CN115073370A

CN115073370A - Novel alkylammonium compound or salt, isomer, preparation method and application thereof

Info

Publication number: CN115073370A
Application number: CN202210216426.5A
Authority: CN
Inventors: 曾燕群; 刘强强; 张涛; 鄢胜勇; 马云龙; 王颖
Original assignee: Chengdu Shuoder Pharmaceutical Co ltd
Current assignee: Chengdu Shuoder Pharmaceutical Co ltd
Priority date: 2021-03-10
Filing date: 2022-03-07
Publication date: 2022-09-20

Abstract

A compound shown as a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide compound, a hydrate, a solvent compound, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I) has a pain-relieving effect, and can be used in medicaments for treating or preventing pain.

Description

Novel alkylammonium compound or salt, isomer, preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to novel alkyl ammonia compounds or salts and isomers thereof, a preparation method thereof and application of a pharmaceutical composition thereof in preparation of treatment and prevention, especially application in treatment of pain, drug addiction, opioid drug synergism, psychosis and the like.

Background

At present, the incidence rate of the pain in the world is about 35-45%, the incidence rate of the pain in the elderly is higher and is about 75% -90%, and the pain is the third treatment field of global ranking and has a huge market. Opioids are the strongest and commonly used central analgesics, and past studies have shown that opioids (such as codeine, morphine, oxycodone, fentanyl) are effective in analgesia. They bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract to relieve pain. Because of its significant analgesic effects, opioid abuse has become a major public health problem in the united states; 78 people die each day due to opioid overdose. Therefore, a strong analgesic with a new target point is urgently needed in clinic.

Sigma receptors are unique non-opioid receptors widely distributed in the central nervous system, and Sigma 1 receptors are involved in the pathophysiology of all major central nervous system disorders, including mood disorders (anxiety and depression), psychosis and schizophrenia, as well as drug addiction and pain. Sigma 1 receptor antagonist S1RA (compound of preparation 1) enhances the analgesic activity of opioid analgesics, and the potentiating effect is antagonized by methylnaltrexone, Sigma 1 receptor agonist, naltrexone. S1RA can also be used for treating pain independently, such as acute neuralgia, sciatica, diabetic neuralgia, inflammatory pain and visceral pain, etc. Secondly, S1RA has no addiction to opioid analgesics and is well tolerated. Currently, S1RA completed 5 phase ii clinical studies in europe, wherein validated clinics for the treatment of oxaliplatin-induced peripheral neuropathy indicated that S1RA was not significant in efficacy; postoperative pain, 400mg of S1RA is given before an operation, and morphine is given after the operation (combined use), so that the consumption of morphine in the S1RA group is increased, but adverse reactions of nausea, vomiting and dizziness are reduced, the dosage of antiemetic drugs is reduced, the average pain intensity is weakened, and the statistical significance is achieved; postoperative neuralgia, 28 days, reduces the pain degree, reaches the statistical significance; the experimental results of the neuropathic pain of diabetes and the postherpetic neuralgia have no statistical significance. Therefore, S1RA has poor effect in a plurality of clinical stages II, and has obvious analgesic effect on postoperative neuralgia after long-term administration, but has good tolerance. Overall clinical results indicate that the analgesic effect of S1RA, either alone or in combination with morphine, remains to be improved.

Through structural analysis of S1RA, the inventor designs a completely new analgesic drug, and after in vivo efficacy test verification of various models is carried out, the inventor unexpectedly finds that the analgesic drug with the analgesic effect which is multiple times stronger than that of S1RA shows very strong analgesic effect when being independently used in a mouse acetic acid writhing test, a rat hot plate test and a rat thermal radiation tail flick test under low dose.

Disclosure of Invention

The compound of the invention is a novel analgesic, and the compounds of the examples show good analgesic effect in animals. In a mouse acetic acid writhing experiment, when 1mg/kg of the compound is administered by intraperitoneal injection, the compound still has extremely strong analgesic effect; and example compound 5 and example compound 10 also showed strong analgesic effect in rat hot plate analgesic test (1mg/kg, i.v.) and rat thermal radiation tail flick test (4mg/kg, i.v.), whereas the same dose of S1RA was comparable to the blank control group under the same test conditions and showed no analgesic effect.

In one aspect, the invention relates to a compound of formula I or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula I,

wherein, ring A is substituted or unsubstituted C5-10 carbocyclyl, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted heterocyclyl consisting of 5-10 atoms, or substituted or unsubstituted heteroaryl consisting of 5-10 atoms;

x is N or C;

y is O or S or NH;

z is N or C, and the dotted line represents the C to which it is attached to form a double or single bond;

r1 is selected from hydrogen, deuterium, substituted OR unsubstituted alkyl, substituted OR unsubstituted cycloalkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted aryl, substituted OR unsubstituted aralkyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted heterocyclylalkyl, -COR4, -C (O) OR4, -C (O) NR4R5, -C-NR4, -oc (O) R4, -NR4C (O) R5, -N ═ CR 4R5, -NR4R5, -NO2, -CN, -SR4, -OR4, OR halogen;

r2 and R3 are independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclyl group;

n is selected from 0, 1,2,3,4, 5 or 6;

r4 and R5 are each independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycloalkyl, or taken together they form a fused ring system.

Further, the compound shown in the formula I or the stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in the formula I,

wherein ring A is C _5-6 Substituted or unsubstituted carbocyclyl, C _5-6 Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group consisting of 5 to 6 atoms;

y is O or S;

R ¹ selected from hydrogen, substituted or unsubstituted C _1-12 Alkyl, substituted or unsubstituted C _4-12 Cycloalkyl, substituted or unsubstituted C _2-12 Alkenyl, substituted or unsubstituted C _5-12 Aryl, substituted or unsubstituted C _5-12 A heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, or halogen;

R ² and R ³ Independently selected from hydrogen, deuterium, substituted or unsubstituted C _1-12 Alkyl, substituted or unsubstituted C _4-12 Cycloalkyl, substituted or unsubstituted C _2-12 Alkenyl, substituted or unsubstituted C _5-10 Aryl, substituted or unsubstituted C _5-10 Heterocyclyl, or taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3-to 15-membered heterocyclyl group;

n is selected from 0, 1,2,3,4, 5, 6.

Further, the compound shown in the formula I, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof has a structure shown in a general formula I',

wherein B, C, D is selected from C or N, and B, C, D is at most two N;

n is selected from 0, 1,2 or 3;

wherein the substituents are selected from one or more of deuterium, halogen, hydroxy, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkylthio, amino, C ₁ -C ₆ Alkylamino radical, C ₁ -C ₆ Alkanoylamino group, C ₅ -C ₁₀ Aryl radical, C ₅ -C ₁₀ Aralkyl radical, C ₅ -C ₁₀ Heterocyclic group, NO ₂ 、CN、CF ₃ Or taken together they form a fused ring system.

Further, the compound as shown in formula I, or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof has a structure shown in a general formula I':

y is O or S;

R ¹ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furan ring, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted dibenzothienyl, substituted or unsubstituted alkoxy, substituted or unsubstituted propyl, substituted or unsubstituted allyl;

R ² and R ³ Independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted arylethyl, substituted or unsubstituted arylheterethyl, or R ² And R ³ Taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinylcyclyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted hexahydropyrimidinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted azocycloctyl, substituted or unsubstituted azepanyl;

wherein the substituents are selected from one or more of deuterium, halogen, hydroxy, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, carboxamido, acetamido, cyclopropylamino, tert-butylamino, NO ₂ 、 CN、CF ₃ 。

n is selected from 1 or 2.

Further, a compound according to formula i, i' or i ", a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof:

R ¹ selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted biphenyl, substituted or unsubstituted dibenzothienyl, substituted or unsubstituted quinolyl; wherein the substituents are selected from one or more of deuterium, halogen, hydroxy, methyl, ethyl, cyclopropyl, t-butyl, methoxy, ethoxy, cyclopropoxy, t-butoxy, methylthio, ethylthio, cyclopropylthio, t-butylthio, amino, methylamino, ethylamino, cyclopropylamino, t-butylamino, carboxamido, acetamido, cyclopropylamino, t-butylamino, NO ₂ 、CN、CF ₃ ；

R ² And R ³ Independently selected from methyl, ethyl or R ² And R ³ Taken together with the nitrogen atom to which they are attached to form morpholinyl, piperazinyl, piperidinyl, azepanyl;

n is selected from 1 or 2.

R ¹ selected from the group consisting of 2-naphthyl, 2-chlorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexyl, allyl, alkenylbutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, pyridyl, methoxy, hydroxy, nitro, amino, 2-chloro-4-fluorophenyl, 2-methyl-4-fluorophenyl, and mixtures thereof, 4-fluoro-2-methoxy, 4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl)Yl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

R ² and R ³ Independently selected from methyl, ethyl;

n is selected from 1 or 2;

wherein R is ¹ And when the substituent is nitro, amino, methoxy or hydroxyl, the substituent is at the 7-position.

Further, compounds according to formula i, i' or i ", stereoisomers or tautomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof:

R ¹ selected from the group consisting of 2-naphthyl, 2-chlorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexyl, allyl, alkenylbutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromo, pyridyl, methyl, methoxy, hydroxy, nitro, amino, 2-chloro-4-fluorophenyl, bromo, pyridyl, methyl, methoxy, hydroxy, nitro, amino, 4-chloro-4-fluorophenyl, and the like, 4-fluoro-2-methoxy, 4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

R ² and R ³ Taken together with the nitrogen atom to which they are attached to form a morpholino ring group;

n is selected from 1 or 2;

wherein R is ¹ And when the substituent is nitro, amino, methoxy, bromine, hydroxyl, methyl or pyridine, the substituent is at the 7-position.

R ¹ selected from 2-naphthyl, 2-chlorphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3,4 dichlorophenyl, 3,4 difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexylAllyl, alkenylbutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromo, pyridyl, methyl, methoxy, hydroxy, nitro, amino, 2-chloro-4-fluorophenyl, 4-fluoro-2-methoxy, 4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

R ² and R ³ Together with the nitrogen atom to which they are attached to form a piperazine ring radical;

n is selected from 1 or 2;

wherein R is ¹ In the case of bromine, the substitution is in the 5 position.

