CN111217776A - Amide derivative containing benzo heterocyclic structure, composition and application - Google Patents

Amide derivative containing benzo heterocyclic structure, composition and application Download PDF

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CN111217776A
CN111217776A CN202010061237.6A CN202010061237A CN111217776A CN 111217776 A CN111217776 A CN 111217776A CN 202010061237 A CN202010061237 A CN 202010061237A CN 111217776 A CN111217776 A CN 111217776A
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王丽韫
童坤
史卫国
程京超
于子兴
任凤霞
周琥
熊颖
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Institute of Pharmacology and Toxicology of AMMS
Academy of Military Medical Sciences AMMS of PLA
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    • C07—ORGANIC CHEMISTRY
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
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    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

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Abstract

The invention belongs to the technical field of medicines, and discloses an amide derivative containing a benzo-heterocycle structure, a composition and application. Wherein, the amide derivative containing the benzo-heterocycle structure is a compound shown as a structural formula I and non-toxic pharmaceutically acceptable salt thereof:
Figure DDA0002374562540000011
or, the amide derivative containing the benzo-heterocycle structure is a compound shown as a structural formula II or a non-toxic pharmaceutically acceptable salt thereof:

Description

Amide derivative containing benzo heterocyclic structure, composition and application
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an amide derivative containing a benzo-heterocycle structure, a composition and application.
Background
The description of the background of the invention pertaining to the related art to which this invention pertains is given for the purpose of illustration and understanding only of the summary of the invention and is not to be construed as an admission that the applicant is explicitly or implicitly admitted to be prior art to the date of filing this application as first filed with this invention.
Neuropathic pain (Neuropathic pain) is a chronic pain, which refers to pain caused by peripheral or central nervous system, primary or secondary damage, dysfunction or transient disorder, and has the characteristics of delayed and repeated onset. Epidemiological studies have shown that the prevalence of neuropathic pain ranges from 6.9 to 10%.
Currently, no specific medicine aiming at neuropathic pain exists clinically, and clinically available analgesics are ineffective in 30-50% of neuropathic pain patients and often cause toxic and side effects. Therefore, the development of drugs for treating neuropathic pain is urgent.
Sodium channel blockers are one of a class of drugs that have been shown to be effective in treating neuropathic pain, and are also the most active class of drugs in the current field of anti-neuropathic pain drug research.
Disclosure of Invention
The invention aims to provide an amide derivative containing a benzo-heterocycle structure, a composition and application.
The invention provides an amide derivative containing a benzo-heterocycle structure, which is a compound shown in a structural formula I and a non-toxic pharmaceutically acceptable salt thereof:
Figure BDA0002374562530000011
in structural formula I:
n＝1，X1is a carbon atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, n ═ 1, X1Is a nitrogen atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, n ═ 2, X1Is a carbon atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5Straight or branched chain alkyl ofThe chiral carbon connected with R is in R type or S type;
or, the amide derivative containing the benzo-heterocycle structure is a compound shown as a structural formula II or a non-toxic pharmaceutically acceptable salt thereof:
Figure BDA0002374562530000021
in structural formula II:
n＝1，X1is a carbon atom, X2Is a nitrogen atom, an oxygen atom or a sulfur atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, n ═ 2, X1Is an oxygen atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound of formula I is represented by formula Ia:
Figure BDA0002374562530000022
in the structural formula Ia, the substituted position of benzofuran is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound shown in the structural formula I is shown in a formula Ib:
Figure BDA0002374562530000023
in the structural formula Ib, 1H-benzo [ d]The imidazole substitution position is 4, 5, 6 or 7, the connection position of the benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound represented by the structural formula I is represented by the formula Ic:
Figure BDA0002374562530000031
in the structural formula Ic, the substitution position of the quinoline ring is 5, 6, 7 or 8, the connection position of the benzene ring is meta or para, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound shown in the structural formula II is shown in a formula IIa:
Figure BDA0002374562530000032
in the structural formula IIa, the substituted position of indoline is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound of formula II is of formula IIb:
Figure BDA0002374562530000033
in the structural formula IIb, the substituted position of 2, 3-dihydrobenzofuran is 4, 5, 6 or 7, the benzene ring connecting position is meta or para, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
Further, the compound of formula II is of formula IIc:
Figure BDA0002374562530000034
in the formula IIc, 2, 3-dihydrobenzo [ b ]]The substituted position of the thiophene is 4, 5, 6 or 7, the connecting position of the benzene ring is meta or para, and R is C1–C5Linear or branched alkyl of (A), withThe chiral carbon configuration connected with R is R type or S type.
Further, the compound of formula II is of formula IId:
Figure BDA0002374562530000035
in the formula IId, 2, 3-dihydrobenzo [ b ]][1,4]The substituted position of the dioxin is 5-position or 6-position, the connecting position of the benzene ring is meta-position or para-position, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
In a second aspect, the present invention provides a pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises the above amide derivative containing a benzo-heterocycle structure, the pharmaceutical composition comprises an excipient, and the pharmaceutical composition is a solution, a tablet, a capsule or an injection.
The third aspect of the present invention provides an application of a benzo-hetero ring structure-containing amide derivative, wherein the benzo-hetero ring structure-containing amide derivative is the above-mentioned benzo-hetero ring structure-containing amide derivative, and the application is to apply the benzo-hetero ring structure-containing amide derivative to analgesics.
The invention has the following beneficial effects:
the amide derivative containing the benzo heterocyclic structure has higher sodium ion channel Nav1.7, has strong analgesic activity.
Detailed Description
The present application is further described below with reference to examples.
In the following description, different "one embodiment" or "an embodiment" may not necessarily refer to the same embodiment, in order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art. Various embodiments may be replaced or combined, and other embodiments may be obtained according to the embodiments without creative efforts for those skilled in the art.
The inventor designs and synthesizes a series of novel compounds shown by structural formulas I and II:
Figure BDA0002374562530000041
in structural formula I:
1.n＝1，X1when being a carbon atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
2.n＝1，X1When it is a nitrogen atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
3.n＝2，X1When being a carbon atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
In structural formula II:
when n is 1, X1Is a carbon atom, X2Is a nitrogen atom, an oxygen atom or a sulfur atom, R is a hydrogen atom or C1-C5Linear or branched alkyl groups of (a).
When n is 2, X1、X2Are all oxygen atoms, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
The activity evaluation result shows that the compound shows high analgesic activity and selectively inhibits a sodium ion channel Nav1.7。
The present invention provides compounds represented by structural formula i:
Figure BDA0002374562530000051
in structural formula I: n is 1, X1When being a carbon atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a). n is 1, X1When it is a nitrogen atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a). n is 2, X1When being a carbon atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
The present invention provides compounds represented by structural formula ii:
Figure BDA0002374562530000052
in structural formula II: when n is 1, X1Is a carbon atom, X2Is a nitrogen atom, an oxygen atom or a sulfur atom, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a). When n is 2, X1、X2Are all oxygen atoms, R is a hydrogen atom or C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the configuration of the chiral carbon associated with R in either structure I or structure II is R-type or S-type.
In certain embodiments, R in structural formula I or structural formula II is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a target compound represented by formula Ia:
Figure BDA0002374562530000053
in the structural formula Ia, the substituted position of benzofuran is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the chiral carbon configuration associated with R in formula Ia is R or S.
In certain embodiments, R in structure Ia is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a target compound represented by formula Ib:
Figure BDA0002374562530000061
in the structural formula Ib, 1H-benzo [ d]The imidazole substitution position is 4, 5, 6 or 7, the connection position of the benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the configuration of the chiral carbon to which R is attached in structural formula Ib is R or S.
In certain embodiments, R in structure Ib is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a target compound of formula Ic:
Figure BDA0002374562530000062
in the structural formula Ic, the substitution position of the quinoline ring is 5, 6, 7 or 8, the connection position of the benzene ring is meta or para, and R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the configuration of the chiral carbon to which R is attached in structural formula Ic is R or S.
In certain embodiments, R in structural formula Ic is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
In certain embodiments, a compound of structural formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
Figure BDA0002374562530000063
Figure BDA0002374562530000071
the invention also provides a compound represented by formula IIa or a pharmaceutically acceptable salt thereof:
Figure BDA0002374562530000072
in the structural formula IIa, the substituted position of indoline is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the configuration of the chiral carbon associated with R in structural formula IIa is R or S.
In certain embodiments, R in structural formula IIa is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a compound represented by formula IIb or a pharmaceutically acceptable salt thereof:
Figure BDA0002374562530000073
in the structural formula IIb, the substituted position of 2, 3-dihydrobenzofuran is 4, 5, 6 or 7, the benzene ring connecting position is meta or para, and R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the chiral carbon configuration associated with R in structural formula IIb is R-type or S-type.
In certain embodiments, R in formula IIb is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a compound represented by formula IIc:
Figure BDA0002374562530000081
in the formula IIc, 2, 3-dihydrobenzo [ b ]]The substituted position of the thiophene is 4, 5, 6 or 7, the connecting position of the benzene ring is meta or para, and R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the chiral carbon configuration associated with R in structural formula IIc is R or S.
In certain embodiments, R in formula IIc is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
The present invention also provides a compound represented by formula IId:
Figure BDA0002374562530000082
in the formula IId, 2, 3-dihydrobenzo [ b ]][1,4]The substituted position of the dioxin is 5-position or 6-position, the connecting position of the benzene ring is meta-position or para-position, and R is C1–C5Linear or branched alkyl groups of (a).
In certain embodiments, the chiral carbon configuration associated with R in formula IId is R or S.
In certain embodiments, R in formula IId is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2-dimethyl-propyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-ethyl-propyl.
In certain embodiments, a compound of structural formula II, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure BDA0002374562530000083
Figure BDA0002374562530000091
the invention also provides a pharmaceutical composition which contains the compound shown in the formula I, the formula Ia, the formula Ib, the formula Ic, the formula II, the formula IIa, the formula IIb, the formula IIc and the formula IId or pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable excipient or carrier. These pharmaceutical compositions may be solutions, tablets, capsules or injections; these pharmaceutical compositions may be administered by injection route or orally. The invention also provides application of a compound shown in formula I, formula Ia, formula Ib, formula Ic, formula II, formula IIa, formula IIb, formula IIc and formula IId or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound shown in formula I, formula Ia, formula Ib, formula Ic, formula II, formula IIa, formula IIb, formula IIc and formula IId or the pharmaceutically acceptable salt thereof as an active ingredient in preparing a medicament serving as an analgesic.
The term "pharmaceutical composition" as used herein means a composition containing one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity. Vectors described herein include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin. The excipient is an additive except the main drug in the pharmaceutical preparation, has stable property, no incompatibility with the main drug, no side effect and no influence on curative effect, is not easy to deform, crack, mildew or moth eating at normal temperature, has no harm to a human body and no physiological effect, does not generate chemical or physical effect with the main drug, does not influence the content determination of the main drug, and the like. Such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice, etc. in the Chinese medicinal pill; base portion in semisolid formulations ointments, creams; preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid preparations can all be referred to as excipients.
The compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof may be administered by the following routes: parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes, or as inhalants.
The compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof may be formulated into various suitable dosage forms according to the administration route.
When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
Typically, an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10000 mg/kg body weight/day. Suitably, the dose is from about 0.01 mg/kg body weight/day to about 1000mg/kg body weight/day. The dosage range may be about 0.01 to 1000mg/kg of subject body weight per day, every second day, or every third day, more usually 0.1 to 500mg/kg of subject body weight. Exemplary treatment regimens are once every two days or once a week or once a month. The formulation is typically administered multiple times, and the interval between single doses may be daily, weekly, monthly or yearly. Alternatively, the formulation may be administered as a sustained release formulation, in which case less frequency of administration is required. The dose and frequency will vary depending on the half-life of the formulation in the subject. It may also vary depending on whether prophylactic or therapeutic treatment is carried out. In prophylactic applications, relatively low doses are administered chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or halted, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a prophylactic regimen can be administered to the patient.
Synthesis of target Compound represented by formula Ia starting with benzenedicarboxaldehyde (1a) as the starting Material and reducing with sodium borohydrideGenerating hydroxymethyl benzaldehyde (2a), reacting 2a with N-bromosuccinimide and triphenyl phosphorus to generate bromomethyl benzaldehyde (3a), reacting 3a with hydroxy benzofuran at KI and K2CO3Or Cs2CO3Generating an intermediate (4a) under the action of the reaction, and generating the target compound Ia by the 4a and alaninamide hydrochloride under the action of triethylamine and potassium borohydride.
The synthetic route for the compound of formula Ia is shown below:
Figure BDA0002374562530000111
in the structural formula Ia, the substituted position of benzofuran is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown as the formula Ib takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, the 2a reacts with N-bromosuccinimide and triphenyl phosphorus to generate bromomethyl benzaldehyde (3a), and the 3a reacts with hydroxyl 1H-benzo [ d ]]Imidazole in KI and K2CO3Or Cs2CO3Generating an intermediate (4b) under the action of the intermediate, and generating a target compound Ib by the 4b and alaninamide hydrochloride under the action of triethylamine and potassium borohydride.
