Novel alkylamine compounds or salts, isomers, preparation methods and uses thereof

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to novel alkylamino compounds or their salts, isomers, preparation methods and pharmaceutical compositions thereof, and their use in the preparation of treatments and preventions, especially in the treatment of pain, drug addiction, opioid drug enhancement, mental illness and the like. Background Art

[0002] At present, the incidence of pain in the world is about 35-45%, and the incidence in the elderly is even higher, about 75%-90%. Pain has become the third most common treatment area in the world, and the market is huge. Opioids are currently the strongest and most commonly used central analgesics. Past studies have shown that opioids (such as codeine, morphine, oxycodone, and fentanyl) can effectively relieve pain. They bind to opioid receptors in the brain, spinal cord, and gastrointestinal tract to reduce pain. It is precisely because of the significant analgesic effect of opioids that their abuse has become a major public health problem in the United States; 78 people die every day from opioid overdose. Therefore, there is an urgent need for powerful analgesics with new targets in clinical practice.

[0003] Sigma receptors are unique non-opioid receptors that are widely distributed in the central nervous system. σ1 receptors are associated with the pathophysiology of all major central nervous system diseases, including mood disorders (anxiety and depression), psychosis and schizophrenia, as well as drug addiction and pain. Sigma 1 receptor antagonist S1RA (Compound of Preparation Example 1) can enhance the analgesic activity of opioid analgesics, and the potentiation effect can be antagonized by methylnaltrexone, σ1 receptor agonists, and naltrexone. S1RA can also be used alone to treat pain, such as showing strong analgesic effects in animal models of acute neuralgia, sciatica, diabetic neuralgia, inflammatory pain, and visceral pain. Secondly, S1RA does not have the addictiveness of opioid analgesics and has good tolerance. At present, S1RA has completed 5 clinical phase II studies in Europe. Among them, the confirmatory clinical study for the treatment of oxaliplatin-induced peripheral neuropathy showed that the efficacy of S1RA was not significant; for postoperative pain, 400 mg S1RA was given before surgery, and morphine (combined) was given after surgery. The morphine consumption in the S1RA group increased, but the adverse reactions of nausea, vomiting and dizziness decreased, the amount of antiemetic drugs was reduced, and the average pain intensity was weakened, which was statistically significant; for postoperative neuralgia, the pain level was reduced in 28 days, which was statistically significant; the experimental results of diabetic neuralgia and postherpetic neuralgia were not statistically significant. Therefore, S1RA did not have a good effect in multiple clinical phase II, and only had a significant analgesic effect on postoperative neuralgia with long-term medication, but it was well tolerated. The overall clinical results show that the analgesic effect of S1RA, whether used alone or in combination with morphine, needs to be improved.

[0004] Through structural analysis of S1RA, the inventors designed a new analgesic drug, and after conducting in vivo efficacy tests in multiple models, they unexpectedly discovered an analgesic drug whose analgesic effect is orders of magnitude stronger than that of S1RA. At low doses, it showed very strong analgesic effects when used independently in the mouse acetic acid writhing test, the rat hot plate test, and the rat thermal radiation tail flick test. Summary of the invention

[0005] The compound of the present invention is a new type of analgesic, and the example compounds show good analgesic effect in animals. In the acetic acid writhing test in mice, when 1 mg / kg of the compound of the present invention is intraperitoneally injected, it still has a very strong analgesic effect; and Example Compound 5 and Example Compound 10 also show strong analgesic effect in the rat hot plate analgesia test (1 mg / kg, iv) and the rat thermal radiation tail flick test (4 mg / kg, iv), but the same dose of S1RA under the same experimental conditions is equivalent to the blank control group and does not show analgesic effect.

[0006] In one aspect, the present invention relates to a compound of formula I or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula I,

[0007]

[0008] Wherein, Ring A is a substituted or unsubstituted C5-10 carbocyclic group, a substituted or unsubstituted C5-10 aryl group, a substituted or unsubstituted heterocyclic group consisting of 5-10 atoms, or a substituted or unsubstituted heteroaryl group consisting of 5-10 atoms;

[0009] X is N or C;

[0010] Y is O or S or NH;

[0011] Z is N or C, and the dotted line represents the C connected to it to form a double bond or a single bond;

[0012] 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=CR4R5, -NR4R5, -NO2, -CN, -SR4, -OR4 or halogen;

[0013] 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 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl group;

[0014] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0015] R4 and R5 are each independently selected from 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 together they form a fused ring system.

[0016] Further, the compound as shown in formula I or the stereoisomer, geometric isomer, tautomer, nitrogen oxide compound, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in formula I,

[0017]

[0018] Among them, ring A is C 5-6 A substituted or unsubstituted carbocyclic group, C 5-6 Substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group consisting of 5-6 atoms;

[0019] Y is O or S;

[0020] Z is N or C, and the dotted line represents the C connected to it to form a double bond or a single bond;

[0021] R 1 is 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 heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, substituted or unsubstituted amino group or halogen;

[0022] R 2 and R 3 are 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 5-10Heterocyclyl, or together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 15-membered heterocyclyl group;

[0023] n is selected from 0, 1, 2, 3, 4, 5, 6.

[0024] Further, the compound described in Formula I, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in Formula I',

[0025]

[0026] Wherein, B, C, and D are selected from C or N, and at most two of B, C, and D are N;

[0027] R 1 is 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 heterocyclic group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, substituted or unsubstituted amino group or halogen;

[0028] R 2 and R 3 are 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 together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 15-membered heterocyclyl group;

[0029] n is selected from 0, 1, 2 or 3;

[0030] wherein the substituent is selected from one or more of deuterium, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, amine, C1-C6 alkylamino, C1-C6 alkanoylamide, C5-C 10 Aryl, C5-C 10 Aralkyl, C5-C 10 heterocyclic group, NO2, CN, CF3, or together they form a fused ring system.