R ¹ selected from the group consisting of 2-naphthyl, 2-chlorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3,4 dichlorophenyl, 3,4 difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexyl, allyl, alkenylbutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromo, pyridyl, methyl, 3-pyridyl, methoxy, nitro, amino, 2-chloro-4-fluorophenyl, and cyclopropyl, 4-fluoro-2-methoxy, 4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

R ² and R ³ Taken together with the nitrogen atom to which they are attached to form a piperidinyl group;

n is selected from 1 or 2;

wherein R is ¹ Nitro, amino, methoxy, bromo, methyl, substituted in position 7.

R ² and R ³ Taken together with the nitrogen atom to which they are attached to form an azepanyl group;

n is selected from 1 or 2.

Further, the present invention relates to compounds of formula i, i', i ", preferably compounds including, but not limited to, compounds selected from the group consisting of:

1- (2-Morpholinoethyl) -7- (naphthalen-2-yl) quinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7- (naphthalen-2-yl) quinoxalin-2 (1H) -one

7- (2-chlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7-bromo-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one

7- (4-fluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (4-fluoro-2-methylphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7-phenyl-3, 4-dihydroquinolin-2 (1H) -one

7- (3, 5-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (3, 4-dichlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (3, 4-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7- (4- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (4-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (2-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7- (2- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (2- (methylthio) phenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-Morpholinoethyl) -7- (pyridin-3-yl) -3, 4-dihydroquinolin-2 (1H) -one

7- (3, 4-dichlorophenyl) -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

7- (naphthalen-2-yl) -1- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- [2- (methylthio) phenyl ] -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

7- (dibenzo [ b, d ] thiophen-3-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

4- [1- (2-Morpholinoethyl) -2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl ] benzonitrile

1'- (2-morpholinoethyl) -3', 4 '-dihydro- [ -4,7' -bisquinoline ] -2'(1' H) -one

1- (3-Morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one

1- [2- (azepan-1-yl) ethyl ] -7- (2-methylthiophenyl) -3, 4-dihydroquinolin-2 (1H) -one

1- [2- (azepan-1-yl) ethyl ] -6-methoxy-3, 4-dihydroquinolin-2 (1H) -one

7- (2-chlorophenyl) -1- [2- (dimethylamino) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

6- (3, 4-dichlorophenyl) -1- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- (3-Fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

6- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

6- (3-Fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- ([1,1' -biphenyl ] -3-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

7- ([1,1' -biphenyl ] -4-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

1- (2-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinoline-2 (1H) -thione.

Further, the present invention relates to compounds of formula i, i', i ", or pharmaceutically acceptable salts, isomers thereof, wherein the hydrogen in said compounds may be substituted by one or more deuterium.

Further, the present invention relates to processes for the preparation of compounds of formula i, key intermediates and salts thereof.

The method comprises the following steps:

reacting a compound II with organic boric acid (III) or organic boric acid ester (IV) in a solvent such as 1,4-dioxane, DMF, DMSO, DME, 1,4-dioxane/H2O and the like, Pd (PPh3)4, Pd (dppf) Cl2, Pd (PPh3)2Cl2, Pd (Cy3)2Cl2, Pd (OAc)2 and other catalysts, reacting the compound II with a compound VI in solvents such as DMF, DMSO, CH3CN and THF, and reacting the compound II with bases such as Na2CO3, K2CO3, Cs2CO3 and CsF at the temperature of 80-160 ℃ for 8-16 hours to obtain a key intermediate V, and further reacting the key intermediate V with the compound VI in solvents such as DMF, DMSO, CH3CN and THF, and reacting the key intermediate V with K2CO3, Cs2CO3, CsF and NaH at the temperature of 0-120 ℃ for substitution reaction to obtain a compound I after 4-16 hours.

The second method comprises the following steps:

the compounds II and VI are subjected to substitution reaction with K2CO3, Cs2CO3, CsF and NaH in DMF, DMSO, CH3CN and THF solvents at the temperature of 0-120 ℃ to obtain a compound VII after 4-16 hours, the compound VII is continuously subjected to reaction with organic boric acid (III) or organic borate (IV) in solvents such as 1,4-dioxane, DMF, DMSO, DME and 1,4-dioxane/H2O and catalysts such as Pd (PPh3)4, Pd (dppf) Cl2, Pd (PPh3)2Cl2, Pd (Cy3)2Cl2 and Pd (OAc)2 for 8-16 hours at the temperature of 80-160 ℃ under the action of bases such as Na2CO3, K2CO3, Cs2CO3 and CsF, and the like to obtain a compound I.

Wherein X is Br or Cl, Z is C or N, Y is O or S, and the dotted line represents that C connected with Z forms a single bond or a double bond;

furthermore, the invention relates to the use of compounds of formula I, I' for the preparation of a medicament for the treatment or prevention of pain.

Detailed Description

The present invention will be described in further detail with reference to examples and experimental examples, which are provided for illustration of the technical solution of the present invention and are not intended to limit the present invention, and any equivalent replacement in the field made in accordance with the disclosure of the present invention is within the scope of the present invention.

The structure of the compound is nuclear magnetic resonance ( ¹ H NMR) or liquid mass spectrometry (LC-MS).

The liquid mass spectrometer (LC-MS) is Agilent G6120B (used with liquid Agilent 1260); nuclear magnetic resonance apparatus ( ¹ H NMR is Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance: ( ¹ H NMR) shifts (δ) are given in parts per million (ppm) and the solvent is determined to be CDCl ₃ Internal standard is Tetramethylsilane (TMS), chemical shift is 10 ^-6 (ppm) is given as a unit.

The term "room temperature" in the present invention means a temperature of 10 to 25 ℃.

Example 1: preparation of 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinolin-2 (1H) -one

Step one, compound IIa (2.24g, 10mmol), compound VIa (2.24g, 15mmol), Cs are reacted at room temperature ₂ CO ₃ (9.75g, 30mmol) was added to DMF (30mL) and heated to 100 deg.C for 6h, and the starting material was reacted completely. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 3:1, dried and dried in vacuo to give 2.87g of the product as a yellow oil. Yield: 85 percent.

¹ H NMR(400MHz，CDCl ₃ )δ7.68–7.60(m，2H)，7.42(d，J＝8.3Hz，1H)，7.34(dd， J＝8.3，1.6Hz，1H)，6.70(d，J＝9.4Hz，1H)，4.47–4.30(m，2H)，3.80–3.67(m，4H)， 2.73–2.53(m，6H)。

Step two, compound VIIa (2.87g, 8.5mmol), compound naphthalen-2-ylboronic acid (1.76g, 10.2mmol), CsF (1.55g, 10.2mmol) were added to 1,4-dioxane/H at room temperature ₂ O (30mL, V/V. 5/1) was replaced with nitrogen, and Pd (dppf) Cl was further added ₂ (0.62g, 0.85mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the crude product was purified with the eluent petroleum ether: ethyl acetate 2:1 column chromatography, spin-dried, and dried in vacuo to afford 2.62g of the product as a yellow oil: 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinolin-2 (1H) -one. Yield: 80% and the purity is 99.53%.

ESI-MS:m/z＝385.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.06(s，1H)，7.98–7.83(m，5H)，7.78–7.71(m，2H)， 7.56–7.46(m，3H)，6.74(d，J＝9.4Hz，1H)，4.54–4.41(m，2H)，3.80–3.68(m，4H)， 2.76–2.56(m，6H)。

Example 2: preparation of 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinoxalin-2 (1H) -one

Step one, adding a compound IIa (2.25g, 10mmol), a compound VIa (2.24g, 15mmol) and NaH (1.2g, 30mmol) into DMSO (30mL) at room temperature, heating to 100 ℃, and reacting for 6h until the raw materials are completely reacted. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the crude product was purified with the eluent petroleum ether: acetic acid ethyl esterThe ester 3:1 was passed through the column, spun dry and dried in vacuo to give 2.74g of the product as a yellow oil. Yield: 81 percent. ESI-MS: M/z 339.2(M + H) ⁺ 。

Step two, compound VIIb (2.74g, 8.1mmol), compound naphthalen-2-ylboronic acid (1.67g, 9.72mmol), Cs were reacted at room temperature ₂ CO ₃ (3.17g, 9.72mmol) was added to DMF (30mL), the mixture was purged with nitrogen, and Pd (dppf) Cl was further added ₂ (0.62g, 0.85mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried in vacuo to give 2.56g of the product as a yellow oil: 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinoxalin-2 (1H) -one. Yield: 82.0% and the purity is 99.42%.

ESI-MS:m/z＝386.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.40(d，J＝76.1Hz，1H)，8.21–8.06(m，2H)，8.02–7.64 (m，6H)，7.62–7.47(m，2H)，4.71–4.37(m，2H)，3.80–3.63(m，4H)，2.97–2.70(m， 2H)，2.62–2.51(m，4H)。

Example 3: preparation of 7-bromo-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound IIa (2.26g, 10mmol), compound VIa (2.24g, 15mmol), CsF (4.56g, 30mmol) were added to THF (50mL) at room temperature, heated to 100 deg.C and reacted for 6h, with the starting materials completely reacted. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the crude product was purified with the eluent petroleum ether: passing through a column with ethyl acetate of 3:1, rotatingDry and dry in vacuo to give 2.92g of product as a yellow oil. Yield: 86% and the purity is 99.42%.

ESI-MS:m/z＝340.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.32(d，J＝1.7Hz，1H)，7.13(dd，J＝7.9，1.8Hz，1H)， 7.03(d，J＝8.0Hz，1H)，4.03(t，J＝6.9Hz，2H)，3.77–3.65(m，4H)，2.91–2.78(m，2H)， 2.69–2.46(m，8H)。

Example 4: preparation of 7- (2-chlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, in the manner of example 3, 7-bromo-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one (VIIc) is prepared;

step two, compound VIIc (2.88g, 8.5mmol), compound 2-chlorobenzeneboronic acid (1.59g, 10.2mmol), Cs at room temperature ₂ CO ₃ (3.32g, 10.2mmol) was added to DMSO (30mL), the mixture was purged with nitrogen, and Pd (dppf) Cl was further added ₂ (0.62g, 0.85mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried in vacuo to give 2.57g of a white oil: 7- (2-chlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one, yield: 81.5% and the purity is 99.32%.