The synthetic route for the compound of formula Ib is shown below:
Figure BDA0002374562530000112
in the structural formula Ib, 1H-benzo [ d]The imidazole substitution position is 4, 5, 6 or 7, the connection position of the benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown as the formula Ic takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, 2a reacts with N-bromosuccinimide and triphenyl phosphorus to generate bromomethyl benzaldehyde (3a), and the bromomethyl benzaldehyde (3a) is further reacted with hydroxyquinoline at KI and K2CO3Or Cs2CO3Under the action of the intermediate (4c), the intermediate (4c) and alaninamide hydrochloride generate the target compound Ic under the action of triethylamine and potassium borohydride.
The synthetic route for the compound of formula Ic is shown below:
Figure BDA0002374562530000121
in the structural formula Ic, the substitution position of the quinoline ring is 5, 6, 7 or 8, the connection position of the benzene ring is meta or para, and R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown in the formula IIa takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, bromomethyl benzaldehyde (3a) is generated by reaction of 2a, N-bromosuccinimide and triphenyl phosphorus, and then bromomethyl benzaldehyde (3a) and hydroxyl indoline are reacted at KI and K2CO3Or Cs2CO3Generating an intermediate (4d) under the action of the intermediate, and generating a target compound IIa by the 4d and alaninamide hydrochloride under the action of triethylamine and potassium borohydride.
The synthetic route for the compounds of formula IIa is shown below:
Figure BDA0002374562530000122
in the structural formula IIa, the substituted position of the indoline is 5, 6, 7 or 8, the connecting position of the benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown as the formula IIb takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, 2a reacts with N-bromosuccinimide and triphenyl phosphorus to generate bromomethyl benzaldehyde (3a), and the 3a reacts with hydroxyl substituted 2, 3-dihydrobenzofuran at KI and K2CO3Or Cs2CO3Generating an intermediate (4e) under the action of the intermediate, and generating a target compound IIb by the 4e and alanine amide hydrochloride under the action of triethylamine and potassium borohydride.
The synthetic route for the compounds of formula IIb is shown below:
Figure BDA0002374562530000131
in the structural formula IIb, the substituted position of the 2, 3-dihydrobenzofuran is 4, 5, 6 or 7, the connecting position of the benzene ring is meta or para, R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown as the formula IIc takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, bromomethyl benzaldehyde (3a) is generated by reaction of 2a, N-bromosuccinimide and triphenyl phosphorus, and then bromomethyl benzaldehyde (3a) and hydroxyl substituted 2, 3-dihydrobenzo [ b ]]Thiophene in KI and K2CO3Or Cs2CO3Generating an intermediate (4f) under the action of the intermediate, and generating a target compound IIc by the 4f and alaninamide hydrochloride under the action of triethylamine and potassium borohydride.
The synthetic route for the compounds of formula IIc is shown below:
Figure BDA0002374562530000132
in the formula IIc, 2, 3-dihydrobenzo [ b ]]The substituted position of the thiophene is 4, 5, 6 or 7, the connecting position of the benzene ring is meta or para, and R is C1–C5Linear or branched alkyl groups of (a).
The synthesis of the target compound shown as the formula II d takes benzene dicarbaldehyde (1a) as an initial raw material, hydroxymethyl benzaldehyde (2a) is generated by reduction of sodium borohydride, bromomethyl benzaldehyde (3a) is generated by reaction of 2a, N-bromosuccinimide and triphenyl phosphorus, and then bromomethyl benzaldehyde (3a) and hydroxyl substituted 2, 3-dihydrobenzo [ b ]][1,4]Dioxin is found in KI and K2CO3Or Cs2CO3Under the action of the intermediate, 4g of the intermediate is generated, and 4g of the intermediate and alaninamide hydrochloride generate a target compound IId under the action of triethylamine and potassium borohydride.
The synthetic route for the compounds of formula Id is shown below:
Figure BDA0002374562530000133
in the formula IId, 2, 3-dihydrobenzo [ b ]][1,4]The substituted position of the dioxin is 5-position or 6-position, the connecting position of the benzene ring is meta-position or para-position, R is C1–C5Linear or branched alkyl groups of (a).
Example 1 Synthesis of (S) -2- (4- ((benzofuran-4-) oxymethyl) benzylamino) propanamide (Ia-1)
Figure BDA0002374562530000141
1.1 Synthesis of p-hydroxymethylbenzaldehyde (2a-1) and m-hydroxymethylbenzaldehyde (2a-2)
Figure BDA0002374562530000142
One 250mL eggplant-shaped bottle was taken, 10.00g (74.55mmol) of terephthalaldehyde 1a-1 or isophthalaldehyde 1a-2 was added thereto, and 50mL of ethanol and 80mL of tetrahydrofuran were further added and dissolved therein. Under the condition of ice-bath stirring, 0.85g (22.46mmol) of sodium borohydride is added in three times, and after the addition, the reaction is continued for more than 6h under the condition of ice-bath. Monitoring the reaction progress by thin layer chromatography until point 1a-1 or 1a-2 completely disappears, stopping the reaction, quenching the reaction solution by 3mol/L hydrochloric acid, adjusting the pH to 4-5, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a brown yellow oily substance, dissolving the residue by 50mL each of ethyl acetate and water, separating the solution, extracting the aqueous phase by ethyl acetate twice, 30mL each time, combining the organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering to remove the sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (elution of PE: EA ═ 3: 1) to obtain colorless transparent liquid p-hydroxymethylbenzaldehyde (2a-1, 7.50g, yield 73.89%) or m-hydroxymethylbenzaldehyde (2a-2, 5.63g, yield 55.57%).
1.2 Synthesis of p-bromomethylbenzaldehyde (3a-1) and m-bromomethylbenzaldehyde (3a-2)
Figure BDA0002374562530000143
A100 mL eggplant-shaped bottle was taken, 2.50g (18.36mmol) of 2a-1 or 2a-2 was added, and the mixture was dissolved in 40mL of methylene chloride, 4.90g (27.53mmol) of N-bromosuccinimide was added with stirring, and then 9.63g (36.72mmol) of triphenylphosphine was added in four times under ice-cooling, and the reaction was carried out at room temperature for 3 hours or more. Monitoring the reaction progress by thin layer chromatography until point 2a-1 or 2a-2 completely disappears, filtering, adding 40mL of water into the filtrate, separating the liquid, extracting the water phase twice by dichloromethane with 20mL each time, combining the organic phases, drying by anhydrous sodium sulfate, filtering to remove the sodium sulfate, distilling under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA is 10:1 elution) to obtain white loose solid p-bromomethylbenzaldehyde (3a-1, 1.30g, yield 35.76%) or m-bromomethylbenzaldehyde (3a-2, 1.09g, yield 30.07%).
1.34 Synthesis of- ((benzofuran-4-) oxymethyl) benzaldehyde (4a-1) and 3- ((benzofuran-4-) oxymethyl) benzaldehyde (4a-2)
Figure BDA0002374562530000151
Taking 100mL eggplant-shaped bottle, adding 0.52g (3.88mmol) of 4-hydroxybenzofuran and 1.31g (4.03mmol) of Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.92g (4.66mmol) of 3a-1 or 3a-2 and 0.10g (0.58mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin-layer chromatography until the 4-hydroxybenzofuran point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is a pale yellow solid, dissolving the residue with 30mL of each of water and ethyl acetate, separating, extracting the aqueous phase with ethyl acetate twice, 15mL each time, combining organic phases, washing with water, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, separating (PE: EA ═ 10:1 elution) to obtain a pale yellow oily 4- ((benzofuran-4-) oxymethyl) benzaldehyde (4a-1, 0.72g, yield 73.47%) or 3- ((benzofuran-4-) oxymethyl) benzaldehyde (4a-2, 0.78g, yield 79.24%).
Synthesis of 4(S) -2- (4- ((benzofuran-4-) oxymethyl) benzylamino) propanamide (Ia-1)
Figure BDA0002374562530000152
Adding 0.53g (4.28mmol) of L-alaninamide hydrochloride, 0.87g (8.57mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 0.72g (2.86mmol) of 4a-1 into the reaction solution, continuing to react at room temperature for 2h, adding 0.92g (17.14mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until the point 4a-1 completely disappears, distilling under reduced pressure to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-1, 0.52g, 55.91% yield). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.90(d,1H),7.21–7.46(m,7H),6.87–7.04(m,3H),5.23(s,2H),3.55–3.72(dd,2H),3.04(d,1H),1.14(d,3H),0.84–0.87(t,1H)。
Example 2 Synthesis of (S) -2- (3- ((benzofuran-4-) oxymethyl) benzylamino) propanamide (Ia-2)
Figure BDA0002374562530000153
Taking one 100mL eggplant-shaped bottle, adding 0.59g (4.70mmol) of L-alaninamide hydrochloride, 0.95g (9.40mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.79g (3.13mmol) of 4a-2 into the reaction solution, continuing to react at room temperature for 2h, adding 1.01g (18.80mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4a-2 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow oily substance (Ia-2, 0.93g, 91.18%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.91(d,1H),7.21–7.48(m,7H),6.87–7.03(m,3H),5.24(s,2H),3.56–3.73(dd,2H),3.01–3.04(q,1H),1.23(s,1H),1.17(d,3H)。
Example 3 Synthesis of (S) -2- (4- ((benzofuran-5-) oxymethyl) benzylamino) propanamide (Ia-3)
Figure BDA0002374562530000161
3.14 Synthesis of- ((benzofuran-5-) oxymethyl) benzaldehyde (4a-3) and 3- ((benzofuran-5-) oxymethyl) benzaldehyde (4a-4)
Figure BDA0002374562530000162
Taking 100mL eggplant-shaped bottle, adding 0.69g (5.15mmol) of 5-hydroxybenzofuran and 1.74g (5.35mmol) of Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 1.02g (5.15mmol) of 3a-1 or 3a-2 and 0.13g (0.77mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin layer chromatography until the 5-hydroxybenzofuran point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, dissolving the residue with 20mL of each of water and ethyl acetate, separating the solution, extracting the aqueous phase with ethyl acetate twice, 10mL each time, combining the organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering to remove the sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, separating by column chromatography (PE: EA ═ 12:1 elution) to obtain a white solid 4- ((benzofuran-5-) oxymethyl) benzaldehyde (4a-3, 0.72g, yield 55.38%) or 3- ((benzofuran-5-) oxymethyl) benzaldehyde (4a-4, 0.65g, yield 50.00%).
3.2 Synthesis of (S) -2- (4- ((benzofuran-5-) oxymethyl) benzylamino) propanamide (Ia-3)
Figure BDA0002374562530000163
Adding 0.53g (4.28mmol) of L-alaninamide hydrochloride, 0.87g (8.57mmol) of triethylamine and 30mL of methanol into one eggplant-shaped bottle of 100mL, stirring at room temperature for 1h, adding 0.72g (2.86mmol) of 4a-3 into the reaction solution, continuing to react at room temperature for 2h, adding 0.93g (17.16mmol) of potassium borohydride into the reaction solution three times, and refluxing after the addition is finishedAnd reacting for 3h, monitoring the reaction progress by using thin layer chromatography until the point 4a-3 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a white solid, stirring the residue by using 100-200 meshes silica gel, and performing column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-3, 0.65g, yield 69.89%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.94(d,1H),7.24–7.39(m,8H),6.87–7.02(m,3H),5.10(s,2H),3.53–3.71(dd,2H),2.99–3.04(q,1H),1.13(d,3H)。
Example 4 Synthesis of (S) -2- (3- ((benzofuran-5-) oxymethyl) benzylamino) propanamide (Ia-4)
Figure BDA0002374562530000171
Taking one 100mL eggplant-shaped bottle, adding 0.48g (3.78mmol) of L-alaninamide hydrochloride, 0.78g (7.74mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.65g (2.86mmol) of 4a-4 into the reaction solution, continuing to react at room temperature for 2h, adding 0.83g (15.48mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4a-4 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-4, 0.73g, and the yield is 86.90%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.95(d,1H),7.25–7.34(m,8H),6.87–7.02(m,3H),5.10(s,2H),3.55–3.72(dd,2H),3.01–3.05(q,1H),1.13(d,3H)。
Example 5 Synthesis of (S) -2- (4- ((benzofuran-6-) oxymethyl) benzylamino) propanamide (Ia-5)
Figure BDA0002374562530000172
5.14 Synthesis of- ((benzofuran-6-) oxymethyl) benzaldehyde (4a-5) and 3- ((benzofuran-6-) oxymethyl) benzaldehyde (4a-6)
Figure BDA0002374562530000173
A100 mL eggplant-shaped bottle was taken, and 1.12g (8.36mmol) of 6-hydroxybenzofuran and 2.83g (8.69mmol) of Cs were added2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, putting 1.66g (8.36mmol) of 3a-1 or 3a-2 and 0.21g (1.25mmol) of KI into the reaction solution, refluxing at 80 ℃ after the completion of the addition for more than 4h, monitoring the reaction progress by thin layer chromatography until the 6-hydroxybenzofuran point disappears completely, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a tan solid, and the residue is stirred with 100-200 mesh silica gel and separated by column chromatography (PE: EA: 10: 1) to obtain a white solid, namely 4- ((benzofuran-6-) oxymethyl) benzaldehyde (4a-5, 1.18g, yield 55.92%) or 3- ((benzofuran-6-) oxymethyl) benzaldehyde (4a-6, 1.36g, yield 66.67%).
