrole-2-carboxylic acid derivative and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2997966A1 (en) * 2014-09-16 2016-03-23 Sanofi Naphthyl Sulfonamide Pyrrolidine Derivatives as KEAP-1 Modulators for the Treatment of Diabetes, Obesity, Dyslipidemia and Related Disorders
CN105566241A (en) * 2016-01-18 2016-05-11 中国药科大学 1-sulfonamide-4-aryloxy compound, preparation method and medical application of 1-sulfonamide-4-aryloxy compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2997966A1 (en) * 2014-09-16 2016-03-23 Sanofi Naphthyl Sulfonamide Pyrrolidine Derivatives as KEAP-1 Modulators for the Treatment of Diabetes, Obesity, Dyslipidemia and Related Disorders
CN105566241A (en) * 2016-01-18 2016-05-11 中国药科大学 1-sulfonamide-4-aryloxy compound, preparation method and medical application of 1-sulfonamide-4-aryloxy compound

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AHMED F. ABDEL-MAGID: "Therapeutic Potential for Modulation of Nrf2-Keap‑1 Signaling Pathway as Treatment for Diabetes and Other Disorders", 《ACS MEDICINAL CHEMISTRY LETTERS》 *
MENGCHEN LU ET AL.: "Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
MENG-CHEN LU ET AL.: "Polar Recognition Group Study of Keap1-Nrf2 Protein−Protein Interaction Inhibitors", 《ACS MEDICINAL CHEMISTRY LETTERS》 *
姚争光 等: "Nrf2 -Keap1蛋白相互作用小分子抑制剂的研究进展", 《中国药物化学杂志》 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108752245A (en) * 2018-07-16 2018-11-06 宁夏医科大学 Naphthalene sulfonylamide acetamides and its application and pharmaceutical composition
JP7301433B2 (en) 2019-07-24 2023-07-03 中国▲薬▼科大学 Naphthalenesulfonamide compounds, methods of preparation, and uses
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WO2021012721A1 (en) * 2019-07-24 2021-01-28 中国药科大学 Naphthalenesulfonamide compound, preparation method, and application
US11773057B2 (en) 2019-07-24 2023-10-03 China Pharmaceutical University Naphthalenesulfonamide compound, preparation method, and application
JP2022541180A (en) * 2019-07-24 2022-09-22 中国▲薬▼科大学 Naphthalenesulfonamide compounds, methods of preparation, and uses
AU2020317159B2 (en) * 2019-07-24 2022-11-17 China Pharmaceutical University Naphthalenesulfonamide compound, preparation method, and application
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