ESI-MS:m/z＝371.5(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.52–7.46(m，1H)，7.37–7.29(m，3H)，7.24(d，J＝7.6 Hz，1H)，7.20(d，J＝1.3Hz，1H)，7.06(dd，J＝7.6，1.5Hz，1H)，4.14–4.07(m，2H)， 3.72–3.61(m，4H)，3.01–2.89(m，2H)，2.73–2.59(m，4H)，2.59–2.48(m，4H)。

Example 5: preparation of 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 2-naphthaleneboronic acid to give the title compound as a white oil in yield: 81.2% and the purity is 99.60%.

ESI-MS:m/z＝387.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.01(d，J＝1.1Hz，1H)，7.96–7.85(m，3H)，7.71(dd， J＝8.5，1.8Hz，1H)，7.56–7.47(m，2H)，7.45(d，J＝1.3Hz，1H)，7.36(dd，J＝7.7，1.5 Hz，1H)，7.28(d，J＝7.7Hz，1H)，4.24–4.15(m，2H)，3.75–3.64(m，4H)，3.01–2.90(m， 2H)，2.75–2.62(m，4H)，2.61–2.45(m，4H)。

Example 6: preparation of 7- (4-fluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-fluorobenzeneboronic acid to give the title compound as a white oil in yield: 83.1% and the purity is 99.51%.

ESI-MS:m/z＝455.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.55–7.48(m，2H)，7.28–7.21(m，2H)，7.20–7.10(m，3H)，4.19–4.13(m，2H)，3.74–3.63(m，4H)，2.99–2.89(m，2H)，2.76–2.59(m，4H)， 2.59–2.47(m，4H)。

Example 7: preparation of 7- (4-fluoro-2-methylphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-fluoro-2-methylbenzeneboronic acid to give the title compound as a white oil in yield: 82.2% and the purity is 99.75%.

ESI-MS:m/z＝369.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.23–7.14(m，2H)，7.02–6.89(m，4H)，4.12–4.06(m， 2H)，3.72–3.60(m，4H)，3.01–2.87(m，2H)，2.73–2.65(m，2H)，2.62–2.55(m，2H)， 2.56–2.46(m，4H)，2.27(s，3H)。

Example 8: preparation of 1- (2-morpholinoethyl) -7-phenyl-3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of phenylboronic acid to give the title compound as a white oil in yield: 79.5 percent and the purity is 99.20 percent.

ESI-MS:m/z＝337.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.59–7.53(m，2H)，7.49–7.43(m，2H)，7.41–7.35(m， 1H)，7.31(s，1H)，7.24(s，2H)，4.20–4.12(m，2H)，3.75–3.64(m，4H)，2.93(dd，J＝8.5， 6.2Hz，2H)，2.72–2.60(m，4H)，2.60–2.48(m，4H)。

Example 9: preparation of 7- (3, 5-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 3, 5-difluorophenylboronic acid to give the title compound as a white oil in yield: 81.6% and the purity is 99.47%.

ESI-MS:m/z＝373.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.29(d，J＝1.3Hz，1H)，7.27(s，1H)，7.21–7.16(m，1H)， 7.13–7.04(m，2H)，6.85–6.78(m，1H)，4.19–4.12(m，2H)，3.76–3.63(m，4H)，2.98– 2.90(m，2H)，2.73–2.59(m，4H)，2.60–2.48(m，4H)。

Example 10: preparation of 7- (3, 4-dichlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 3, 4-dichlorophenylboronic acid to give the title compound as a white oil in yield: 79.9 percent and the purity is 99.58 percent.

ESI-MS:m/z＝405.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ ) δ 7.64(d, J ═ 2.1Hz, 1H), 7.52(d, J ═ 8.3Hz, 1H), 7.39(dd, J ═ 8.3, 2.2Hz, 1H), 7.29-7.22 (m, 2H), 7.18(dd, J ═ 7.7, 1.6Hz, 1H), 4.17-4.12 (m, 2H), 3.75-3.63 (m, 4H), 2.99-2.88 (m, 2H), 2.73-2.59 (m, 4H), 2.59-2.48 (m, 4H). Example 11: preparation of 7- (3, 4-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 3, 4-difluorophenylboronic acid to give the title compound as a white oil in yield: 78.2% and 99.32% purity.

ESI-MS:m/z＝373.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.40–7.32(m，1H)，7.30–7.20(m，4H)，7.16(dd，J＝7.7，1.6Hz，1H)，4.20–4.12(m，2H)，3.76–3.62(m，4H)，2.99–2.89(m，2H)，2.73–2.60(m， 4H)，2.59–2.49(m，4H)。

Example 12: preparation of 1- (2-morpholinoethyl) -7- (4- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4- (trifluoromethoxy) phenylboronic acid to give the title compound as a white oil in yield: 83.2% and the purity is 99.64%.

ESI-MS:m/z＝421.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.60–7.54(m，2H)，7.31(d，J＝8.1Hz，2H)，7.26–7.22 (m，2H)，7.19(dd，J＝7.7，1.5Hz，1H)，4.21–4.11(m，2H)，3.75–3.64(m，4H)，2.99–2.88(m，2H)，2.74–2.59(m，4H)，2.60–2.47(m，4H)。

Example 13: preparation of 7- (4-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-methoxyphenylboronic acid to give the title compound as a white oil in yield: 82.1% and the purity is 99.09%.

ESI-MS:m/z＝367.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.56–7.45(m，2H)，7.28–7.27(m，1H)，7.25–7.14(m， 2H)，7.04–6.95(m，2H)，4.20–4.09(m，2H)，3.86(s,3H)，3.75–3.65(m，4H)，2.92(dd， J＝8.5，6.2Hz，2H)，2.73–2.61(m，4H)，2.60–2.48(m，4H)。

Example 14: preparation of 7- (2-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 2-methoxyphenylboronic acid to give the title compound as a white oil in yield: 81.2% and the purity is 99.39%.

ESI-MS:m/z＝367.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.38–7.27(m，3H)，7.23–7.13(m，2H)，7.08–6.98(m， 2H)，4.19–4.05(m，2H)，3.83(s，3H)，3.72–3.61(m，4H)，2.97–2.87(m，2H)，2.71–2.61 (m，4H)，2.60–2.47(m，4H)。

Example 15: preparation of 1- (2-morpholinoethyl) -7- (2- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 2- (trifluoromethoxy) phenylboronic acid to give the title compound as a white oil in yield: 80.7 percent and the purity is 99.10 percent.

ESI-MS:m/z＝421.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.44–7.38(m，2H)，7.32(d，J＝0.8Hz，1H)，7.23–7.12 (m，4H)，4.13–4.02(m，2H)，3.70–3.57(m，4H)，2.92–2.81(m，2H)，2.64–2.54(m， 4H)，2.50–2.44(m,4H)。

Example 16: preparation of 7- (2- (methylthio) phenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 2-methylthiophenylboronic acid to give the title compound as a white oil in yield: 80.7 percent and the purity is 99.28 percent.

ESI-MS:m/z＝383.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.39–7.33(m，1H)，7.31–7.27(m，1H)，7.25–7.20(m， 3H)，7.18(d，J＝1.2Hz，1H)，7.04(dd，J＝7.6，1.4Hz，1H)，4.15–4.05(m，2H)，3.71– 3.59(m，4H)，2.99–2.88(m，2H)，2.74–2.59(m，4H)，2.58–2.48(m，4H)，2.39(s，3H)。

Example 17: preparation of 1- (2-morpholinoethyl) -7- (pyridin-3-yl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 3-pyridineboronic acid to give the title compound as a white oil in yield: 82.5% and the purity is 99.29%.

ESI-MS:m/z＝338.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.83(d，J＝1.9Hz，1H)，8.62(dd，J＝4.8，1.5Hz，1H)， 7.89–7.82(m，1H)，7.40(dd，J＝7.9，4.8Hz，1H)，7.33–7.26(m，2H)，7.25–7.18(m， 1H)，4.21–4.10(m，2H)，3.76–3.62(m，4H)，3.04–2.89(m，2H)，2.75–2.60(m，4H)，2.60–2.48(m，4H)。

Example 18: preparation of 7- (3, 4-dichlorophenyl) -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound IIc (2.26g, 10mmol), 3, 4-dichlorophenylboronic acid (2.29g, 12mmol), Cs were added at room temperature ₂ CO ₃ (3.91g, 12mmol) was added to 1,4-dioxane (30mL), and after nitrogen substitution, Pd (Ph) was added ₃ P) ₄ (1.16g, 1mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 3:1, dried and dried in vacuo to give 2.33g of the product as a yellow oil. Yield: 80.1 percent. ESI-MS: M/z 292.2(M + H) ⁺ 。

Step two, adding the compound Va (2.34g, 9.31mmol) and the compound VIb (2.06g, 13.96mmol) into anhydrous THF (30mL), adding NaH (0.56g, 13.96mmol) in batches, heating to room temperature, reacting for 6h, and completely reacting the raw materials. Addition of H ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried and dried in vacuo to give 2.87g of the product as a yellow oil. Yield: 76.3 percent and the purity is 99.90 percent.

ESI-MS:m/z＝404.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.72(d，J＝1.9Hz，1H)，7.54–7.48(m，2H)，7.38(d， J＝1.2Hz，1H)，7.25–7.14(m，2H)，4.34–4.19(m，2H)，3.01–2.88(m，2H)，2.88–2.71 (m，6H)，2.72–2.61(m，2H)。

Example 19: preparation of 7- [3- (naphthalen-2-yl) phenyl ] -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure for the preparation of example 18, the 3, 4-dichlorophenylboronic acid from step one was replaced with an equimolar amount of 2-naphthaleneboronic acid to give the title compound as a pale brown solid in yield: 81.2% and the purity is 99.63%.