5.2 Synthesis of (S) -2- (4- ((benzofuran-6-) oxymethyl) benzylamino) propanamide (Ia-5)
Figure BDA0002374562530000181
Adding 0.87g (7.02mmol) of L-alaninamide hydrochloride, 1.42g (14.04mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 1.18g (4.68mmol) of 4a-5 into the reaction solution, continuing to react at room temperature for 2h, adding 1.51g (28.08mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4a-5 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a white solid, stirring the residue by silica gel with 100-200 meshes, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain the white solid (Ia-5, 1.26g, and the yield is 82.89%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.86(d,1H),7.34–7.53(m,8H),6.86–7.01(m,3H),5.12(s,2H),3.52–3.70(dd,2H),2.99–3.03(q,1H),1.13(d,3H)。
Example 6 Synthesis of (S) -2- (3- ((benzofuran-6-) oxymethyl) benzylamino) propanamide (Ia-6)
Figure BDA0002374562530000182
Adding 1.02g (8.21mmol) of L-alaninamide hydrochloride, 1.66g (16.41mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 1.38g (5.47mmol) of 4a-6 into the reaction solution, continuing to react at room temperature for 2h, adding 1.77g (32.82mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4a-6 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-6, 1.41g, and the yield is 79.21%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.87(d,1H),7.30–7.54(m,8H),6.86–6.97(m,3H),5.13(s,2H),3.54–3.71(dd,2H),2.99–3.04(q,1H),1.13(d,3H)。
Example 7 Synthesis of (S) -2- (4- ((benzofuran-7-) oxymethyl) benzylamino) propanamide (Ia-7)
Figure BDA0002374562530000191
7.14 Synthesis of- ((benzofuran-7-) oxymethyl) benzaldehyde (4a-7) and 3- ((benzofuran-7-) oxymethyl) benzaldehyde (4a-8)
Figure BDA0002374562530000192
A100 mL eggplant-shaped bottle was taken, and 1.10g (8.21mmol) of 7-hydroxybenzofuran and 2.78g (8.53mmol) of Cs were added2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, putting 1.63g (8.21mmol) of 3a-1 or 3a-2 and 0.20g (1.23mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the completion of the addition, monitoring the reaction progress by thin layer chromatography until the 7-hydroxybenzofuran point disappears completely, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a yellow-green solid, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA: 10: 1) to obtain a white solid, namely 4- ((benzofuran-7-) oxymethyl) benzaldehyde (4a-7, 1.42g, yield 68.60%) or 3- ((benzofuran-7-) oxymethyl) benzaldehyde (4a-8, 1.39g, yield 67.15%).
7.2 Synthesis of (S) -2- (4- ((benzofuran-7-) oxymethyl) benzylamino) propanamide (Ia-7)
Figure BDA0002374562530000193
Adding 1.42g (11.43mmol) of L-alaninamide hydrochloride, 2.31g (22.85mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 1.92g (7.62mmol) of 4a-7 into the reaction solution, continuing to react at room temperature for 2h, adding 2.46g (5.69mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until the point 4a-7 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-7, 1.52g, yield 61.29%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.86(d,1H),7.31–7.54(m,8H),6.88–6.96(m,3H),5.12(s,2H),3.54–3.71(dd,2H),2.99–3.03(q,1H),1.14(d,3H)。
Example 8 Synthesis of (S) -2- (3- ((benzofuran-7-) oxymethyl) benzylamino) propanamide (Ia-8)
Figure BDA0002374562530000201
Adding 1.39g (11.19mmol) of L-alaninamide hydrochloride, 2.26g (22.37mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 1.88g (7.46mmol) of 4a-8 into the reaction solution, continuing to react at room temperature for 2h, adding 2.41g (44.72mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the reaction is finished, monitoring the reaction progress by thin-layer chromatography until 4a-8 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ia-8, 1.50g, yield 61.98%). ESIMS M/z 325.15[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.87(d,1H),7.29–7.55(m,8H),6.86–6.98(m,3H),5.13(s,2H),3.54–3.71(dd,2H),3.00–3.04(q,1H),1.13(d,3H)。
Example 9 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-4-) oxymethyl) benzylamino) propanamide (Ib-1)
Figure BDA0002374562530000202
9.14 Synthesis of- ((1H-benzo [ d ] imidazol-4-) oxymethyl) benzaldehyde (4b-1) and 3- ((1H-benzo [ d ] imidazol-4-) oxymethyl) benzaldehyde (4b-2)
Figure BDA0002374562530000203
One 250mL eggplant-shaped bottle was taken, and 3.00g (22.36mmol) of 4-hydroxy-1H-benzo [ d ] was added]Imidazole, 7.59g (23.28mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1H, adding 4.43g (22.36mmol) of 3a-1 or 3a-2 and 0.56g (3.38mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4H after the addition is finished, and monitoring the reaction process by thin layer chromatography until 4-hydroxy-1H-benzo [ d ] is reached]Removing imidazole point, filtering, distilling the filtrate under reduced pressure to remove solvent, collecting the residue as brown yellow solid, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (eluting with DCM: MeOH ═ 40: 1) to obtain white solid 4- ((1H-benzo [ d)]Imidazole-4-) oxymethyl) benzaldehyde (4b-1, 1.04g, yield 18.44%) or 3- ((1H-benzo [ d%]Imidazole-4-) oxymethyl) benzaldehyde (4b-2, 1.15g, yield 20.39%).
9.2 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-4-) oxymethyl) benzylamino) propanamide (Ib-1)
Figure BDA0002374562530000211
Adding 0.78g (6.20mmol) of L-alaninamide hydrochloride, 1.25g (12.39mmol) of triethylamine and 30mL of methanol into one eggplant-shaped bottle of 100mL, stirring at room temperature for 30min, adding 1.04g (4.13mmol) of 4b-1 into the reaction solution, continuing to react at room temperature for 2h, adding 1.34g (24.78mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the addition is finished, monitoring the reaction process by thin-layer chromatography until 4b-1 point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is light yellow solid, and the residue is 100-200 meshesSilica gel mixing, column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain white solid (Ib-1, 1.18g, yield 88.06%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.11(s,1H),6.80–7.46(m,10H),5.29(s,2H),3.54–3.72(dd,2H),3.00–3.05(q,1H),1.14(d,3H)。
Example 10 Synthesis of (S) -2- (3- ((1H-benzo [ d ] imidazol-4-) oxymethyl) benzylamino) propanamide (Ib-2)
Figure BDA0002374562530000212
Taking one 100mL eggplant-shaped bottle, adding 0.85g (6.84mmol) of L-alaninamide hydrochloride, 1.38g (13.68mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 1.15g (4.56mmol) of 4b-2 into the reaction solution, continuing to react for 2h at room temperature, adding 1.48g (27.44mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4b-2 point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain white solid (Ib-2, 1.10g, and the yield is 74.32%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.11(s,1H),7.08–7.50(m,10H),5.30(s,2H),3.56–3.73(dd,2H),3.01–3.06(q,1H),1.14(d,3H)。
Example 11 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-5-) oxymethyl) benzylamino) propanamide (Ib-3)
Figure BDA0002374562530000213
11.14 Synthesis of- ((1H-benzo [ d ] imidazol-5-) oxymethyl) benzaldehyde (4b-3) and 3- ((1H-benzo [ d ] imidazol-5-) oxymethyl) benzaldehyde (4b-4)
Figure BDA0002374562530000221
One 250mL eggplant-shaped bottle was taken, and 3.00g (22.36mmol) of 5-hydroxy-1H-benzo [ d ] was added]Imidazole, 7.59g (23.28mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1H, adding 4.43g (22.36mmol) of 3a-1 or 3a-2 and 0.56g (3.38mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4H after the addition is finished, and monitoring the reaction process by thin layer chromatography until 5-hydroxy-1H-benzo [ d ] is reached]Removing imidazole point, filtering, distilling the filtrate under reduced pressure to remove solvent, collecting the residue as brown yellow solid, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (eluting with DCM: MeOH ═ 40: 1) to obtain white solid 4- ((1H-benzo [ d)]Imidazole-5-) oxymethyl) benzaldehyde (4b-3, 1.72g, yield 30.50%) or 3- ((1H-benzo [ d ]]Imidazole-5-) oxymethyl) benzaldehyde (4b-4, 0.90g, yield 15.96%).
11.2 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-5-) oxymethyl) benzylamino) propanamide (Ib-3)
Figure BDA0002374562530000222
Adding 1.18g (9.47mmol) of L-alaninamide hydrochloride, 2.27g (22.43mmol) of triethylamine and 50mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 30min, adding 1.89g (7.49mmol) of 4b-3 into the reaction solution, continuing to react at room temperature for 2h, adding 2.44g (45.24mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until 4b-3 point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ib-3, 1.42g, yield 58.44%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.06–8.12(d,1H),6.85–7.53(m,10H),5.10(s,2H),3.52–3.70(dd,2H),2.98–3.03(q,1H),1.13(d,3H)。
Example 12 Synthesis of (S) -2- (3- ((1H-benzo [ d ] imidazol-5-) oxymethyl) benzylamino) propanamide (Ib-4)
Figure BDA0002374562530000223
Taking one eggplant-shaped bottle of 100mL, adding 0.67g (5.34mmol) of L-alaninamide hydrochloride, 1.08g (10.71mmol) of triethylamine and 30mL of methanol, and keeping the mixture at room temperatureStirring for 30min, adding 0.90g (4.56mmol) of 4b-4 into the reaction solution, continuing to react at room temperature for 2h, adding 1.12g (20.76mmol) of potassium borohydride into the reaction solution for three times, carrying out reflux reaction for 3h after the addition is finished, monitoring the reaction progress by thin layer chromatography until the point 4b-4 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is yellow solid, stirring the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain white solid (Ib-4, 0.62g, yield 53.45%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.09(s,1H),6.88–7.45(m,10H),5.11(s,2H),3.52–3.73(dd,2H),2.99–3.07(q,1H),1.14(d,3H)。
Example 13 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-6-) oxymethyl) benzylamino) propanamide (Ib-5)
Figure BDA0002374562530000231
13.14 Synthesis of- ((1H-benzo [ d ] imidazol-6-) oxymethyl) benzaldehyde (4b-5) and 3- ((1H-benzo [ d ] imidazol-6-) oxymethyl) benzaldehyde (4b-6)
Figure BDA0002374562530000232
One 250mL eggplant-shaped bottle was taken, and 3.00g (22.36mmol) of 6-hydroxy-1H-benzo [ d ] was added]Imidazole, 7.59g (23.28mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1H, adding 4.43g (22.36mmol) of 3a-1 or 3a-2 and 0.56g (3.38mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4H after the addition is finished, and monitoring the reaction process by thin layer chromatography until the reaction reaches 6-hydroxy-1H-benzo [ d ] is completed]Removing imidazole point, filtering, distilling the filtrate under reduced pressure to remove solvent, collecting the residue as brown yellow solid, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (eluting with DCM: MeOH ═ 40: 1) to obtain white solid 4- ((1H-benzo [ d)]Imidazole-6-) oxymethyl) benzaldehyde (4b-5, 1.63g, yield 28.90%) or 3- ((1H-benzo [ d ]]Imidazole-6-) oxymethyl) benzaldehyde (4b-6, 1.23g, yield 21.81%).
13.2 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-6-) oxymethyl) benzylamino) propanamide (Ib-5)
Figure BDA0002374562530000233
Adding 1.18g (9.47mmol) of L-alaninamide hydrochloride, 2.27g (22.43mmol) of triethylamine and 50mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 30min, adding 1.89g (7.49mmol) of 4b-5 into the reaction solution, continuing to react at room temperature for 2h, adding 2.44g (45.24mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until 4b-5 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ib-5, 1.56g, yield 66.67%). ESIMS M/z 324.16[ M + H ]]+；1HNMR(400MHz,DMSO-d6):8.10(s,1H),6.90–7.44(m,10H),5.14(s,2H),3.56–3.75(dd,2H),3.01–3.08(q,1H),1.14(d,3H)。
Example 14 Synthesis of (S) -2- (3- ((1H-benzo [ d ] imidazol-6-) oxymethyl) benzylamino) propanamide (Ib-6)
Figure BDA0002374562530000241
Taking one 100mL eggplant-shaped bottle, adding 0.92g (7.30mmol) of L-alaninamide hydrochloride, 1.48g (14.64mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 1.23g (6.23mmol) of 4b-6 into the reaction solution, continuing to react for 2h at room temperature, adding 1.53g (29.27mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4b-6 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ib-6, 1.23g, yield 77.85%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.09(s,1H),6.89–7.46(m,10H),5.13(s,2H),3.49–3.70(dd,2H),2.99–3.05(q,1H),1.13(d,3H)。
Example 15 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-7-) oxymethyl) benzylamino) propanamide (Ib-7)
Figure BDA0002374562530000242
15.14 Synthesis of- ((1H-benzo [ d ] imidazol-7-) oxymethyl) benzaldehyde (4b-7) and 3- ((1H-benzo [ d ] imidazol-7-) oxymethyl) benzaldehyde (4b-8)
Figure BDA0002374562530000243
One 250mL eggplant-shaped bottle was taken, and 3.00g (22.36mmol) of 7-hydroxy-1H-benzo [ d ] was added]Imidazole, 7.59g (23.28mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1H, adding 4.43g (22.36mmol) of 3a-1 or 3a-2 and 0.56g (3.38mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4H after the addition is finished, and monitoring the reaction process by thin layer chromatography until 7-hydroxy-1H-benzo [ d ] is reached]Removing imidazole point, filtering, distilling the filtrate under reduced pressure to remove solvent, collecting the residue as brown yellow solid, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (eluting with DCM: MeOH ═ 40: 1) to obtain white solid 4- ((1H-benzo [ d)]Imidazole-7-) oxymethyl) benzaldehyde (4b-7, 1.60g, yield 28.37%) or 3- ((1H-benzo [ d ]]Imidazole-7-) oxymethyl) benzaldehyde (4b-8, 1.33g, yield 23.58%).
15.2 Synthesis of (S) -2- (4- ((1H-benzo [ d ] imidazol-7-) oxymethyl) benzylamino) propanamide (Ib-7)
Figure BDA0002374562530000251
Adding 1.00g (8.02mmol) of L-alaninamide hydrochloride, 1.92g (18.99mmol) of triethylamine and 50mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 30min, adding 1.60g (6.34mmol) of 4b-7 into the reaction solution, continuing to react at room temperature for 2h, adding 2.07g (38.38mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the reaction is finished, monitoring the reaction progress by thin-layer chromatography until the point 4b-7 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ib-7, 1.58g, 76.70%).ESIMS m/z 324.16[M+H]+；1H NMR(400MHz,DMSO-d6):8.12(s,1H),6.91–7.47(m,10H),5.16(s,2H),3.52–3.76(dd,2H),3.02–3.09(q,1H),1.14(d,3H)。
Example 16 Synthesis of (S) -2- (3- ((1H-benzo [ d ] imidazol-7-) oxymethyl) benzylamino) propanamide (Ib-8)
Figure BDA0002374562530000252
Taking one 100mL eggplant-shaped bottle, adding 0.99g (7.99mmol) of L-alaninamide hydrochloride, 1.60g (15.82mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 1.33g (6.74mmol) of 4b-8 into the reaction solution, continuing to react for 2h at room temperature, adding 1.65g (30.67mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until 4b-8 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (Ib-8, 0.83g, and the yield of 48.53%). ESIMS M/z 324.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.09(s,1H),6.88–7.44(m,10H),5.13(s,2H),3.49–3.73(dd,2H),2.98–3.07(q,1H),1.14(d,3H)。
Example 17 Synthesis of (S) -2- (4- ((quinoline-5-) oxymethyl) benzylamino) propanamide (Ic-1)
Figure BDA0002374562530000253
17.14 Synthesis of- ((quinoline-5-) oxymethyl) benzaldehyde (4c-1) and 3- ((quinoline-5-) oxymethyl) benzaldehyde (4c-2)
Figure BDA0002374562530000261
A100 mL eggplant-shaped bottle was taken, and 1.00g (6.89mmol) of 5-hydroxyquinoline and 0.99g (7.16mmol) of K were added2CO3And 40mL of anhydrous ethanol, stirring at room temperature for 1h, adding 1.36g (6.89mmol) of 3a-1 or 3a-2 and 0.17g (1.03mmol) of KI into the reaction solution, and refluxing at 80 deg.C for 4h or more after the addition is completed to obtain the final productMonitoring the reaction progress by thin layer chromatography until 5-hydroxyquinoline point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a black solid, dissolving the residue by 50mL of each of water and ethyl acetate, separating the solution, extracting the water phase twice by 30mL of each of ethyl acetate, combining the organic phases, washing the water and saturated saline water once, drying the anhydrous sodium sulfate, filtering to remove the sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 1:1 elution) to obtain pale yellow solid 4- ((quinoline-5-) oxymethyl) benzaldehyde (4c-1, 0.88g, yield 48.62%) or 3- ((quinoline-5-) oxymethyl) benzaldehyde (4c-2, 1.14g, yield 62.98%).
17.2 Synthesis of (S) -2- (4- ((quinoline-5-) oxymethyl) benzylamino) propanamide (Ic-1)
Figure BDA0002374562530000262
Taking one 100mL eggplant-shaped bottle, adding 0.63g (5.02mmol) of L-alaninamide hydrochloride, 1.02g (10.04mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.88g (3.34mmol) of 4c-1 into the reaction solution, continuing to react for 2h at room temperature, adding 1.08g (20.07mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until the point 4c-1 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-1, 0.74g, the yield of 66.07%). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.90–8.91(m,1H),8.56(d,1H,J＝8.4Hz),7.02–7.70(m,10H),5.31(s,2H),3.54–3.72(dd,2H),2.99–3.04(q,1H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 18 Synthesis of (S) -2- (3- ((quinoline-5-) oxymethyl) benzylamino) propanamide (Ic-2)
Figure BDA0002374562530000263
A100 mL eggplant-shaped bottle was charged with 0.81g (6.50mmol) of L-alaninamide hydrochloride and 1.32g (13).00mmol) of triethylamine and 40mL of methanol, stirring for 30min at room temperature, adding 1.14g (4.33mmol) of 4c-2 into the reaction solution, continuing to react for 2h at room temperature, adding 1.40g (25.99mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reflux reaction, monitoring the reaction process by using thin-layer chromatography until the point 4c-2 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a yellow solid, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to give a pale yellow solid (Ic-2, 1.17g, 80.69% yield). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.91–8.92(m,1H),8.58(d,1H,J＝8.4Hz),7.04–7.70(m,10H),5.32(s,2H),3.58–3.80(dd,2H),3.01–3.07(q,1H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 19 Synthesis of (S) -2- (4- ((quinolin-6-) oxymethyl) benzylamino) propanamide (Ic-3)
Figure BDA0002374562530000271
19.14 Synthesis of- ((quinoline-6-) oxymethyl) benzaldehyde (4c-3) and 3- ((quinoline-6-) oxymethyl) benzaldehyde (4c-4)
Figure BDA0002374562530000272
A100 mL eggplant-shaped bottle was taken, and 1.00g (18.36mmol) of 6-hydroxyquinoline and 0.99g (7.16mmol) of K were added2CO3And 40mL of anhydrous ethanol, stirring at room temperature for 1h, adding 1.36g (6.89mmol) of 3a-1 or 3a-2 and 0.17g (1.03mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin layer chromatography until the 6-hydroxyquinoline point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is a black solid, dissolving the residue with 50mL of each of water and ethyl acetate, separating the solution, extracting the aqueous phase with ethyl acetate twice, 30mL each time, combining the organic phases, washing with water and saturated saline water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (PE: EA ═ 1:1 elution) to obtain light yellow solid 4- ((quinoline-6-) oxymethyl) benzaldehyde (4c-3, 0.92g of a mixture of (A) and (B),yield 50.83%) or 3- ((quinoline-6-) oxymethyl) benzaldehyde (4c-4, 1.14g, yield 67.40%).
19.2 Synthesis of (S) -2- (4- ((quinoline-6-) oxymethyl) benzylamino) propanamide (Ic-3)
Figure BDA0002374562530000273
Adding 0.66g (5.25mmol) of L-alaninamide hydrochloride, 1.07g (10.50mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 30min, adding 0.92g (3.49mmol) of 4c-3 into the reaction solution, continuing to react at room temperature for 2h, adding 1.13g (20.98mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until the point 4c-3 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-3, 0.96g, 82.05% yield). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.73–8.74(m,1H),8.23–8.25(t,1H),7.93(d,1H,J＝9.0Hz),7.36–7.51(m,8H),7.01(s,1H),5.21(s,2H),3.54–3.72(dd,2H),2.98–3.04(q,1H),1.13(d,3H,J＝7.0Hz)。
EXAMPLE 20 Synthesis of (S) -2- (3- ((quinolin-6-) oxymethyl) benzylamino) propanamide (Ic-4)
Figure BDA0002374562530000281
Taking one 100mL eggplant-shaped bottle, adding 0.85g (6.84mmol) of L-alaninamide hydrochloride, 1.38g (13.68mmol) of triethylamine and 40mL of methanol, stirring for 30min at room temperature, adding 1.20g (4.56mmol) of 4c-4 into the reaction solution, continuing to react for 2h at room temperature, adding 1.48g (27.37mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4c-4 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-4, 1.31g, and the yield of 85.62%). ESIMS m/z 335.16[ alpha ]M+H]+；1H NMR(400MHz,DMSO-d6):8.74–8.75(m,1H),8.24–8.26(q,1H),7.94(d,1H,J＝8.7Hz),7.31–7.50(m,9H),7.02(s,1H),5.23(s,2H),3.56–3.76(dd,2H),3.01–3.06(q,1H),1.14(d,3H,J＝7.0Hz)。
Example 21 Synthesis of (S) -2- (4- ((quinolin-7-) oxymethyl) benzylamino) propanamide (Ic-5)
Figure BDA0002374562530000282
21.14 Synthesis of- ((quinoline-7-) oxymethyl) benzaldehyde (4c-5) and 3- ((quinoline-7-) oxymethyl) benzaldehyde (4c-6)
Figure BDA0002374562530000283
A100 mL eggplant-shaped bottle was taken, and 1.00g (6.89mmol) of 7-hydroxyquinoline and 0.99g (7.16mmol) of K were added2CO3And 40mL of anhydrous ethanol, stirring at room temperature for 1h, adding 1.36g (6.89mmol) of 3a-1 or 3a-2 and 0.17g (1.03mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin layer chromatography until the 7-hydroxyquinoline point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is brown solid, dissolving the residue with 50mL of each of water and ethyl acetate, separating the solution, extracting the aqueous phase with ethyl acetate twice, 30mL each time, combining the organic phases, washing with water and saturated saline solution once, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (PE: EA ═ 1:1 elution) to obtain light yellow solid 4- ((quinoline-7-) oxymethyl) benzaldehyde (4c-5, 0.87g, yield 48.07%) or 3- ((quinoline-7-) oxymethyl) benzaldehyde (4c-6, 0.90g, yield 49.72%).
21.2 Synthesis of (S) -2- (4- ((quinoline-7-) oxymethyl) benzylamino) propanamide (Ic-5)
Figure BDA0002374562530000291
Taking 100mL eggplant-shaped bottle, adding 0.62g (4.96mmol) of L-alaninamide hydrochloric acidStirring the salt, 1.00g (9.92mmol) of triethylamine and 40mL of methanol at room temperature for 30min, adding 0.87g (3.31mmol) of 4c-5 into the reaction liquid, continuing to react at room temperature for 2h, adding 1.07g (19.84mmol) of potassium borohydride into the reaction liquid in three times, refluxing for 3h after the completion of the reaction, monitoring the reaction progress by using thin layer chromatography until the point 4c-5 completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and performing column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-5, 0.87g, and the yield is 78.38%). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.80–8.81(m,1H),8.26–8.29(q,1H),7.89(s,1H),7.31–7.48(m,8H),7.00(s,1H),5.26(s,2H),3.53–3.71(dd,2H),2.98–3.03(q,1H),1.13(d,3H,J＝7.0Hz)。
Example 22 Synthesis of (S) -2- (3- ((quinoline-7-) oxymethyl) benzylamino) propanamide (Ic-6)
Figure BDA0002374562530000292
Taking one 100mL eggplant-shaped bottle, adding 0.64g (5.13mmol) of L-alaninamide hydrochloride, 1.04g (10.26mmol) of triethylamine and 40mL of methanol, stirring for 30min at room temperature, adding 0.90g (3.42mmol) of 4c-6 into the reaction solution, continuing to react for 2h at room temperature, adding 1.11g (20.53mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until 4c-6 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-6, 0.94g, yield 81.74%). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.80–8.82(m,1H),8.27–8.29(q,1H),7.90(d,1H,J＝9.0Hz),7.48–7.50(m,2H),7.30–7.39(m,6H),7.02(s,1H),5.27(s,2H),3.55–3.73(dd,2H),3.00–3.05(q,1H),1.14(d,3H,J＝7.0Hz)。
Example 23 Synthesis of (S) -2- (4- ((quinolin-8-) oxymethyl) benzylamino) propanamide (Ic-7)
Figure BDA0002374562530000301
23.14 Synthesis of- ((quinoline-8-) oxymethyl) benzaldehyde (4c-7) and 3- ((quinoline-8-) oxymethyl) benzaldehyde (4c-8)
Figure BDA0002374562530000302
A100 mL eggplant-shaped bottle was taken, and 1.00g (6.89mmol) of 8-hydroxyquinoline and 0.99g (7.16mmol) of K were added2CO3And 40mL of anhydrous ethanol, stirring at room temperature for 1h, adding 1.36g (6.89mmol) of 3a-1 or 3a-2 and 0.17g (1.03mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin layer chromatography until the 8-hydroxyquinoline point completely disappears, filtering, distilling the filtrate under reduced pressure to remove the solvent, wherein the residue is brown solid, dissolving the residue with 50mL of each of water and ethyl acetate, separating the solution, extracting the aqueous phase with ethyl acetate twice, 30mL each time, combining the organic phases, washing with water and saturated saline solution once, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (PE: EA ═ 1:1 elution) to obtain light yellow solid 4- ((quinoline-8-) oxymethyl) benzaldehyde (4c-7, 0.94g, yield 51.93%) or 3- ((quinoline-8-) oxymethyl) benzaldehyde (4c-8, 1.20g, yield 66.30%).