ESI-MS:m/z＝385.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.05(s，1H)，7.96–7.84(m，3H)，7.75(dd，J＝8.5，1.8Hz， 1H)，7.56–7.45(m，3H)，7.39–7.33(m，1H)，7.30–7.26(m，1H)，4.28–4.16(m，2H)， 3.01–2.88(m，2H)，2.76–2.47(m，8H)，1.70–1.53(m，4H)，1.51–1.36(m，2H)。

Example 20: preparation of 7- [2- (methylthio) phenyl ] -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure for the preparation of example 18, the 2-chlorobenzeneboronic acid in step one was replaced with an equimolar amount of 2- (methylthio) benzeneboronic acid to give the title compound as a pale yellow oil in yield: 82.9 percent and the purity is 99.36 percent.

ESI-MS:m/z＝381.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.38–7.32(m，1H)，7.30–7.27(m，1H)，7.24–7.17(m， 4H)，7.04(dd，J＝7.6，1.5Hz，1H)，4.21–4.05(m，2H)，3.00–2.87(m，2H)，2.75–2.44 (m，8H)，2.39(s，3H)，1.63–1.50(m，4H)，1.48–1.34(m，2H)。

Example 21: preparation of 7- (dibenzo [ b, d ] thiophen-4-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the preparation method of example 4, 2-chlorobenzene boronic acid in step two was replaced with an equimolar amount of dibenzothiophene-4-boronic acid to obtain the title compound as a pale yellow oil in yield: 76.2 percent and the purity is 99.23 percent.

ESI-MS:m/z＝443.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.24–8.11(m，2H)，7.86–7.78(m，1H)，7.57(t，J＝7.6Hz， 1H)，7.54–7.43(m，4H)，7.40–7.29(m，2H)，4.24–4.12(m，2H)，3.72–3.55(m，4H)， 3.07–2.92(m，2H)，2.80–2.68(m，4H)，2.68–2.51(m，4H)。

Example 22: preparation of 4- [1- (2-morpholinoethyl) -2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl ] benzonitrile

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-cyanophenylboronic acid to give the title compound as a pale yellow oil in yield: 80.2 percent and the purity is 99.30 percent.

ESI-MS:m/z＝362.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.78–7.72(m，2H)，7.72–7.64(m，2H)，7.35–7.18(m， 3H)，4.24–4.13(m，2H)，3.80–3.62(m，4H)，3.01–2.88(m，2H)，2.74–2.52(m，8H)。

Example 23: preparation of 1'- (2-morpholinoethyl) -3', 4 '-dihydro- [ -4,7' -bisquinoline ] -2'(1' H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-quinolineboronic acid to give the title compound as a pale yellow oil in yield: 78.9% and 98.71% purity.

ESI-MS:m/z＝388.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.99(d，J＝4.4Hz，1H)，8.23(d，J＝8.2Hz，1H)，7.93(dd， J＝8.4，0.7Hz，1H)，7.84–7.71(m，1H)，7.59–7.50(m，1H)，7.38(d，J＝4.5Hz，1H)， 7.34(d，J＝7.6Hz，1H)，7.23(d，J＝1.2Hz，1H)，7.16(dd，J＝7.6，1.4Hz，1H)，4.14–4.10 (m，2H)，3.68–3.56(m，4H)，3.08–2.97(m，2H)，2.80–2.71(m，2H)，2.70–2.61(m， 2H)，2.62–2.49(m，4H)。

Example 24: preparation of 1- (3-morpholinopropyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound IIc (2.26g, 10mmol), naphthalene-2-boronic acid ester (3.05g, 12mmol), CsF (1.82g, 12mmol) were added to 1,4-dioxane (30mL) at room temperature, and after nitrogen substitution, Pd (dppf) Cl was added ₂ (0.73 g, 1mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate filtered, the filtrate dried, the crude product washed with the eluent petroleum ether: ethyl acetate 3:1 was passed through the column, spun dry and dried in vacuo to give 2.18g of product vb as a yellow oil. Yield: 79.6 percent. ESI-MS: 274.2(M + H) M/z ⁺ 。

Step two, adding the compound vb (2.18g, 8.0mmol) and the compound Vic (2.16g, 11.7mmol) into anhydrous DMF (30mL), adding CsF (1.78g, 11.7mmol), heating to room temperature, reacting for 6h, and completely reacting the raw materials. Addition of H ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried in vacuo to give 2.43g of the product as a yellow oil: 1- (3-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one. Yield: 76.4% and the purity is 98.11%.

ESI-MS:m/z＝401.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ8.00(s，1H)，7.95–7.85(m，3H)，7.70(dd，J＝8.5，1.8Hz， 1H)，7.56–7.47(m，2H)，7.37–7.32(m，2H)，7.30–7.25(m，1H)，4.13–4.05(m，2H)， 3.71–3.62(m，4H)，3.00–2.89(m，2H)，2.75–2.65(m，2H)，2.58–2.43(m，6H)，2.01– 1.92(m，2H)。

Example 25: preparation of 1- [2- (azepan-1-yl) ethyl ] -7- (2-methylthiophenyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound IIc (2.26g, 10mmol), 2-methylthiophenylboronate (3.00g, 12mmol), K at room temperature ₂ CO ₃ (1.66g, 12mmol) was added to DMSO (30mL), the mixture was purged with nitrogen, and Pd (dppf) Cl was further added ₂ (0.73 g, 1mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the crude product was purified with the eluent petroleum ether: ethyl acetate 3:1 column chromatography, spin-dried, and dried in vacuo to afford product vc as a yellow oil in 2.10g, yield: and 78 percent. ESI-MS: M/z 270.2(M + H) ⁺ 。

Step two, adding the compound Vc (2.10g, 7.8mmol) and the compound VI d (1.89g, 11.7mmol) into anhydrous CH at the temperature of 0 DEG C ₃ CN (50mL), adding Cs ₂ CO ₃ (3.89g, 11.7mmol), warmed to room temperature, reacted for 6h, and the starting material reacted completely. Addition of H ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin dried, and the crude product was purified with the eluent petroleum ether: ethyl acetate 2:1 column chromatography, spin-dried, and dried in vacuo to afford 2.33g of the product as a yellow oil: 1- [2- (azepane-1-yl) ethyl]-7- (2-methylthiophenyl) -3, 4-dihydroquinolin-2 (1H) -one. Yield: 75% and the purity is 98.11%.

ESI-MS:m/z＝395.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.38–7.31(m，1H)，7.31–7.27(m，1H)，7.25–7.17(m， 4H)，7.06(dd，J＝7.5，1.4Hz，1H)，4.30–4.18(m，2H)，3.17–3.00(m，6H)，2.99–2.85 (m，2H)，2.75–2.63(m，2H)，2.39(s，3H)，1.93–1.70(m，8H)。

Example 26: preparation of 1- [2- (azepan-1-yl) ethyl ] -6-methoxy-3, 4-dihydroquinolin-2 (1H) -one

At 0 deg.C, compound Id (1.77g, 10mmol), compound VIa (2.42g, 15mmol) were added to anhydrous DMSO (30mL), K was added ₂ CO ₃ (2.07g, 15mmol), warmed to room temperature, reacted for 6h, and the starting material reacted completely. Addition of H ₂ O (30mL), extracted three times with ethyl acetate (50mL x 3), the organic phase was washed successively with water, saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the crude product was purified with the eluent petroleum ether: ethyl acetate 2:1 was passed through the column, spin dried and dried in vacuo to give 2.42g of product viid as a yellow oil. Yield: 80.2 percent and the purity is 98.11 percent.

ESI-MS:m/z＝303.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.04(d，J＝8.8Hz，1H)，6.81–6.68(m，2H)，4.15–4.01(m， 2H)，3.79(s，3H)，2.99–2.76(m，4H)，2.67–2.42(m，8H)，1.71–1.54(m，4H)，1.52–1.40 (m，2H)。

Example 27: preparation of 7- (3, 4-dichlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinoline-2 (1H) -thione

Step one, intermediate 7-bromo-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one (VIIc) was prepared according to the preparation method of example 3

Step two, the compound 7-bromo-1- (2-morpholinomorphinone) -3, 4-dihydroquinolin-2 (1H) -one (2.72g, 8mmol) was dissolved in toluene (40mL), Lawson's reagent (1.64g, 2mmol) was added, the suspension was heated to 120 ℃ and reacted for 4 hours, then the system was cooled to 10 ℃ and a solid was plated out, which was collected by filtration on a Buchner funnel, washed with a small amount of dichloromethane and dried to give 7-bromo-1- (2-morpholinomorphinone) -3, 4-dihydroquinolin-2 (1H) -thione (2.08g) in 73% yield.

Step three, compound IXc (7-bromo-1- (2-morpholinomorphinone) -3, 4-dihydroquinoline-2 (1H) -thione) (2.08g, 5.85mmol), compound 3, 4-dichlorophenylboronic acid (1.42g, 7.44mmol), CsF (1.13g, 10.2mmol) were added to DME (50mL) at room temperature, nitrogen substitution was performed, and Pd (PPh) was added ₃ ) ₂ Cl ₂ (0.44g, 0.85mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried and dried in vacuo to give 1.90g of the product as a yellow oil. Yield: 79.3 percent and the purity is 98.71 percent.