23.2 Synthesis of (S) -2- (4- ((quinoline-8-) oxymethyl) benzylamino) propanamide (Ic-7)
Figure BDA0002374562530000303
Adding 0.67g (5.36mmol) of L-alaninamide hydrochloride, 1.08g (10.71mmol) of triethylamine and 40mL of methanol into one 100mL eggplant-shaped bottle, stirring for 30min at room temperature, adding 0.94g (3.57mmol) of 4c-7 into the reaction solution, continuing to react for 2h at room temperature, adding 1.16g (21.42mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reflux reaction, monitoring the reaction process by thin-layer chromatography until 4c-7 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain white solidSolid (Ic-7, 1.03g, yield 85.83%). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.84–8.86(m,1H),8.30–8.33(q,1H),7.26–7.56(m,9H),7.01(s,1H),5.28(s,2H),3.54–3.72(dd,2H),2.99–3.04(q,1H),1.13(d,3H,J＝7.0Hz)。
EXAMPLE 24 Synthesis of (S) -2- (3- ((quinoline-8-) oxymethyl) benzylamino) propanamide (Ic-8)
Figure BDA0002374562530000311
Taking one 100mL eggplant-shaped bottle, adding 0.85g (6.84mmol) of L-alaninamide hydrochloride, 1.38g (13.68mmol) of triethylamine and 40mL of methanol, stirring for 30min at room temperature, adding 1.20g (3.42mmol) of 4c-8 into the reaction solution, continuing to react for 2h at room temperature, adding 1.48g (27.37mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin layer chromatography until 4c-8 points completely disappear, filtering, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 meshes of silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a light yellow solid (Ic-8, 1.47g, and the yield 96.08%). ESIMS M/z 335.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.85–8.86(m,1H),8.31–8.33(q,1H),7.28–7.57(m,9H),7.01(s,1H),5.29(s,2H),3.56–3.73(dd,2H),3.00–3.06(q,1H),1.13(d,3H,J＝7.0Hz)。
Example 25 Synthesis of (S) -2- (4- ((indolin-4-) oxymethyl) benzylamino) propanamide (IIa-1)
Figure BDA0002374562530000312
25.14 Synthesis of- ((indoline-4-) oxymethyl) benzaldehyde (4d-1) and 3- ((indoline-4-) oxymethyl) benzaldehyde (4d-2)
Figure BDA0002374562530000313
Taking 100mL eggplant-shaped bottle, adding 0.54g (4.00mmol) of 4-hydroxyindoline and 1.36g (4.16mmol) of Cs2CO3And 30mL of absolute ethyl alcohol is stirred for 1h at room temperature, 0.79g (4.00mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI are put into the reaction solution, reflux reaction is carried out at 80 ℃ for more than 4h after the completion of the addition, the reaction progress is monitored by thin layer chromatography until the point of 4-hydroxyindoline completely disappears, the solvent is removed by reduced pressure distillation, the residue is brown solid, the residue is dissolved by 30mL of water and ethyl acetate respectively, liquid separation is carried out, the water phase is extracted twice by ethyl acetate, 15mL each time, organic phases are combined, water washing is carried out, saturated salt water washing is carried out, anhydrous sodium sulfate is dried, sodium sulfate is removed by filtration, the filtrate is removed by reduced pressure distillation, the solvent is removed, the residue is mixed with 100-200 meshes of silica gel, and is separated (PE: EA is eluted by column chromatography) to obtain light yellow oily 4- ((indoline-4-) oxymethyl) benzaldehyde (, 0.61g, yield 60.40%) or 3- ((indolin-4-) oxymethyl) benzaldehyde (4d-2, 0.76g, yield 75.25%).
25.2 Synthesis of (S) -2- (4- ((indolin-4-) oxymethyl) benzylamino) propanamide (IIa-1)
Figure BDA0002374562530000321
Taking one 100mL eggplant-shaped bottle, adding 0.45g (3.60mmol) of L-alaninamide hydrochloride, 0.73g (7.20mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.61g (2.40mmol) of 4d-1 into the reaction solution, continuing to react for 2h at room temperature, adding 0.78g (14.40mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until the point 4d-1 completely disappears, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-1, 0.54g, yield 69.23%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.78–8.81(m,1H),8.51(d,1H,J＝8.4Hz),7.29–7.66(m,9H),7.13(d,1H,J＝7.6Hz),6.91(s,1H),5.13(s,2H),3.46–3.68(dd,2H),2.96–2.98(q,1H),2.60(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 26 Synthesis of (S) -2- (3- ((indolin-4-) oxymethyl) benzylamino) propanamide (IIa-2)
Figure BDA0002374562530000322
Taking one 100mL eggplant-shaped bottle, adding 0.56g (4.49mmol) of L-alaninamide hydrochloride, 0.91g (8.97mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.76g (2.99mmol) of 4d-2 into the reaction solution, continuing to react at room temperature for 2h, adding 0.97g (17.94mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4d-2 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-2, 0.73g, yield 74.49%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.80–8.82(m,1H),8.53(d,1H,J＝8.4Hz),7.32–7.69(m,9H),7.17(d,1H,J＝7.6Hz),6.99(s,1H),5.16(s,2H),3.46–3.69(dd,2H),2.95–2.99(q,1H),2.61(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 27 Synthesis of (S) -2- (4- ((indolin-5-) oxymethyl) benzylamino) propanamide (IIa-3)
Figure BDA0002374562530000323
27.14 Synthesis of- ((indoline-5-) oxymethyl) benzaldehyde (4d-3) and 3- ((indoline-5-) oxymethyl) benzaldehyde (4d-4)
Figure BDA0002374562530000331
Taking 100mL eggplant-shaped bottle, adding 0.54g (4.00mmol) of 5-hydroxyindoline and 1.36g (4.16mmol) of Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition is finished, monitoring the reaction process by thin layer chromatography until the 5-hydroxyindoline point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is a pale yellow solid, dissolving the residue by 30mL of each of water and ethyl acetate, separating the liquid, extracting the aqueous phase twice by 15mL of ethyl acetate, combining the organic phases, washing with water, and extracting with saturated saline water, wherein the saturated saline water is 15mL of each timeWashing, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 12:1 elution) to obtain light yellow oily matter 4- ((indoline-5-) oxymethyl) benzaldehyde (4d-3, 0.72g, yield 71.29%) or 3- ((indoline-5-) oxymethyl) benzaldehyde (4d-4, 0.77g, yield 76.24%).
27.2 Synthesis of (S) -2- (4- ((indolin-5-) oxymethyl) benzylamino) propanamide (IIa-3)
Taking one 100mL eggplant-shaped bottle, adding 0.53g (4.26mmol) of L-alaninamide hydrochloride, 0.86g (8.52mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.72g (2.83mmol) of 4d-3 into the reaction solution, continuing to react at room temperature for 2h, adding 0.92g (17.04mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4d-3 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-3, 0.75g, yield 80.65%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.79–8.82(m,1H),8.51(d,1H,J＝8.4Hz),7.29–7.68(m,9H),7.14(d,1H,J＝7.6Hz),6.96(s,1H),5.15(s,2H),3.47–3.69(dd,2H),2.96–3.00(q,1H),2.61(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 28 Synthesis of (S) -2- (3- ((indolin-5-) oxymethyl) benzylamino) propanamide (IIa-4)
Figure BDA0002374562530000333
Adding 0.57g (4.55mmol) of L-alaninamide hydrochloride, 0.92g (9.09mmol) of triethylamine and 30mL of methanol into one eggplant-shaped bottle of 100mL, stirring at room temperature for 1h, adding 0.77g (3.03mmol) of 4d-4 into the reaction solution, continuing to react at room temperature for 2h, adding 0.98g (18.24mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the addition, and monitoring the reaction progress to 4d-4 by thin-layer chromatographyThe spot was completely disappeared, the solvent was distilled off under reduced pressure to remove the residue as a pale yellow solid, and the residue was stirred with 100-200 mesh silica gel and separated by column chromatography (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-4, 0.63g, yield 63.64%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.84–8.86(m,1H),8.56(d,1H,J＝8.4Hz),7.33–7.69(m,9H),7.16(d,1H,J＝7.6Hz),6.99(s,1H),5.16(s,2H),3.49–3.70(dd,2H),2.97–3.00(q,1H),2.62(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 29 Synthesis of (S) -2- (4- ((indolin-6-) oxymethyl) benzylamino) propanamide (IIa-5)
Figure BDA0002374562530000341
29.14 Synthesis of- ((indoline-6-) oxymethyl) benzaldehyde (4d-5) and 3- ((indoline-6-) oxymethyl) benzaldehyde (4d-6)
Figure BDA0002374562530000342
Taking 100mL eggplant-shaped bottle, adding 0.54g (4.00mmol) of 6-hydroxyindoline and 1.36g (4.16mmol) of Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin-layer chromatography until the 6-hydroxyindoline point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is a pale yellow solid, dissolving the residue with 30mL of each of water and ethyl acetate, separating the solution, extracting the aqueous phase with ethyl acetate twice, 15mL each time, combining organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, separating (PE: EA ═ 12:1 elution by column chromatography) to obtain a pale yellow oily 4- ((indoline-6-) oxymethyl) benzaldehyde (4d-5, 0.75g, yield 74.26%) or 3- ((indolin-6-) oxymethyl) benzaldehyde (4d-6, 0.83g, yield 82.18%).
29.2 Synthesis of (S) -2- (4- ((indolin-6-) oxymethyl) benzylamino) propanamide (IIa-5)
Figure BDA0002374562530000343
Taking one 100mL eggplant-shaped bottle, adding 0.55g (4.43mmol) of L-alaninamide hydrochloride, 0.90g (8.85mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.75g (2.95mmol) of 4d-5 into the reaction solution, continuing to react at room temperature for 2h, adding 0.96g (17.77mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until the point 4d-5 completely disappears, carrying out reduced pressure distillation to remove the solvent, wherein the residue is light yellow solid, stirring the residue by 100-200 meshes of silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain white solid (IIa-5, 0.82g, yield 85.42%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.80–8.83(m,1H),8.52(d,1H,J＝8.4Hz),7.31–7.67(m,9H),7.15(d,1H,J＝7.6Hz),6.98(s,1H),5.16(s,2H),3.48–3.70(dd,2H),2.97–3.00(q,1H),2.61(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 30 Synthesis of (S) -2- (3- ((indolin-6-) oxymethyl) benzylamino) propanamide (IIa-6)
Figure BDA0002374562530000351
Taking one 100mL eggplant-shaped bottle, adding 0.61g (4.93mmol) of L-alaninamide hydrochloride, 0.99g (9.80mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.83g (3.27mmol) of 4d-6 into the reaction solution, continuing to react at room temperature for 2h, adding 1.06g (19.58mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4d-6 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-6, 0.79g, the yield is 73.83%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.87–8.89(m,1H),8.59(d,1H,J＝8.4Hz),7.36–7.74(m,9H),7.20(d,1H,J＝7.6Hz),7.04(s,1H),5.19(s,2H),3.50–3.72(dd,2H),2.98–3.01(q,1H),2.63(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 31 Synthesis of (S) -2- (4- ((indolin-7-) oxymethyl) benzylamino) propanamide (IIa-7)
Figure BDA0002374562530000352
31.14 Synthesis of- ((indoline-7-) oxymethyl) benzaldehyde (4d-7) and 3- ((indoline-7-) oxymethyl) benzaldehyde (4d-8)
Figure BDA0002374562530000353
Taking 100mL eggplant-shaped bottle, adding 0.54g (4.00mmol) of 7-hydroxyindoline and 1.36g (4.16mmol) of Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition is finished, monitoring the reaction progress by thin-layer chromatography until 7-hydroxyindoline completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is a pale yellow solid, dissolving the residue by 30mL of water and ethyl acetate respectively, separating the solution, extracting the aqueous phase twice by 15mL of ethyl acetate, combining organic phases, washing by water, washing by saturated salt water, drying by anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue by 100-200 meshes of silica gel, separating (PE: EA: 12:1 column chromatography) to obtain a pale yellow oily substance 4- ((indoline-7-) oxymethyl) benzaldehyde (4d-7, 0.63g, yield 62.38%) or 3- ((indolin-7-) oxymethyl) benzaldehyde (4d-8, 0.83g, yield 82.18%).