ESI-MS:m/z＝387.3(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ8.07(s，1H)，7.90(d，J＝8.6Hz，1H)，7.82(s，1H)，7.79 (d，J＝8.3Hz，1H)，7.62(dd，J＝8.3，1.7Hz，1H)，7.23(d，J＝8.6Hz，1H)，3.84–3.68(m， 6H)，3.54(brs，2H)，2.88–2.52(m，8H)。

Example 28: preparation of 7- (2-chlorophenyl) -1- [2- (dimethylamino) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound IIc (2.26g, 10mmol), compound VI e (1.61g, 15mmol), K are added at room temperature ₂ CO ₃ (4.14g, 30mmol) was added to CH ₃ CN (50mL), heated to 100 ℃ and reacted for 6h, the starting material was reacted completely. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 3:1, dried and dried in vacuo to give 2.49g of the product vie as a yellow oil. Yield: 83.8 percent. ESI-MS: M/z 297.2(M + H) ⁺ 。

Step two, compound VIIe (2.49g, 8.4mmol), compound 2-chlorobenzeneboronic acid (1.58g, 10.1mmol), CsF (1.53g, 10.2mmol) were added to DMSO (30mL) at room temperature, replaced with nitrogen, and Pd (PPh) was added ₃ ) ₄ (0.97g, 0.84mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50 mL. times.3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried and dried in vacuo to give 2.25g of 7- (2-chlorophenyl) -1- [2- (dimethylamino) ethyl ] ethyl ester as a yellow oily product]-3, 4-dihydroquinolin-2 (1H) -one. Yield: 81.3 percent and the purity is 98.85 percent.

ESI-MS:m/z＝329.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.52–7.46(m，1H)，7.37–7.29(m，3H)，7.24(d，J＝7.6 Hz，1H)，7.20(d，J＝1.3Hz，1H)，7.06(dd，J＝7.6，1.5Hz，1H)，4.13–4.08(m，2H)， 3.00–2.90(m，2H)，2.74–2.60(m，4H)，2.33(s，6H)。

Example 29: preparation of 6- (3, 4-dichlorophenyl) -1- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, 6-bromo-3, 4-dihydroquinolin-2 (1H) -one (2.26g, 10mmol), 3, 4-dichlorophenylboronic acid (2.29g, 12mmol), Cs, at room temperature ₂ CO ₃ (3.91g, 12mmol) was added to 1,4-dioxane (30mL), and after nitrogen substitution, Pd (Ph) was added ₃ P) ₄ (1.16g, 1mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h to complete the reaction of the raw materials. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 3:1, dried and dried in vacuo to give 2.34g of the product as a yellow oil. Yield: 82.8 percent. ESI-MS: M/z 392.2(M + H) ⁺ 。

Step two, adding the compound Va (2.34g, 9.31mmol) and the compound VIb (2.06g, 13.96mmol) into anhydrous THF (30mL), adding NaH (0.56g, 13.96mmol) in batches, heating to room temperature, reacting for 6h, and completely reacting the raw materials. Addition of H ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 2:1, dried and dried in vacuo to give 2.87g of the product as a yellow oil. Yield: 76.3% and 96.24% purity.

ESI-MS:m/z＝404.2(M+H) ⁺ 。

¹ H NMR(400MHz，CDCl ₃ )δ7.64(d，J＝2.1Hz，1H)，7.53–7.33(m，4H)，7.16(d，J ＝8.5Hz，1H)，4.20–4.12(m，2H)，3.77–3.70(m，4H)，3.02–2.92(m，2H)，2.75–2.54(m， 8H)，2.06-2.05(m，2H)。

Example 30: preparation of 7- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step two, compound VIIc (3g, 8.8mmol), allylboronic acid (0.91g, 10.6mmol), CsF (4.01g, 26.4mmol) were added to 1,4-dioxane/H at room temperature ₂ O (60ml, V/V. 5/1) was purged with nitrogen, and Pd (dppf) Cl was further added ₂ (0.64g, 0.88mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h until the raw materials are completely reacted. The reaction was cooled to room temperature and H was added ₂ O (30ml), extracted three times with ethyl acetate (50ml x 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent methanol dichloromethane 20:1, dried and dried in vacuo to give 2.5g of the title compound 7-allyl-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 95% and the purity is 99.19%.

ESI-MS:m/z＝301.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.08(d，J＝7.5Hz，1H)，6.91(s，1H)，6.84(d，J＝7.5Hz， 1H)，5.95(d，J＝6.7Hz，1H)，5.13–5.06(m，2H)，4.12–4.03(m，2H)，3.76–3.65(m， 4H)，3.38(d，J＝6.7Hz，2H)，2.90–2.81(m，2H)，2.64–2.50(m，8H)。

Step three, XI a (1g, 3.3mmol) is dissolved in anhydrous THF (20ml) at room temperature, cooled to-40 ℃ after nitrogen replacement protection, and 1M BH is added dropwise ₃ THF (10 ml). After the dropwise addition, the reaction solution was slowly warmed up to room temperature and reacted for 2 hours. The reaction solution is cooled to 0 ℃ again, and H is added dropwise ₂ O (10ml) quench excess BH ₃ THF, then 0.5M NaOH (10ml) and 35% H were added dropwise ₂ O ₂ (2ml) and reacted at 0 ℃ for 1 h. Addition of H ₂ O (30ml), extracted three times with ethyl acetate (50 ml. x.3), the organic phase was successively treated with water, saturated NaHCO ₃ Washing the solution with saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate, and collecting the crude productThe column was chromatographed with the eluent methanol dichloromethane 20:1, spin dried and dried in vacuo to give 0.3g of the title compound 7- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 28.6 percent and the purity is 99.70 percent.

ESI-MS:m/z＝319.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ6.90(t，J＝7.1Hz，1H)，6.61–6.42(m，2H)，4.50-4.45(m， 1H)，3.78–3.63(m，6H)，3.48–3.38(m，2H)，3.33-3.23(m，2H)，2.75-2.67(m，2H)，2.58 –2.45(m，6H)，1.96–1.88(m，2H)，1.84–1.71(m，2H)。

Example 31: preparation of 7- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, example compound 30(0.9g, 2.8mmol) was dissolved in anhydrous dichloromethane (20ml) at room temperature, purged with nitrogen, cooled to-78 ℃ and diethylaminosulfur trifluoride (0.68g, 4.2mmol) was added dropwise. After the dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was cooled to 0 ℃ and saturated NaHCO was used ₃ Quenching the reaction solution, adding H ₂ O (30ml), extracted three times with dichloromethane (50 ml. x.3), the organic phase was taken in turn with water, saturated NaHCO ₃ The solution was washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and the crude product was purified by column chromatography with the eluent methanol dichloromethane 20:1, dried and dried in vacuo to give 0.4g of the title compound 7- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 44.6 percent and the purity is 99.35 percent.

ESI-MS:m/z＝321.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.09(d，J＝7.5Hz，1H)，6.92(s，1H)，6.86–6.83(m，1H)，4.51–4.43(m，2H)，4.13–4.04(m，2H)，3.71(t，J＝4.5Hz，4H)，2.88–2.83(m，2H)，2.77 –2.70(m，2H)，2.66–2.62(m，2H)，2.60–2.57(m，2H)，2.55(brs，4H)，2.07–1.93(m， 2H)。

Example 32: preparation of 6- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, compound Id (2.26g, 10mmol), compound VIa (2.24g, 15mmol), Cs are mixed at room temperature ₂ CO ₃ (9.75g, 30mmol) was added to DMF (30mL) and heated to 100 deg.C for 6h, and the starting material was reacted completely. The reaction was cooled to room temperature and H was added ₂ O (30mL), extracted three times with ethyl acetate (50mL × 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent petroleum ether ethyl acetate 3:1, dried and dried in vacuo to give 2.86g of compound viif as a yellow oil. Yield: 85 percent.

Step two, compound VIIf (3g, 8.8mmol), allylboronic acid (0.91g, 10.6mmol), CsF (4.01g, 26.4mmol) were added to 1,4-dioxane/H at room temperature ₂ O (60ml, V/V-5/1), replaced with nitrogen, and Pd (dppf) Cl was added ₂ (0.64g, 0.88mmol), replacing with nitrogen again for three times, heating to 100 ℃ under the protection of nitrogen, and reacting for 16h until the raw materials are completely reacted. The reaction was cooled to room temperature and H was added ₂ O (30ml), extracted three times with ethyl acetate (50ml x 3), the organic phase washed successively with water, saturated brine, the organic phase dried over anhydrous sodium sulfate, filtered, the filtrate dried, the crude product chromatographed with the eluent methanol dichloromethane 20:1, dried and dried in vacuo to give 2.4g of the title compound 6-allyl-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 90.9 percent and the purity is 99.23 percent.

ESI-MS:m/z＝301.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.06(dd，J＝8.3，1.5Hz，1H)，7.01–6.96(m，2H)，5.97 –5.91(m，1H)，5.12–5.05(m，2H)，4.12–4.03(m，2H)，3.70(t，J＝4.5Hz，4H)，3.34(d， J＝6.7Hz，2H)，2.92–2.82(m，2H)，2.64–2.61(m，2H)，2.59–2.56(m，2H)，2.54(brs， 4H)。

Step three, XI b (1g, 3.3mmol) is dissolved in anhydrous THF (20ml) at room temperature, cooled to-40 ℃ after nitrogen replacement protection, and 1M BH is added dropwise ₃ THF (10 ml). After the dropwise addition, the reaction solution was slowly warmed up to room temperature and reacted for 2 hours. The reaction solution is cooled to 0 ℃ again, and H is added dropwise ₂ O (10ml) quench excess BH ₃ THF, then 0.5M NaOH (10ml) and 35% H were added dropwise ₂ O ₂ (2ml) and reacted at 0 ℃ for 1 h. Addition of H ₂ O (30ml), extracted three times with ethyl acetate (50 ml. x.3), the organic phase was taken in turn with water, saturated NaHCO ₃ The solution was washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was dried off, and the crude product was purified by column chromatography with the eluent methanol dichloromethane 20:1, dried off and dried in vacuo to give 0.34g of the title compound 6- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 32.5% and purity 99.16%.

ESI-MS:m/z＝319.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.07(dd，J＝8.2，1.8Hz，1H)，7.01(s，1H)，6.98(d，J＝ 8.3Hz，1H)，4.13–4.03(m，2H)，3.75–3.65(m，6H)，2.88–2.83(m，2H)，2.69–2.65(m， 2H)，2.64–2.61(m，2H)，2.59–2.56(m，2H)，2.54(brs，4H)，1.91–1.85(m，2H)。

Example 33: preparation of 6- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Step one, example compound 32(0.9g, 2.8mmol) was dissolved in anhydrous dichloromethane (20ml) at room temperature, and after nitrogen substitution protection, cooled to-78 ℃ and DAST (0.68g, 4.2mmol) was added dropwise. After the dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was cooled to 0 ℃ and saturated NaHCO was used ₃ Solution quenchingReacting, adding H ₂ O (30ml), extracted three times with dichloromethane (50 ml. x.3), the organic phase was taken in turn with water, saturated NaHCO ₃ The solution was washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was dried, and the crude product was purified by column chromatography with the eluent methanol dichloromethane 20:1, dried and dried in vacuo to give 0.43g of the title compound 6- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one as a yellow oil. Yield: 48.2 percent and the purity is 98.99 percent.