31.2 Synthesis of (S) -2- (4- ((indolin-7-) oxymethyl) benzylamino) propanamide (IIa-7)
Figure BDA0002374562530000361
Taking 100mL eggplant-shaped bottle, adding 0.46g (3.71mmol) L-alaninamide hydrochloride, 0.76g (7.47mmol) triethylamine and 30mL methanol, stirring at room temperature for 1h, adding 0.63g (2.48mmol)4d-7 to the reaction solution, continuing to react at room temperature for 2h, adding 0.81g (14.95 mmol)mmol) potassium borohydride is added into the reaction liquid for three times, after the adding, the reflux reaction is carried out for 3 hours, the reaction process is monitored by thin-layer chromatography until the point 4d-7 disappears completely, the solvent is removed by reduced pressure distillation, the residue is light yellow solid, the residue is mixed with 100-200 mesh silica gel, and the mixture is separated by column chromatography (gradient elution: MeOH/DCM, 0-5%) to give a white solid (IIa-7, 0.69g, 85.19% yield). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.84–8.87(m,1H),8.57(d,1H,J＝8.4Hz),7.34–7.72(m,9H),7.19(d,1H,J＝7.6Hz),7.02(s,1H),5.20(s,2H),3.49–3.72(dd,2H),2.98–3.01(q,1H),2.63(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 32 Synthesis of (S) -2- (3- ((indolin-7-) oxymethyl) benzylamino) propanamide (IIa-8)
Figure BDA0002374562530000362
Taking one 100mL eggplant-shaped bottle, adding 0.61g (4.93mmol) of L-alaninamide hydrochloride, 0.99g (9.80mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.83g (3.27mmol) of 4d-8 into the reaction solution, continuing to react at room temperature for 2h, adding 1.06g (19.58mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4d-8 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIa-8, 0.73g, yield 68.22%). ESIMS M/z 325.18[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.83–8.86(m,1H),8.55(d,1H,J＝8.4Hz),7.33–7.70(m,9H),7.18(d,1H,J＝7.6Hz),7.00(s,1H),5.18(s,2H),3.49–3.71(dd,2H),2.97–3.01(q,1H),2.62(s,1H),1.13(d,3H,J＝7.0Hz)。
Example 33 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzylamino) propanamide (IIb-1)
Figure BDA0002374562530000371
33.14 Synthesis of- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzaldehyde (4e-1) and 3- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzaldehyde (4e-2)
Figure BDA0002374562530000372
One eggplant-shaped bottle of 100mL was taken, and 0.54g (3.97mmol) of 4-hydroxy-2, 3-dihydrobenzofuran and 1.35g (4.13mmol) of Cs were added2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin-layer chromatography until the 4-hydroxy-2, 3-dihydrobenzofuran point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is brown solid, dissolving the residue with 30mL of each of water and ethyl acetate, separating, extracting the water phase with ethyl acetate twice, 15mL each time, combining the organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (PE: EA: 12:1 elution) to obtain light yellow 4- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzaldehyde (4e-1) as a pale yellow oily substance, 0.66g, yield 65.35%) or 3- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzaldehyde (4e-2, 0.86g, yield 85.15%).
33.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzylamino) propanamide (IIb-1)
Figure BDA0002374562530000373
Taking one 100mL eggplant-shaped bottle, adding 0.49g (3.91mmol) of L-alaninamide hydrochloride, 0.79g (7.81mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.66g (2.60mmol) of 4e-1 into the reaction solution, continuing to react for 2h at room temperature, adding 0.84g (15.65mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4e-1 point completely disappears, distilling under reduced pressure to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-1, 0.73g, 85.88% yield). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.90–8.94(m,1H),8.59(d,1H,J＝8.4Hz),7.36–7.73(m,8H),7.20(d,1H,J＝7.6Hz),7.05(s,1H),5.31(s,2H),3.55–3.75(dd,2H),3.00–3.04(q,1H),2.67(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 34 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzofuran-4-) oxymethyl) benzylamino) propanamide (IIb-2)
Figure BDA0002374562530000381
Taking one 100mL eggplant-shaped bottle, adding 0.63g (5.09mmol) of L-alaninamide hydrochloride, 1.03g (10.18mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.86g (3.38mmol) of 4e-2 into the reaction solution, continuing to react at room temperature for 2h, adding 1.10g (20.35mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4e-2 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-2, 0.83g, 75.45%). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.90–8.92(m,1H),8.57(d,1H,J＝8.4Hz),7.35–7.72(m,8H),7.17(d,1H,J＝7.6Hz),7.03(s,1H),5.31(s,2H),3.55–3.74(dd,2H),2.99–3.03(q,1H),2.65(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 35 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzylamino) propanamide (IIb-3)
Figure BDA0002374562530000382
Synthesis of 35.14- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzaldehyde (4e-3) and 3- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzaldehyde (4e-4)
Figure BDA0002374562530000383
Taking 100mL eggplant-shaped bottle, adding 0.54g (3.97mmol) of 5-hydroxy-2, 3-dihydrobenzofuran、1.35g(4.13mmol)Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin-layer chromatography until the 5-hydroxy-2, 3-dihydrobenzofuran point disappears completely, distilling under reduced pressure to remove the solvent, wherein the residue is a brown solid, dissolving the residue with 30mL of each of water and ethyl acetate, separating, extracting the aqueous phase with ethyl acetate twice, 15mL each time, combining the organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (PE: EA: 12:1 elution) to obtain a white solid 4- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzaldehyde (4e-3, 0.60g, yield 59.41%) or 3- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzaldehyde (4e-4, 0.78g, yield 77.23%).
35.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzylamino) propanamide (IIb-3)
Figure BDA0002374562530000391
Taking one 100mL eggplant-shaped bottle, adding 0.45g (3.58mmol) of L-alaninamide hydrochloride, 0.72g (7.10mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.60g (2.36mmol) of 4e-3 into the reaction solution, continuing to react for 2h at room temperature, adding 0.76g (14.16mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4e-3 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-3, 0.68g, 88.31% yield). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.90–8.91(m,1H),8.56(d,1H,J＝8.4Hz),7.35–7.70(m,8H),7.17(d,1H,J＝7.6Hz),7.02(s,1H),5.31(s,2H),3.54–3.72(dd,2H),2.99–3.04(q,1H),2.65(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 36 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzofuran-5-) oxymethyl) benzylamino) propanamide (IIb-4)
Figure BDA0002374562530000392
Taking one 100mL eggplant-shaped bottle, adding 0.57g (4.59mmol) of L-alaninamide hydrochloride, 0.93g (9.23mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.78g (3.07mmol) of 4e-4 into the reaction solution, continuing to react at room temperature for 2h, adding 1.00g (18.50mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4e-4 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-4, 0.85g, yield 85.00%). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.91–8.92(m,1H),8.58(d,1H,J＝8.4Hz),7.32–7.70(m,8H),7.18(d,1H,J＝7.6Hz),7.04(s,1H),5.32(s,2H),3.58–3.70(dd,2H),3.01–3.07(q,1H),2.66(s,1H),1.14(d,3H,J＝7.0Hz)。
Example 37 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzylamino) propanamide (IIb-5)
Figure BDA0002374562530000401
37.14 Synthesis of- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzaldehyde (4e-5) and 3- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzaldehyde (4e-6)
Figure BDA0002374562530000402
One eggplant-shaped bottle of 100mL was taken, and 0.54g (3.97mmol) of 6-hydroxy-2, 3-dihydrobenzofuran and 1.35g (4.13mmol) of Cs were added2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition is finished, monitoring the reaction process by thin layer chromatography until the 6-hydroxy-2, 3-dihydrobenzofuran point is completely disappeared, distilling under reduced pressure to remove the solvent, wherein the residue is brown solid and is prepared by adding waterAnd ethyl acetate, each 30mL, the residue was dissolved, separated, the aqueous phase was extracted twice with ethyl acetate, each 15mL, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, the filtrate was distilled under reduced pressure to remove the solvent, the residue was sampled with 100-200 mesh silica gel, and column chromatography was performed (PE: EA ═ 12:1 elution) to give 4- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzaldehyde (4e-5, 0.60g, yield 59.41%) or 3- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzaldehyde (4e-6, 0.80g, yield 79.21%) as a white solid.
37.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzylamino) propanamide (IIb-5)
Figure BDA0002374562530000403
Taking one 100mL eggplant-shaped bottle, adding 0.45g (3.58mmol) of L-alaninamide hydrochloride, 0.72g (7.10mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.60g (2.36mmol) of 4e-5 into the reaction solution, continuing to react for 2h at room temperature, adding 0.76g (14.16mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4e-5 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-5, 0.63g, yield 81.81%). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.38(s,1H),7.26–7.35(m,4H),7.09–7.12(t,1H),7.03(s,1H),6.45–6.49(m,2H),5.01(s,2H),4.49–4.54(t,2H),3.54–3.72(dd,2H),3.05–3.12(t,2H),2.99–3.03(q,1H),1.13(d,3H,J＝7.0Hz)。
Example 38 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzofuran-6-) oxymethyl) benzylamino) propanamide (IIb-6)
Figure BDA0002374562530000411
Taking one eggplant-shaped bottle of 100mL, adding 0.58g (4.69mmol) of L-alaninamide hydrochloride, 0.95g (9.43mmol) of triethylamine and 30mL of methanol, and stirring at room temperatureStirring for 1h, adding 0.80g (3.15mmol) of 4e-6 into the reaction solution, continuing to react for 2h at room temperature, adding 1.03g (19.01mmol) of potassium borohydride into the reaction solution for three times, carrying out reflux reaction for 3h after the addition is finished, monitoring the reaction progress by thin layer chromatography until 4e-6 points completely disappear, carrying out reduced pressure distillation to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-6, 0.65g, yield 63.11%). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.39(s,1H),7.26–7.34(m,4H),7.07–7.10(t,1H),7.01(s,1H),6.44–6.48(m,2H),5.01(s,2H),4.49–4.53(t,2H),3.52–3.70(dd,2H),3.05–3.10(t,2H),2.98–3.03(q,1H),1.13(d,3H,J＝7.0Hz)。
Example 39 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzylamino) propanamide (IIb-7)
Figure BDA0002374562530000412
Synthesis of 39.14- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzaldehyde (4e-7) and 3- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzaldehyde (4e-8)
Figure BDA0002374562530000413
One eggplant-shaped bottle of 100mL was taken, and 0.54g (3.97mmol) of 7-hydroxy-2, 3-dihydrobenzofuran and 1.35g (4.13mmol) of Cs were added2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.79g (3.97mmol) of 3a-1 or 3a-2 and 0.10g (0.60mmol) of KI into the reaction solution, carrying out reflux reaction at 80 ℃ for more than 4h after the addition, monitoring the reaction progress by thin layer chromatography until the 7-hydroxy-2, 3-dihydrobenzofuran point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is brown solid, dissolving the residue with 30mL of each of water and ethyl acetate, separating, extracting the water phase with ethyl acetate twice (15 mL each time), combining the organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (PE: EA is 12:1 elution) to obtain a white solidThe bulk 4- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzaldehyde (4e-7, 0.79g, yield 78.22%) or 3- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzaldehyde (4e-8, 0.80g, yield 79.21%).
39.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzylamino) propanamide (IIb-7)
Figure BDA0002374562530000421
Taking one 100mL eggplant-shaped bottle, adding 0.59g (4.76mmol) of L-alaninamide hydrochloride, 0.95g (9.37mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.79g (3.11mmol) of 4e-7 into the reaction solution, continuing to react for 2h at room temperature, adding 1.00g (18.55mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4e-7 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIb-7, 0.63g, yield 62.38%). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.39(s,1H),7.27–7.35(m,4H),7.07–7.12(t,1H),7.03(s,1H),6.45–6.48(m,2H),5.01(s,2H),4.49–4.52(t,2H),3.52–3.69(dd,2H),3.05–3.11(t,2H),2.98–3.04(q,1H),1.13(d,3H,J＝7.0Hz)。
EXAMPLE 40 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzofuran-7-) oxymethyl) benzylamino) propanamide (IIb-8)
Figure BDA0002374562530000422
Adding 0.58g (4.69mmol) of L-alaninamide hydrochloride, 0.95g (9.43mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 1h, adding 0.80g (3.15mmol) of 4e-8 into the reaction solution, continuing to react at room temperature for 2h, adding 1.03g (19.01mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the addition, monitoring the reaction process by thin-layer chromatography until the 4e-8 point completely disappears, distilling under reduced pressure to remove the solvent, wherein the residue is light yellow solid, stirring the residue with 100-200 mesh silica gel, and carrying out column chromatography separation(gradient elution: MeOH/DCM, 0-5%) to give a white solid (IIb-8, 0.81g, 73.64% yield). ESIMS M/z 326.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.38(s,1H),7.25–7.33(m,4H),7.07–7.11(t,1H),7.00(s,1H),6.46–6.49(m,2H),5.02(s,2H),4.49–4.54(t,2H),3.54–3.70(dd,2H),3.06–3.11(t,2H),2.98–3.04(q,1H),1.14(d,3H,J＝7.0Hz)。
Example 41 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-4-) oxymethyl) benzylamino) propanamide (IIc-1)
Figure BDA0002374562530000431
41.14 Synthesis of- ((2, 3-dihydrobenzo [ b ] thiophene-4-) oxymethyl) benzaldehyde (4f-1) and 3- ((2, 3-dihydrobenzo [ b ] thiophene-4-) oxymethyl) benzaldehyde (4f-2)
Figure BDA0002374562530000432
One eggplant-shaped bottle of 100mL is taken and added with 0.54g (3.55mmol) of 4-hydroxy-2, 3-dihydrobenzo [ b ]]Thiophene, 1.20g (3.69mmol) Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.70g (3.55mmol) of 3a-1 or 3a-2 and 0.09g (0.54mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until 4-hydroxy-2, 3-dihydrobenzo [ b ] b]Removing thiophene point completely, distilling under reduced pressure to remove solvent, dissolving residue with water and ethyl acetate each 30mL, separating liquid, extracting water phase twice with ethyl acetate, each time 15mL, combining organic phase, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling filtrate under reduced pressure to remove solvent, mixing residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 10: 1) to obtain light yellow solid 4- ((2, 3-dihydrobenzo [ b ] b]Thiophene-4-) oxymethyl) benzaldehyde (4f-1, 0.77g, yield 80.21%) or 3- ((2, 3-dihydrobenzo [ b ]]Thiophene-4-) oxymethyl) benzaldehyde (4f-2, 0.86g, yield 89.58%).