ESI-MS:m/z＝321.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.11–7.06(m，1H)，7.03–6.97(m，2H)，4.50–4.41(m， 2H)，4.08(t，J＝7.3Hz，2H)，3.72(brs，4H)，2.88-2.85(m，2H)，2.72–2.67(m，2H)，2.65 –2.49(m，8H)，2.04-1.94(m，2H)。

Example 34: preparation of 7- ([1,1' -biphenyl ] -3-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the procedure of example 4, the 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 3-biphenylboronic acid to give the title compound as a pale yellow oil in yield: 83.2% and the purity is 99.77%.

ESI-MS:m/z＝413.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.76(s，1H)，7.63(d，J＝7.6Hz，2H)，7.60(d，J＝7.1Hz， 1H)，7.56–7.51(m，2H)，7.47(t，J＝7.6Hz，2H)，7.38(t，J＝7.4Hz，1H)，7.36(s，1H)， 7.29(d，J＝7.7Hz，1H)，7.25(s，1H)，4.16(t，J＝7.2Hz，2H)，3.65(t，J＝4.3Hz，4H)， 2.97–2.92(m，2H)，2.71–2.67(m，2H)，2.64(t，J＝7.2Hz，2H)，2.55(brs，4H)。

Example 35: preparation of 7- ([1,1' -biphenyl ] -4-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one

Following the preparation method of example 4, 2-chlorobenzeneboronic acid in step two was replaced with an equimolar amount of 4-biphenylboronic acid to obtain the title compound as a pale yellow oil in yield: 81.1% and the purity is 99.93%.

ESI-MS:m/z＝413.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ7.69(d，J＝8.2Hz，2H)，7.65(d，J＝8.2Hz，4H)，7.47(t， J＝7.7Hz，2H)，7.39–7.35(m，2H)，7.28(dd，J＝7.6，1.3Hz，1H)，7.25(d，1H)，4.17(t， J＝7.2Hz，2H)，3.70(t，J＝4.5Hz，4H)，2.97–2.90(m，2H)，2.71–2.63(m，4H)，2.56(brs， 4H)。

Example 36: preparation of 1- (2-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinoline-2 (1H) -thione

By following the procedure of example 27, 3, 4-dichlorophenylboronic acid in step three was replaced with an equimolar amount of 2-naphthalene boronic acid to obtain the title compound as a pale yellow oil in yield: 80.1% and the purity is 98.57%.

ESI-MS:m/z＝403.2(M+H) ⁺ 。

¹ H NMR(800MHz，CDCl ₃ )δ8.39–8.18(m，2H)，8.13–7.74(m，6H)，7.66–7.47(m， 3H)，5.41–5.28(m，1H)，4.75(brs，2H)，4.18–4.04(m，1H)，3.93–3.42(m，6H)，2.94– 2.48(m，4H)，2.12–1.95(m，2H)。

Preparation example 1: preparation of 4- { 2- [ [ 5-methyl-1- (naphthalen-2-yl) -1H-pyrazol-3-yl ] oxy ] ethyl } morpholine

Step one, compound 1h (10)g, 61mmol) was dissolved in 100mL of toluene, and 100mL of ethyl acetate was added to the reaction solution. The temperature of the reaction solution is reduced to 0 ℃ in an ice bath, acetic anhydride (7.74g, 75mmol) is slowly dripped into the reaction solution, and after dripping, the temperature is naturally raised to the room temperature for reaction overnight. The starting material was detected by TLC (dichloromethane: methanol: 10:1) to be reacted completely. 100mL of water was added to the reaction mixture, the pH was adjusted to 9-10 with saturated Na2CO3 solution, the reaction mixture was extracted with ethyl acetate (100 mL. times.3), and the organic phase was extracted with saturated NaHCO ₃ The solution, water and saturated brine were washed with water and dried over anhydrous sodium sulfate. The organic phase was filtered, the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate: 5: 1-2: 1) to give compound 2h (7.6 g, pale yellow oil). Yield: 62.3 percent. ESI-MS: M/z 201.2(M + H) ⁺ 。

Step two, slowly adding the compound 2h (6g, 30mmol) and ethyl acetoacetate (4.85g, 45mmol) into phosphorus tribromide (10mL) under the protection of nitrogen, heating the reaction solution to 50 ℃, and carrying out heat preservation reaction for 2 hours. The completion of the reaction of the starting materials was checked by TLC (petroleum ether: ethyl acetate ═ 1: 1). The reaction was cooled to room temperature, poured into 100mL dichloromethane, 50mL ice water added, extracted with dichloromethane (100mL x 3) and the organic phase saturated NaHCO ₃ The solution, water and saturated brine were washed with water and dried over anhydrous sodium sulfate. The organic phase was filtered, the filtrate was concentrated to give a crude product which was purified by column chromatography (petroleum ether: ethyl acetate: 5: 1-2: 1) to give compound 3h (2.2g, white solid). Yield: 32.7 percent. ESI-MS: M/z 225.2 (M + H) ⁺ 。

Step three, compound 3h (2g, 8.9mmol), N- (2-chloroethyl) morpholine hydrochloride (1.6g, 10.7mmol) was added to 10mL DMF under nitrogen and NaH (0.72g, 17.8mmol) was added in portions while cooling on ice. The reaction solution was heated to 60 ℃ and reacted for 4 hours. The completion of the reaction of the starting materials was checked by TLC (petroleum ether: ethyl acetate ═ 1: 1). The reaction mixture was cooled to room temperature, poured into 100mL of ethyl acetate, 50mL of ice water was added, extraction was performed with ethyl acetate (100mL × 3), and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtering the organic phase, concentrating the filtrate to obtain crude product, and purifying the crude product by column chromatography (petroleum ether: ethyl acetate: 5: 1-1: 1) to obtain compound 4h (2.3 g)White solid). Yield: 76.6 percent. ESI-MS: 338.2(M + H) M/z ⁺ 。

Step four, dissolving the compound 4h (2.3g, 6.8mmol) in 3mL of anhydrous ethyl acetate, dropwise adding ethyl acetate/HCl (2.5N, 3mL) under ice bath, naturally returning to room temperature after dropping, and reacting overnight. The reaction solution was filtered, and the filter residue was washed three times with anhydrous ethyl acetate, and the solid was dried to obtain the title compound of preparation example 1 (2.1g, white solid) in yield: 82.7% purity 98.47%.

¹ H NMR(400MHz，CDCl ₃ )δ7.95–7.78(m，4H)，7.60(dd，J＝8.7，2.1Hz，1H)，7.55 –7.47(m，2H)，5.73(s，1H)，4.38(t，J＝5.6Hz，2H)，3.79–3.71(m，4H)，2.81(t，J＝5.6 Hz，2H)，2.65–2.50(m，4H)，2.36(s，3H)。

Test example 1: acetic acid writhing test in mice

1. Test materials

1.1 test reagents

1.2 test apparatus

1mL syringe, stopwatch, micropipette, electronic balance, 15mL centrifuge tube, 50mL centrifuge tube, and the like.

2. Laboratory animal

Kunming mouse, half male and female, weighing 22-25g, was provided by Woodhoo Biotechnology, Inc.

3. Test method

3.1 preparation of test article

HCl was added to the saline to adjust the pH to 4.5 for later use.

Weighing each compound, adding 100 mu L DMSO, shaking for dissolution, and adding the normal saline hydrochloric acid solution to prepare a2 mg/mL test solution. If there is still insoluble matter, heating to dissolve.

Preparation of 3.20.8% acetic acid solution

Taking 0.2mL of glacial acetic acid in a 50mL centrifuge tube, adding 1.8mL of physiological saline, fully shaking and uniformly mixing, adding 23mL of physiological saline, shaking and uniformly mixing to obtain the acetic acid solution with the required concentration. The solution is prepared at present, and a centrifuge tube cover is screwed after each use to prevent acetic acid from volatilizing and influencing the test result.

3.3 administration and Observation of writhing frequency

The test was carried out in a quiet environment at room temperature of 23-25 ℃. Mice were numbered before dosing and placed in correspondingly numbered squirrel cages for 15 min. After the adaptation is finished, the mice are injected with 10mL/kg of medicine by intraperitoneal injection, the administration doses are respectively 20mg/kg, 5mg/kg, 2.5mg/kg, 1mg/kg and 0.5mg/kg, and the negative control group is administered with physiological saline with the same volume. 10min after administration, the mice were injected with 10mL/kg of the acetic acid solution in the abdominal cavity, immediately placed in mouse cages, and the number of writhing of the mice was observed within 15 min. The indexes of the twisted body are as follows: a writhing is considered to occur when the mouse develops the typical abdominal concavity with characteristic reactions of trunk twist, hip elevation and hind limb elongation.

4. Analysis of results

Taking the average writhing frequency of 10 mice within 15min as the judgment standard of the analgesic effect strength of the example compound, the smaller the average writhing frequency of each group is, the stronger the analgesic effect of the example compound is, and the average writhing frequency of the mice of each group is as follows:

TABLE 1-1 mean number of writhing in mice injected intraperitoneally with 20mg/kg of the compound of the experimental example

Numbering	Mean number of writhing in mice
		Blank group	32.3
Preparation example 1	26
		Example 2	14.2
Example 3	10.3
		Example 4	0.0
Example 5	0.0
		Example 6	0.0
Example 7	0.0

As shown in the table above, examples 2 and 3 exhibited a certain analgesic effect compared to the blank group; the compounds of example 4, example 5, example 6 and example 7 all had potent analgesic effects in the 20mg/kg group. Preparation example 1 at doses up to 20mg/kg, still showed no statistically significant analgesic activity in the mouse acetate writhing test compared to the blank.

TABLE 1-2 mean number of writhing in mice injected intraperitoneally with 5mg/kg of the compound of the experimental example

Numbering	Mean number of writhing of mice
		DMSO	29.6
Preparation example 1	31.3
		Example 4	3.5
Example 5	0.0
		Example 6	11.28
Example 7	2.0
		Example 8	10.4
Example 9	9.5
		Example 10	0.1
Example 11	11.9
		Example 12	16.6
Example 13	12.6
		Example 14	2.4
Example 15	0.0
		Example 16	7.8
Example 17	17.9
		Example 18	2.1
Example 19	0.5
		Example 20	1.3
Example 21	15.6
		Example 22	9.5
Example 23	0.2
		Example 24	2.9
Example 25	1.6
		Example 26	2.5
Example 36	4.1

As shown in the above table, after 5mg/kg of the example compound was administered by intraperitoneal injection, the example compounds 4 to 27 all showed strong analgesic effects in the mouse writhing acetosa test, particularly, the examples 5, 7, 10, 14, 15, 19, 20, 23, 24, 25, 26 and 27; preparation example 1 in this condition, no statistically significant analgesic activity was shown in the mouse acetate writhing test in comparison with the blank.

TABLE 1-3 mean number of writhing in mice injected intraperitoneally with 2.5mg/kg of the compound of the experimental example

Numbering	Average number of writhing in mice
		Blank group	30.2
Preparation example 1	28.5
		Example 4	1.3
Example 5	0.0
		Example 6	19.1
Example 7	9.1
		Example 8	15.3
Example 9	18.8
		Example 10	1.9
Example 11	18.1
		Example 12	25.6
Example 13	5.4
		Example 14	0.2
Example 15	0.0
		Example 16	1.4
Example 17	24.8
		Example 18	12
Example 19	5.6
		Example 20	4.4
Example 22	19.7
		Example 23	3.8
Example 24	13.6
		Example 25	12.5
Example 26	11.5
		Example 28	20.8
Example 29	18.3
		Example 36	15.3

As shown in the above table, after 2.5mg/kg of the compound of example was administered intraperitoneally, example 4, example 5, example 7, example 10, example 13, example 14, example 15, example 16, example 20, example 24, and example 26 all showed strong analgesic effects in the mouse acetic acid writhing test, as compared to the blank group. Preparation example 1 in the mouse acetic acid writhing test conducted under this condition, no statistically significant analgesic activity was exhibited as compared with the blank group.

TABLE 1-4 mean number of writhing in mice given 1mg/kg of the compound of the experimental example intraperitoneally

As shown in the above table, after intraperitoneal administration of 1mg/kg of the example compound, the example compounds 5, 10, 15, and 16 also showed significant analgesic effects in the mouse acetic writhing test. Preparation example 1 in the mouse acetic acid writhing test carried out under this condition, no statistically significant analgesic activity was exhibited as compared with the blank group.

TABLE 1-5 mean number of writhing in mice when 0.5mg/kg of the compound of the experimental example was injected intraperitoneally

Numbering	Average number of writhing in mice
		DMSO	29.6
Preparation example 1	31.2
		Example 5	10.3
Example 10	15.2
		Example 15	18.9
Example 16	20.1

As shown in the above table, the compounds of examples 5, 10, 15 and 16, after intraperitoneal administration of 0.5mg/kg of the compound of example, also showed analgesic effect in the mouse writhing acetosa test, especially the compound described in example 5, compared to the blank group. Preparation example 1 in the mouse acetic acid writhing test carried out under this condition, no statistically significant analgesic activity was exhibited as compared with the blank group.

Test example 2: test of Effect on Heat conduction induced pain-like response in mice (Hot plate test)

1. Test materials

1.1 test reagents

Name of reagent	Batch number	Source
			Kolliphor HS-15	48328768E0	Production by BASF applied chemical Co., Ltd
0.9% sodium chloride injection	w215080801	Sichuan Koran pharmaceutical industry Co., Ltd
			Carboxymethyl cellulose	#G1226001	Aladdin
High-grade carbon ink	201604285	Guizhou Boss Chemical Industry Co.,Ltd.
			Medicinal carbon sheet	48160118	Hebei Changtian Pharmaceutical Co.,Ltd.

1.2 test apparatus

Pipettor, centrifuging tube, electronic balance, syringe, mouse fixer, intelligent hot plate appearance, ruler, scissors, tweezers, enema needle etc..

2. Laboratory animal

Kunming mouse, all-female mouse, 18-22g, by WUDOSHIMIANIMA GmbH supply.

3. Test method

3.1 preparation of test article

HCl was added to the saline to adjust the pH to 4.5 for later use.

Accurately weighing 2mg of each of the compounds in the preparation examples 1, 5 and 10, respectively adding 1mL of 50% HS-15 solution, uniformly mixing, then adding 1mL of normal saline hydrochloric acid solution, and fully dissolving and uniformly mixing to obtain 1mg/mL of test solution.

3.2 test procedures

Taking 90 KM full-female mice, 18-22g, measuring the basic pain threshold value on a hot plate at 55 +/-0.5 ℃, and selecting 40 mice with the pain threshold value of 5-30s for experiments. The pain threshold of 40 qualified mice is measured 2 times before administration at intervals of 5min, and the average value is taken as the basic pain threshold. The mice were randomly divided into 4 groups, namely a blank control group, 10 compound groups of preparation example 1, example 5 and example 10, each group was administered in the tail vein (the control group was administered with 0.9% physiological saline in the same amount), the administration volume was 1mL/kg, the pain threshold of the mice was measured at 30, 60 and 120min after administration, and the difference between the pain threshold of each drug group and the pain threshold of the blank control group was statistically compared according to 60s for those with the pain threshold exceeding 60 s.

4. Test results and discussion

TABLE 2-1 influence of the Compounds of preparation example 1, example 5, example 10 on Hot plate induced pain threshold in mice

Note: "+ compared to blank, P < 0.05; ". compared to blank, P < 0.01.

As can be seen from the above table, the compounds of examples 5 and 10 can increase the pain threshold of the mice at 30min and 60min after administration, and have statistical difference compared with the blank group; the compound of preparation example 1 has no obvious effect of improving the pain threshold value of mice at 30min, 60min and 120min after administration, and has no statistical difference with a blank group.

Test example 3: thermal radiation tail flick test for rat

3.1 test materials

3.1.1 basic information of the test article

Compound numbering	Trait(s)	Batch number	Source
				Preparation example 1	White oil	20180314	Self-made
Example 5	Pale yellow oil	20180813	Self-made
				Example 10	Pale yellow oil	20180802	Self-made

3.1.2 test reagents

Name of reagent	Batch number	Source
			Kolliphor HS-15	69889088Q0	Beijing Phoenix gift treasure seeking medical science and medicine GmbH
0.9% sodium chloride injection	w214011102	Sichuan Koran pharmaceutical industry Co., Ltd

3.1.3 test apparatus

A 1mL syringe, a timer, a micropipette, an electronic balance, a 15mL centrifuge tube, a 50mL centrifuge tube, a rat tail light pain tester, and the like.

3.2 Experimental animals

SD rats, all females, weighing 160-.

3.3 test methods

3.3.1 preparation of test article

HCl was added to the saline to adjust the pH to 4.5 for later use.

Weighing about 20mg of each compound in a 50mL centrifuge tube, adding a normal saline hydrochloric acid solution to prepare a sample solution of 1mg/mL, and heating the insoluble compound to assist dissolution. Preparation example 1 after 100. mu.L of 50% HS-15 was added for solubilization, a 1mg/mL test solution was prepared by adding physiological saline.

3.3.2 administration and detection

After the acclimation period, rats were subjected to a pain threshold measurement the day before the administration. The lower 1/3 part of the tail is selected as a pain test point, the test is carried out for 3 times, the test interval time is not less than 5min, and the average value of the 3 times of tests is taken as the basic pain threshold of each rat. The pain threshold is set as the latency period (TFL) from the start of irradiation to the tail flick reaction, and the power of the pain measuring instrument is adjusted to 99%. Animals with basal pain thresholds less than 2s or greater than 10s were culled. Based on the basal pain threshold, 24 animals were selected and randomly divided into 4 groups of 6 animals each:

the administration was performed according to the above table and the pain threshold after administration was tested at 30, 60, 120min after administration, respectively.

3.4 test results and discussion

The percentage of maximal analgesic effect (MPE%) and the rate of increase in pain threshold were calculated according to the following formulas:

percent maximal analgesic effect (MPE%) (TFL-basal TFL)/(15-basal TFL) × 100% post-dose

Pain threshold increase rate (%) (TFL-basic TFL after administration)/basic TFL × 100%

This experiment completed a rat thermal radiation tail flick test of 3 compounds. The test results are as follows:

table 3-1: test compound thermal radiation drift test results

Note: "+ compared to saline group, P < 0.05; "x" compared to saline group, P < 0.01;

as can be seen from the above table:

under the test condition, when the administration dose is 4mg/kg, the analgesic effect of the rats is the best 30min after administration, namely, the analgesic effect of the rats in example 5 (the maximum analgesic effect is 100%, and the pain threshold increasing rate is 92.87%) and the analgesic effect of the rats in example 10 (the maximum analgesic effect is 73.65%, and the pain threshold increasing rate is 82.12%); no analgesic effect was observed in preparation example 1;

secondly, under the test condition, when the administration dose is 4mg/kg, the rats still have better analgesic effect 60min after administration, and example 5 (the maximum analgesic effect is 87.41%, and the pain threshold improvement rate is 82.23%); example 10 (maximum analgesic effect 31.54%, pain threshold increase rate 35.87%) the analgesic effect is significantly reduced; no analgesic effect was observed in preparation example 1;

③ under the test condition, when the administration dose is 4mg/kg, the rats still have better analgesic effect in example 5 (maximum analgesic effect 59.85%, pain threshold increasing rate 52.02%) 120min after administration, but the analgesic effect is obviously reduced; example 10 (maximum analgesic effect 10.81%, pain threshold improvement rate 16.99%) analgesic effect was further significantly reduced, with weaker analgesic effect; no analgesic effect was observed in preparation example 1;

thus, the analgesic effect of the compounds of examples 5 and 10 was tested by the rat thermal tail flick test and the results showed that: under the condition of the test, the compound in the example 5 has the best analgesic effect, and has obvious statistical difference (P <0.01) compared with physiological saline at 30min, 60min and 120 min; the compound of example 10 has the next lowest analgesic effect, has better analgesic effect at 30min of administration, has obvious statistical difference (P <0.01) compared with the normal saline, has statistical difference (P <0.05) compared with the normal saline at 60min of administration, and then has gradually reduced analgesic effect; the compound of preparation example 1 has no observed analgesic effect, has no statistical difference (P >0.05) compared with physiological saline at 30min, 60min and 120min, and has no influence on the pain threshold of rats.