Synthesis of 41(S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-4-) oxymethyl) benzylamino) propanamide (IIc-1)
Figure BDA0002374562530000433
Taking one 100mL eggplant-shaped bottle, adding 0.53g (4.28mmol) of L-alaninamide hydrochloride, 0.87g (8.55mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.77g (2.85mmol) of 4f-1 into the reaction solution, continuing to react for 2h at room temperature, adding 0.92g (17.10mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4f-1 point completely disappears, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-1, 0.73g, yield 72.72%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.28(s,1H),6.99–7.33(m,6H),6.46–6.49(m,2H),5.00(s,2H),4.45–4.51(t,2H),3.50–3.69(dd,2H),2.98–3.04(q,1H),2.83–2.91(t,2H),1.14(d,3H,J＝7.0Hz)。
Example 42 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] thiophene-4-) oxymethyl) benzylamino) propanamide (IIc-2)
Figure BDA0002374562530000441
Taking one 100mL eggplant-shaped bottle, adding 0.59g (4.77mmol) of L-alaninamide hydrochloride, 0.97g (9.54mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.86g (3.18mmol) of 4f-2 into the reaction solution, continuing to react at room temperature for 2h, adding 1.03g (19.08mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4f-2 point completely disappears, distilling under reduced pressure to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-2, 0.88g, 78.57% yield). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.29(s,1H),6.99–7.34(m,6H),6.47–6.49(m,2H),5.01(s,2H),4.44–4.50(t,2H),3.50–3.68(dd,2H),2.98–3.05(q,1H),2.83–2.92(t,2H),1.13(d,3H,J＝7.0Hz)。
Example 43 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-5-) oxymethyl) benzylamino) propanamide (IIc-3)
Figure BDA0002374562530000442
Synthesis of 43.14- ((2, 3-dihydrobenzo [ b ] thiophene-5-) oxymethyl) benzaldehyde (4f-3) and 3- ((2, 3-dihydrobenzo [ b ] thiophene-5-) oxymethyl) benzaldehyde (4f-4)
Figure BDA0002374562530000443
Taking 100mL eggplant-shaped bottle, adding 0.54g (3.55mmol) of 5-hydroxy-2, 3-dihydrobenzo [ b ]]Thiophene, 1.20g (3.69mmol) Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.70g (3.55mmol) of 3a-1 or 3a-2 and 0.09g (0.54mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until the 5-hydroxy-2, 3-dihydrobenzo [ b ] b]Removing thiophene point completely, distilling under reduced pressure to remove solvent, dissolving residue with water and ethyl acetate each 30mL, separating liquid, extracting water phase twice with ethyl acetate, each time 15mL, combining organic phase, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling filtrate under reduced pressure to remove solvent, mixing residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 10: 1) to obtain light yellow solid 4- ((2, 3-dihydrobenzo [ b ] b]Thiophene-5-) oxymethyl) benzaldehyde (4f-3, 0.87g, yield 90.63%) or 3- ((2, 3-dihydrobenzo [ b ]]Thiophene-5-) oxymethyl) benzaldehyde (4f-4, 0.86g, yield 89.58%).
43.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-5-) oxymethyl) benzylamino) propanamide (IIc-3)
Figure BDA0002374562530000451
A100 mL eggplant-shaped bottle was charged with 0.60g (4.84mmol) of L-alaninamide hydrochloride, 0.98g (9.66mmol) of triethylamine and 30mL of methanol, and the mixture was stirred at room temperature for 30min to obtain a mixture (0).87g (3.22mmol) of 4f-3 is added into the reaction liquid, the reaction is continued for 2h at room temperature, 1.04g (19.32mmol) of potassium borohydride is added into the reaction liquid three times, the reflux reaction is completed for 3h, the reaction progress is monitored by thin layer chromatography until the point 4f-3 is completely disappeared, the solvent is removed by reduced pressure distillation, the residue is pale yellow solid, the residue is stirred by 100-200 meshes of silica gel, and the white solid (IIc-3, 0.79g and the yield is 69.91%) is obtained by column chromatography separation (gradient elution: MeOH/DCM, 0-5%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.31(s,1H),6.97–7.34(m,6H),6.48–6.51(m,2H),5.03(s,2H),4.47–4.52(t,2H),3.50–3.70(dd,2H),2.99–3.03(q,1H),2.85–2.93(t,2H),1.14(d,3H,J＝7.0Hz)。
Example 44 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] thiophene-5-) oxymethyl) benzylamino) propanamide (IIc-4)
Figure BDA0002374562530000452
Taking one 100mL eggplant-shaped bottle, adding 0.59g (4.77mmol) of L-alaninamide hydrochloride, 0.97g (9.54mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.86g (3.18mmol) of 4f-4 into the reaction solution, continuing to react at room temperature for 2h, adding 1.03g (19.08mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4f-4 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-4, 0.90g, 80.36%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.30(s,1H),7.01–7.32(m,6H),6.47–6.51(d,2H),5.04(s,2H),4.42–4.51(t,2H),3.50–3.69(dd,2H),2.98–3.05(q,1H),2.83–2.90(t,2H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 45 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-6-) oxymethyl) benzylamino) propanamide (IIc-5)
Figure BDA0002374562530000453
Synthesis of 45.14- ((2, 3-dihydrobenzo [ b ] thiophene-6-) oxymethyl) benzaldehyde (4f-5) and 3- ((2, 3-dihydrobenzo [ b ] thiophene-6-) oxymethyl) benzaldehyde (4f-6)
Figure BDA0002374562530000461
One eggplant-shaped bottle of 100mL is taken and added with 0.54g (3.55mmol) of 6-hydroxy-2, 3-dihydrobenzo [ b ]]Thiophene, 1.20g (3.69mmol) Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.70g (3.55mmol) of 3a-1 or 3a-2 and 0.09g (0.54mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until the reaction reaches 6-hydroxy-2, 3-dihydrobenzo [ b ] b]Removing thiophene point completely, distilling under reduced pressure to remove solvent, dissolving residue with water and ethyl acetate each 30mL, separating liquid, extracting water phase twice with ethyl acetate, each time 15mL, combining organic phase, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling filtrate under reduced pressure to remove solvent, mixing residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 10: 1) to obtain light yellow solid 4- ((2, 3-dihydrobenzo [ b ] b]Thiophene-6-) oxymethyl) benzaldehyde (4f-5, 0.74g, yield 77.09%) or 3- ((2, 3-dihydrobenzo [ b ]]Thiophene-6-) oxymethyl) benzaldehyde (4f-6, 0.83g, yield 86.46%).
45.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-6-) oxymethyl) benzylamino) propanamide (IIc-5)
Figure BDA0002374562530000462
Adding 0.51g (4.12mmol) of L-alaninamide hydrochloride, 0.83g (8.22mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring for 30min at room temperature, adding 0.74g (2.74mmol) of 4f-5 into the reaction solution, continuing to react for 2h at room temperature, adding 0.89g (16.43mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the addition, monitoring the reaction process by thin-layer chromatography until 4f-5 points completely disappear, carrying out reduced pressure distillation to remove the solvent, mixing the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%),a white solid was obtained (IIc-5, 0.58g, yield 60.42%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.29(s,1H),6.99–7.34(m,6H),6.48–6.48(m,2H),5.03(s,2H),4.48–4.54(t,2H),3.52–3.70(dd,2H),2.99–3.04(q,1H),2.84–2.92(t,2H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 46 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] thiophene-6-) oxymethyl) benzylamino) propanamide (IIc-6)
Figure BDA0002374562530000463
Taking one 100mL eggplant-shaped bottle, adding 0.57g (4.60mmol) of L-alaninamide hydrochloride, 0.93g (9.21mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.83g (3.07mmol) of 4f-6 into the reaction solution, continuing to react at room temperature for 2h, adding 0.99g (18.41mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4f-6 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-6, 0.90g, 83.33% yield). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.27(s,1H),6.98–7.31(m,6H),6.45–6.47(m,2H),5.04(s,2H),4.43–4.50(t,2H),3.50–3.69(dd,2H),2.98–3.03(q,1H),2.84–2.92(t,2H),1.14(d,3H,J＝7.0Hz)。
Example 47 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-7-) oxymethyl) benzylamino) propanamide (IIc-7)
Figure BDA0002374562530000471
47.14 Synthesis of- ((2, 3-dihydrobenzo [ b ] thiophene-7-) oxymethyl) benzaldehyde (4f-7) and 3- ((2, 3-dihydrobenzo [ b ] thiophene-7-) oxymethyl) benzaldehyde (4f-8)
Figure BDA0002374562530000472
Adding 100mL of eggplant-shaped bottle0.54g (3.55mmol) of 7-hydroxy-2, 3-dihydrobenzo [ b ]]Thiophene, 1.20g (3.69mmol) Cs2CO3And 30mL of anhydrous ethanol, stirring at room temperature for 1h, adding 0.70g (3.55mmol) of 3a-1 or 3a-2 and 0.09g (0.54mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until the reaction process reaches 7-hydroxy-2, 3-dihydrobenzo [ b ] b]Removing thiophene point completely, distilling under reduced pressure to remove solvent, dissolving residue with water and ethyl acetate each 30mL, separating liquid, extracting water phase twice with ethyl acetate, each time 15mL, combining organic phase, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling filtrate under reduced pressure to remove solvent, mixing residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA ═ 10: 1) to obtain light yellow solid 4- ((2, 3-dihydrobenzo [ b ] b]Thiophene-7-) oxymethyl) benzaldehyde (4f-7, 0.74g, yield 77.09%) or 3- ((2, 3-dihydrobenzo [ b ]]Thiophene-7-) oxymethyl) benzaldehyde (4f-8, 0.77g, yield 80.21%).
47.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] thiophene-7-) oxymethyl) benzylamino) propanamide (IIc-7)
Figure BDA0002374562530000473
Taking one 100mL eggplant-shaped bottle, adding 0.51g (4.12mmol) of L-alaninamide hydrochloride, 0.83g (8.22mmol) of triethylamine and 30mL of methanol, stirring for 30min at room temperature, adding 0.74g (2.74mmol) of 4f-7 into the reaction solution, continuing to react for 2h at room temperature, adding 0.89g (16.43mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4f-7 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-7, 0.88g, 91.67%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.31(s,1H),7.03–7.37(m,6H),6.49–6.48(m,2H),5.05(s,2H),4.47–4.54(t,2H),3.54–3.72(dd,2H),2.99–3.07(q,1H),2.83–2.92(t,2H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 48 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] thiophene-7-) oxymethyl) benzylamino) propanamide (IIc-8)
Figure BDA0002374562530000481
Taking one 100mL eggplant-shaped bottle, adding 0.53g (4.27mmol) of L-alaninamide hydrochloride, 0.86g (8.54mmol) of triethylamine and 30mL of methanol, stirring at room temperature for 1h, adding 0.77g (2.85mmol) of 4f-8 into the reaction solution, continuing to react at room temperature for 2h, adding 0.92g (17.08mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction process by thin-layer chromatography until 4f-8 points completely disappear, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IIc-8, 0.89g, yield 88.65%). ESIMS M/z 352.14[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.30(s,1H),7.01–7.34(m,6H),6.47–6.48(m,2H),5.04(s,2H),4.47–4.53(t,2H),3.50–3.69(dd,2H),2.99–3.05(q,1H),2.84–2.91(t,2H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 49 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-) oxymethyl) benzylamino) propanamide (IId-1)
Figure BDA0002374562530000482
Synthesis of 49.14- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-) oxymethyl) benzaldehyde (4g-1) and 3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-) oxymethyl) benzaldehyde (4g-2)
Figure BDA0002374562530000483
One eggplant-shaped bottle of 100mL is taken and added with 2.50g (16.44mmol) of 5-hydroxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxin, 5.57g (17.10mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1h, adding 3.25g (16.44mmol) of 3a-1 or 3a-2 and 0.41g (2.47mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until the 5-hydroxy-2, 3-dihydrobenzo [ b ] b][1,4]Completely eliminating dioxin point, distilling under reduced pressure to remove solvent, dissolving residue with 50mL each of water and ethyl acetate, separating liquid, extracting water phase twice with ethyl acetate, 25mL each time, combining organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling filtrate under reduced pressure to remove solvent, mixing residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA is 10: 1) to obtain white solid 4- ((2, 3-dihydrobenzo [ b ] b][1,4]Dioxin-5-) oxymethyl) benzaldehyde (4g-1, 0.33g, yield 7.43%) or 3- ((2, 3-dihydrobenzo [ b ]][1,4]Dioxin-5-) oxymethyl) benzaldehyde (4g-2, 1.63g, yield 36.71%).
49.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-) oxymethyl) benzylamino) propanamide (IId-1)
Figure BDA0002374562530000491
Adding 0.23g (1.83mmol) of L-alaninamide hydrochloride, 0.37g (3.67mmol) of triethylamine and 30mL of methanol into one 100mL eggplant-shaped bottle, stirring at room temperature for 30min, adding 0.33g (1.22mmol) of 4g-1 into the reaction solution, continuing to react at room temperature for 2h, adding 0.40g (7.33mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4g-1 point completely disappears, carrying out reduced pressure distillation to remove the solvent, stirring the residue with 100-200 mesh silica gel, carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IId-1, 0.17g, yield 40.48%). ESIMS M/z 342.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.28–7.41(m,5H),7.01(s,1H),6.46–6.72(m,3H),5.03(s,2H),4.22(s,4H),3.54–3.71(dd,2H),2.99–3.04(q,1H),1.13(d,3H,J＝7.0Hz)。
EXAMPLE 50 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-) oxymethyl) benzylamino) propanamide (IId-2)
Figure BDA0002374562530000492
Taking 100mL eggplant-shaped bottle, adding 1.13g (9.05mmol) LAlanyl amide hydrochloride, 1.83g (18.12mmol) triethylamine and 50mL methanol, stirring at room temperature for 1h, adding 1.63g (6.04mmol) of 4g-2 into the reaction solution, continuing to react at room temperature for 2h, adding 1.95g (36.24mmol) of potassium borohydride into the reaction solution three times, refluxing for 3h after the completion of the reaction, monitoring the reaction progress by thin layer chromatography until 4g-2 points completely disappear, distilling under reduced pressure to remove the solvent, collecting the residue as a pale yellow solid, stirring the residue with 100-200 mesh silica gel, and performing column chromatography (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IId-2, 1.83g, yield 88.83%). ESIMS M/z 342.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.33–7.39(m,5H),7.00(s 1H),6.46–6.73(m,3H),5.02(s,2H),4.21(s,4H),3.52–3.70(dd,2H),2.98–3.03(q,1H),1.13(d,3H,J＝7.0Hz)。
EXAMPLE 51 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-) oxymethyl) benzylamino) propanamide (IId-3)
Figure BDA0002374562530000501
51.14 Synthesis of- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-) oxymethyl) benzaldehyde (4g-3) and 3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-) oxymethyl) benzaldehyde (4g-4)
Figure BDA0002374562530000502
One eggplant-shaped bottle of 100mL is taken and added with 2.50g (16.44mmol) of 6-hydroxy-2, 3-dihydrobenzo [ b][1,4]Dioxin, 5.57g (17.10mmol) Cs2CO3And 60mL of anhydrous ethanol, stirring at room temperature for 1h, adding 3.25g (16.44mmol) of 3a-1 or 3a-2 and 0.41g (2.47mmol) of KI into the reaction solution, refluxing at 80 ℃ for more than 4h after the addition is finished, and monitoring the reaction process by thin layer chromatography until the reaction process reaches 6-hydroxy-2, 3-dihydrobenzo [ b ] b][1,4]Removing dioxin point completely, distilling under reduced pressure to remove solvent, dissolving the residue with 50mL each of water and ethyl acetate, separating, extracting the water phase with ethyl acetate twice, each time 25mL, combining the organic phases, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering to remove sodium sulfate, distilling the filtrate under reduced pressure to remove sodium sulfateMixing the solvent and residue with 100-200 mesh silica gel, and separating by column chromatography (PE: EA is 10: 1) to obtain white solid 4- ((2, 3-dihydrobenzo [ b)][1,4]Dioxin-6-) oxymethyl) benzaldehyde (4g-3, 1.42g, yield 31.97%) or 3- ((2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-) oxymethyl) benzaldehyde (4g-4, 1.89g, yield 42.57%).
51.2 Synthesis of (S) -2- (4- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-) oxymethyl) benzylamino) propanamide (IId-3)
Figure BDA0002374562530000503
Adding 0.98g (7.87mmol) of L-alaninamide hydrochloride, 1.60g (15.79mmol) of triethylamine and 50mL of methanol into one 100mL eggplant-shaped bottle, stirring for 30min at room temperature, adding 1.42g (5.25mmol) of 4g-3 into the reaction solution, continuing to react for 2h at room temperature, adding 1.70g (31.54mmol) of potassium borohydride into the reaction solution three times, carrying out reflux reaction for 3h after the completion of the reaction, monitoring the reaction progress by thin-layer chromatography until 4g-3 points completely disappear, carrying out reduced pressure distillation to remove the solvent, mixing the residue with 100-200 mesh silica gel, and carrying out column chromatography separation (gradient elution: MeOH/DCM, 0-5%) to obtain a white solid (IId-3, 0.99g, yield 55.00%). ESIMS M/z 342.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.29–7.42(m,5H),7.02(s,1H),6.46–6.73(m,3H),5.04(s,2H),4.24(s,4H),3.54–3.70(dd,2H),3.00–3.04(q,1H),1.14(d,3H,J＝7.0Hz)。
EXAMPLE 52 Synthesis of (S) -2- (3- ((2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-) oxymethyl) benzylamino) propanamide (IId-4)
Figure BDA0002374562530000511
Adding 1.21g (10.49mmol) of L-alaninamide hydrochloride, 2.13g (21.01mmol) of triethylamine and 50mL of methanol into one eggplant-shaped bottle of 100mL, stirring at room temperature for 1h, adding 1.89g (7.00mmol) of 4g-4 g of reaction liquid, continuing to react at room temperature for 2h, adding 2.27g (42.02mmol) of potassium borohydride into the reaction liquid three times, carrying out reflux reaction for 3h after the addition, monitoring the reaction progress by thin-layer chromatography until 4g-4 points completely disappear, and distilling under reduced pressure to remove dissolved potassium borohydrideThe solvent is pale yellow solid, the residue is stirred with 100-200 mesh silica gel and separated by column chromatography (gradient elution: MeOH/DCM, 0-5%) to obtain white solid (IId-4, 1.81g, yield 75.73%). ESIMS M/z 342.16[ M + H ]]+；1H NMR(400MHz,DMSO-d6):7.32–7.38(m,5H),6.99(s,1H),6.45–6.72(m,3H),5.01(s,2H),4.20(s,4H),3.52–3.69(dd,2H),2.97–3.02(q,1H),1.13(d,3H,J＝7.0Hz)。
Example 53 evaluation of analgesic Effect of intraperitoneal administration in the formalin model in mice
An ICR (CD-1) male mouse (with the weight of 22-25 g) is randomly divided into a blank group, a positive medicine group and a compound group to be tested, 8 mice in each group are placed into a PVC (polyvinyl chloride) observation box for adaptation for 30min after being subjected to intraperitoneal administration at the dose of 10mg/kg, then 20 mu L of 2.7% (v/v) formalin solution is injected subcutaneously into the right hind paw of the mouse, the hind paw is quickly placed back into the PVC observation box for observation, and the time of the hind paw of a phase II (15-30 min) mouse licking the right is recorded as the phase II pain reaction time.
The mean of phase II pain response times was calculated for each group of mice. The phase II pain inhibition rate of the positive drug group and the test compound group can be calculated by the following formula:
pain inhibition (%) - (time for licking phase II in the blank mouse-time for licking phase II in the drug mouse)/time for licking phase II in the blank mouse × 100%
TABLE 1 results of the intraperitoneal administration test
Figure BDA0002374562530000512
Figure BDA0002374562530000521
As can be seen from the results in Table 1, all compounds showed a certain analgesic activity at a dose of 10 mg/kg; wherein the analgesic activity of the compounds Ia-2, Ia-5, Ib-2, Ib-3, Ib-4, Ic-2, Ic-4, Ic-7, IIa-3, IIb-3, IIb-4, IIc-4, IId-1 and IId-2 is better than that of the positive drug ralfinamide, and the analgesic activity of the compounds Ia-3, Ia-8, Ib-5, IIa-7, IIc-5 and IId-3 is equivalent to that of the positive drug ralfinamide.
Example 54 sodium ion channel Nav1.7 evaluation of retardation
The experiment is based on the patch clamp technology, and the evaluation of each compound on the inactivated state sodium ion channel Na on an in vitro cell modelv1.7, tested at a concentration of 10 μ M. The results are given in the following table:
TABLE 2 Pair of inactive sodium ion channels Nav1.7 evaluation results of retardation
Figure BDA0002374562530000522
Figure BDA0002374562530000531
As is clear from the results in Table 2, the compounds Ia-1, Ia-2, Ia-6, IIa-3 and IIc-4 are directed to the sodium channel Nav1.7 the inhibition was superior or comparable to that of ralfinamide, the positive drug.
It should be noted that the above embodiments can be freely combined as necessary. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The benzo-heterocycle structure-containing amide derivative is a compound shown as a structural formula I and a non-toxic pharmaceutically acceptable salt thereof:
Figure FDA0002374562520000011
in structural formula I:
n＝1，X1is a carbon atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5The linear or branched alkyl group of (a),the configuration of the chiral carbon connected with R is R type or S type;
or, n ═ 1, X1Is a nitrogen atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, n ═ 2, X1Is a carbon atom, X2Is a nitrogen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, the amide derivative containing the benzo-heterocycle structure is a compound shown as a structural formula II or a non-toxic pharmaceutically acceptable salt thereof:
Figure FDA0002374562520000012
in structural formula II:
n＝1，X1is a carbon atom, X2Is a nitrogen atom, an oxygen atom or a sulfur atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type;
or, n ═ 2, X1Is an oxygen atom, X2Is an oxygen atom, R is a hydrogen atom or C1–C5The chiral carbon configuration connected with R is R type or S type.
2. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula I is represented by formula Ia:
Figure FDA0002374562520000013
in the structural formula Ia, the substituted position of benzofuran is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
3. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula I is represented by formula Ib:
Figure FDA0002374562520000021
in the structural formula Ib, 1H-benzo [ d]The imidazole substitution position is 4, 5, 6 or 7, the connection position of the benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
4. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula I is represented by formula Ic:
Figure FDA0002374562520000022
in the structural formula Ic, the substitution position of the quinoline ring is 5, 6, 7 or 8, the connection position of the benzene ring is meta or para, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
5. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula II is represented by formula IIa:
Figure FDA0002374562520000023
in the structural formula IIa, the substituted position of indoline is 4, 5, 6 or 7, the connecting position of benzene ring is meta or para, R is C1–C5The chiral carbon configuration connected with R is R type or S type.
6. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula II is represented by formula lib:
Figure FDA0002374562520000024
in the structural formula IIb, the substituted position of 2, 3-dihydrobenzofuran is 4, 5, 6 or 7, the benzene ring connecting position is meta or para, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
7. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula II is represented by formula IIc:
Figure FDA0002374562520000031
in the formula IIc, 2, 3-dihydrobenzo [ b ]]The substituted position of the thiophene is 4, 5, 6 or 7, the connecting position of the benzene ring is meta or para, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
8. The benzo-heterocycle structure-containing amide derivative of claim 1, wherein said compound of formula II is represented by formula IId:
Figure FDA0002374562520000032
in the formula IId, 2, 3-dihydrobenzo [ b ]][1,4]The substituted position of the dioxin is 5-position or 6-position, the connecting position of the benzene ring is meta-position or para-position, and R is C1–C5The chiral carbon configuration connected with R is R type or S type.
9. A pharmaceutical composition, wherein the active ingredient of the pharmaceutical composition comprises the benzo-heterocycle structure-containing amide derivative according to any one of claims 1 to 8, the pharmaceutical composition comprises an excipient, and the pharmaceutical composition is a solution, a tablet, a capsule or an injection.
10. Use of the benzo-heterocycle-structure-containing amide derivative according to any one of claims 1 to 8 for preparing an analgesic agent.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021104507A1 (en) * 2019-11-28 2021-06-03 岳千奥 Substituted phenoxyamide derivative, use thereof and drugs for treating parkinson's disease
WO2022256679A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels
WO2022256622A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2022256842A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels
WO2022256702A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran-2-carboxamides as modulators of sodium channels
WO2022256708A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Solid dosage forms and dosing regimens comprising (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide
WO2022256676A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran analogs as modulators of sodium channels
WO2023205465A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026614A1 (en) * 1997-11-21 1999-06-03 Euro-Celtique S.A. Substituted 2-aminoacetamides and the use thereof
CN104761531A (en) * 2014-01-03 2015-07-08 中国人民解放军军事医学科学院毒物药物研究所 Compound with analgesic activity, and pharmaceutical applications thereof
CN107522647A (en) * 2016-06-21 2017-12-29 中国人民解放军军事医学科学院毒物药物研究所 α aminoamide derivatives and its medical usage containing indolyl radical

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999026614A1 (en) * 1997-11-21 1999-06-03 Euro-Celtique S.A. Substituted 2-aminoacetamides and the use thereof
CN104761531A (en) * 2014-01-03 2015-07-08 中国人民解放军军事医学科学院毒物药物研究所 Compound with analgesic activity, and pharmaceutical applications thereof
CN107522647A (en) * 2016-06-21 2017-12-29 中国人民解放军军事医学科学院毒物药物研究所 α aminoamide derivatives and its medical usage containing indolyl radical

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021104507A1 (en) * 2019-11-28 2021-06-03 岳千奥 Substituted phenoxyamide derivative, use thereof and drugs for treating parkinson's disease
WO2022256679A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels
WO2022256622A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2022256842A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels
WO2022256702A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran-2-carboxamides as modulators of sodium channels
WO2022256708A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Solid dosage forms and dosing regimens comprising (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide
WO2022256676A1 (en) 2021-06-04 2022-12-08 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofuran analogs as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2023205465A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
WO2023205463A1 (en) 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain
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