In conclusion, the novel alkylammonium compound provided by the invention shows excellent analgesic effect in a mouse acetic acid writhing test, an influence test on a mouse pain-like reaction caused by heat conduction and a rat heat radiation tail flick test.

Claims

1. A compound which is a compound represented by the formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide compound, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound represented by the formula (I),

x is N or C;

y is O or S;

z is N or C, and the dotted line represents C connected to form a double or single bond;

R ¹ selected from hydrogen, substituted or unsubstituted C _1-12 Alkyl, substituted or unsubstituted C _3-12 Cycloalkyl, substituted or unsubstituted C _2-12 Alkenyl, substituted or unsubstituted C _5-12 Aryl, substituted or unsubstituted C _5-12 A heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, or halogen;

R ² and R ³ Independently selected from hydrogen, deuterium, substituted or unsubstituted C _1-12 Alkyl, substituted or unsubstituted C _3-12 Cycloalkyl, substituted or unsubstituted C _2-12 Alkenyl, substituted or unsubstituted C _5-10 Aryl, substituted or unsubstituted C _5-10 Heterocyclyl, or taken together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3-to 15-membered heterocyclyl group;

n is selected from 0, 1,2,3,4, 5 or 6.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, having the structure of formula I',

wherein B, C, D is selected from C or N, and B, C, D at least one, and at most two, are N;

y is O or S;

R ¹ selected from hydrogen, substituted or unsubstituted C _1-12 Alkyl, substituted or unsubstituted C _3-12 Cycloalkyl, substituted or unsubstituted C _2-12 Alkenyl, substituted or unsubstituted C _5-12 Aryl, substituted orUnsubstituted C _5-12 A heterocyclic group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, or halogen;

n is selected from 0, 1,2,3,4, 5 or 6;

3. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, having the structure shown in formula i ":

y is O or S;

R ¹ is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstitutedSubstituted or unsubstituted thiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furan rings, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted dibenzothienyl, substituted or unsubstituted alkoxy, substituted or unsubstituted propyl, substituted or unsubstituted allyl;

wherein the substituents are selected from one or more of deuterium, halogen, hydroxy, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, carboxamido, acetamido, cyclopropylamino, tert-butylamino, NO ₂ 、CN、CF ₃ 。

n is selected from 1 or 2.

4. A compound, stereoisomer or tautomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, according to claims 1-3, characterized in that:

R ¹ selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted biphenyl, substituted or unsubstituted dibenzothienyl, substituted or unsubstituted quinolyl; wherein the substituents are selected from one or more of deuterium, halogen, hydroxy, methyl,Ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, carboxamido, acetamido, cyclopropylamino, tert-butylamino, NO ₂ 、CN、CF ₃ ；

R ² And R ³ Independently selected from methyl, ethyl or R ² And R ³ Together with the nitrogen atom to which they are attached form morpholinyl, piperazinylcyclyl, piperidinyl, azepanyl;

n is selected from 1 or 2.

5. The compound of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:

R ¹ selected from the group consisting of 2-naphthyl, 2-chlorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3,4 dichlorophenyl, 3,4 difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexyl, allyl, cyclobutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, pyridyl, methoxy, hydroxy, nitro, amino, 2-chloro-4-fluorophenyl, t, 4-fluoro-2-methoxy, 4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

R ² and R ³ Independently selected from methyl, ethyl;

n is selected from 1 or 2;

6. The compound of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:

n is selected from 1 or 2;

7. The compound of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:

R ¹ selected from the group consisting of 2-naphthyl, 2-chlorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, phenyl, 3, 5-difluorophenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 4- (trifluoromethoxy) phenyl, cyclohexyl, allyl, alkenylbutyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2- (trifluoromethoxy) phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromo, pyridyl, methyl, methoxy, hydroxy, nitro, amino, 2-chloro-4-fluorophenyl, bromo, pyridyl, methyl, methoxy, hydroxy, nitro, amino, 4-chloro-4-fluorophenyl, and the like, 4-fluoro-2-methoxy4-fluoro-2- (trifluoromethyl) phenyl, 4-chloro-2-methoxyphenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-bis (trifluoromethyl) phenyl, 4-chloro-2- (trifluoromethyl) phenyl;

n is selected from 1 or 2;

wherein R is ¹ In the case of bromine, the substitution is in the 5 position.

8. The compound of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:

n is selected from 1 or 2;

9. The compound of claims 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:

n is selected from 1 or 2.

10. The compound of claim 1, selected from the following compounds, or a pharmaceutically acceptable salt thereof:

11. the compound of claim 1, selected from the following compounds, or a pharmaceutically acceptable salt or prodrug thereof:

1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (naphthalen-2-yl) quinoxalin-2 (1H) -one;

7- (2-chlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7-bromo-1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (4-fluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (4-fluoro-2-methylphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7-phenyl-3, 4-dihydroquinolin-2 (1H) -one;

7- (3, 5-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3, 4-dichlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3, 4-difluorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (4- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (4-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (2-methoxyphenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (2- (trifluoromethoxy) phenyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (2- (methylthio) phenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (pyridin-3-yl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3, 4-dichlorophenyl) -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one;

7- (naphthalen-2-yl) -1- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- [2- (methylthio) phenyl ] -1- [2- (piperidin-1-yl) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one;

7- (dibenzo [ b, d ] thiophen-4-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

4- [1- (2-morpholinoethyl) -2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl ] benzonitrile;

1'- (2-morpholinoethyl) -3', 4 '-dihydro- [ -4,7' -bisquinoline ] -2'(1' H) -one;

1- (3-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinolin-2 (1H) -one;

1- [2- (azepan-1-yl) ethyl ] -7- (2-methylthiophenyl) -3, 4-dihydroquinolin-2 (1H) -one;

1- [2- (azepan-1-yl) ethyl ] -6-methoxy-3, 4-dihydroquinolin-2 (1H) -one;

1- (2-morpholinoethyl) -7- (naphthalen-2-yl) -3, 4-dihydroquinoline-2 (1H) -thione;

7- (2-chlorophenyl) -1- [2- (dimethylamino) ethyl ] -3, 4-dihydroquinolin-2 (1H) -one;

6- (3, 4-dichlorophenyl) -1- (2- (piperidin-1-yl) ethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

6- (3-hydroxypropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

6- (3-fluoropropyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- ([1,1' -biphenyl ] -3-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- ([1,1' -biphenyl ] -4-yl) -1- (2-morpholinoethyl) -3, 4-dihydroquinolin-2 (1H) -one;

7- (3, 4-dichlorophenyl) -1- (2-morpholinoethyl) -3, 4-dihydroquinoline-2 (1H) -thione.

12. The compound, or a pharmaceutically acceptable salt, isomer thereof, of claims 1-11, wherein a hydrogen in the compound is substituted with one or more deuterium.

13. A process for the preparation of the compounds of claims 1-11 or isomers, key intermediates thereof, comprising the steps of:

reacting a compound of the formula II with an organoboronic acid (III) or organoboronate (IV) in the presence of 1,4-dioxane, DMF, DMSO, DME or 1,4-dioxane/H ₂ In a solvent such as O in Pd (PPh) ₃ ) ₄ 、Pd(dppf)Cl ₂ 、Pd(PPh ₃ ) ₂ Cl ₂ 、Pd(Cy ₃ ) ₂ Cl ₂ Or Pd (OAc) ₂ Under the catalysis of an isocatalyst, and Na ₂ CO ₃ 、K ₂ CO ₃ 、Cs ₂ CO ₃ Or CsF and other alkalis, reacting for 8-16 hours at the temperature of 80-160 ℃ to prepare the key intermediate compound of formula V;

reacting said compound of formula V with a compound of formula VI in DMF, DMSO, CH ₃ In CN or THF solvent, with K ₂ CO ₃ 、Cs ₂ CO ₃ And CsF or NaH, at 0-120 deg.C, to produce substitution reaction for 4-16 hours to obtain the compound of formula I.

。

14. A process for the preparation of the compounds of claims 1-11 or isomers, key intermediates thereof, comprising the steps of:

reacting a compound of formula II and a compound of formula VI in DMF, DMSO, CH ₃ CN, THF solvent, in K ₂ CO ₃ 、Cs ₂ CO ₃ And CsF or NaH under the alkaline condition at 0-120 ℃ for 4-16 hours to obtain the compound shown in the formula VII.

Continuing said compound of formula VII over Na ₂ CO ₃ 、K ₂ CO ₃ 、Cs ₂ CO ₃ Or CsF and the like under alkaline conditions, reacting with organic boric acid shown in formula III or organic boric acid ester shown in formula IV in the presence of 1,4-dioxane and DMFDMSO, DME or 1,4-dioxane/H ₂ O in Pd (PPh) or the like ₃ ) ₄ 、Pd(dppf)Cl ₂ 、Pd(PPh ₃ ) ₂ Cl ₂ 、Pd(Cy ₃ ) ₂ Cl ₂ Or Pd (OAc) ₂ Reacting for 8-16 hours at the temperature of 80-160 ℃ under the catalysis of catalysts to obtain the compound shown in the formula I.

。

15. Use of a compound according to claims 1-11 for the manufacture of a medicament for the treatment or prevention of pain.