[0031] Further, the compound described in Formula I, or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug, has the structure shown in Formula I":

[0032]

[0033] Y is O or S;

[0034] Z is N or C, and the dotted line represents the C connected to it to form a double bond or a single bond;

[0035] R 1 is a substituted or unsubstituted cyclopropyl group, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted cyclopentyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted furan ring, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted dibenzothienyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted propyl group, or a substituted or unsubstituted allyl group;

[0036] R 2 and R 3 R is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted arylethyl, substituted or unsubstituted aromatic heteromethyl, substituted or unsubstituted aromatic heteroethyl, or 2 and R 3 The nitrogen atom to which they are attached together forms a substituted or unsubstituted morpholine ring group, a substituted or unsubstituted piperazine ring group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted hexahydropyrimidinyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted azocyclooctanyl group, or a substituted or unsubstituted azepanyl group;

[0037] Wherein, the substituent is selected from one or more of deuterium, halogen, hydroxyl, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropyloxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, formamide, acetamide, cyclopropionamide, tert-butyramide, NO2, CN, CF3.

[0038] n is selected from 1 or 2.

[0039] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0040] R 1Selected from 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 substituent is selected from one or more of deuterium, halogen, hydroxyl, methyl, ethyl, cyclopropyl, tert-butyl, methoxy, ethoxy, cyclopropyloxy, tert-butoxy, methylthio, ethylthio, cyclopropylthio, tert-butylthio, amino, methylamino, ethylamino, cyclopropylamino, tert-butylamino, formamide, acetamide, cyclopropionamide, tert-butyramide, NO2, CN, CF3;

[0041] R 2 and R 3 Independently selected from methyl, ethyl or R 2 and R 3 The nitrogen atoms to which they are attached together form morpholine ring groups, piperazine ring groups, piperidinyl groups, and azepanyl groups;

[0042] n is selected from 1 or 2.

[0043] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0044] R 1 is selected from 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, allyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 2-methylthiophenyl, 4-dibenzothiophenyl, 4-cyanophenyl 1-Hydroxyphenyl, 1-Hydroxypropyl ...

[0045] R 2 and R 3 Independently selected from methyl, ethyl;

[0046] n is selected from 1 or 2;

[0047] Where R 1 When it is nitro, amino, methoxy or hydroxy, the substitution is at the 7-position.

[0048] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0049] R 1 is selected from 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, allyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromine, 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;

[0050] R 2 and R 3 The nitrogen atoms to which they are attached together form a morpholine ring group;

[0051] n is selected from 1 or 2;

[0052] Where R 1 When it is nitro, amino, methoxy, bromine, hydroxyl, methyl or pyridine, the substitution is at the 7-position.

[0053] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0054] R 1is selected from 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, allyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromine, 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;

[0055] R 2 and R 3 The nitrogen atoms to which they are attached together form a piperazine ring group;

[0056] n is selected from 1 or 2;

[0057] Among them, R 1 When it is bromine, the substitution is at the 5-position.

[0058] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0059] R 1 is 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, allyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 2-methylthiophenyl, 4-dibenzothiophenyl, 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, 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;

[0060] R 2 and R 3 The nitrogen atoms to which they are attached together form the piperidinyl group;

[0061] n is selected from 1 or 2;

[0062] Where R 1 When it is nitro, amino, methoxy, bromine or methyl, the substitution is at the 7-position.

[0063] Further, the compound described in Formula I, I' or I", its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate, solvate or prodrug:

[0064] R 1 is selected from 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, allyl, n-propyl, isopropyl, n-butyl, ethyl, cyclopropyl, 4-methoxyphenyl, 2-methoxyphenyl, 2-(trifluoromethoxy)phenyl, 2-methylthiophenyl, 4-dibenzothienyl, 4-cyanophenyl, 4-quinolyl, 3-hydroxypropyl, 3-fluoropropyl, biphenyl, 3-hydroxyphenyl, 2-aminophenyl, bromine, 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;

[0065] R 2 and R 3 The nitrogen atoms to which they are attached together form the azepanyl group;

[0066] n is selected from 1 or 2.

[0067] Further, the present invention relates to compounds of formula I, I', I", preferably compounds include, but are not limited to, selected from the following compounds or pharmaceutically acceptable salts or prodrugs thereof:

[0068]

[0069]

[0070]

[0071]

[0072] Further, the present invention relates to compounds of formula I, I', I", preferably compounds include, but are not limited to, selected from the following compounds or pharmaceutically acceptable salts or prodrugs thereof:

[0073] 1-(2-Morpholinoethyl)-7-(naphthalen-2-yl)quinolin-2(1H)-one

[0074] 1-(2-Morpholinoethyl)-7-(naphthalen-2-yl)quinoxalin-2(1H)-one

[0075] 7-(2-Chlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0076] 7-Bromo-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0077] 1-(2-Morpholinoethyl)-7-(naphthalen-2-yl)-3,4-dihydroquinolin-2(1H)-one

[0078] 7-(4-Fluorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0079] 7-(4-Fluoro-2-methylphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0080] 1-(2-Morpholinoethyl)-7-phenyl-3,4-dihydroquinolin-2(1H)-one

[0081] 7-(3,5-Difluorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0082] 7-(3,4-Dichlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0083] 7-(3,4-Difluorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0084] 1-(2-Morpholinoethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-2(1H)-one

[0085] 7-(4-Methoxyphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0086] 7-(2-Methoxyphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0087] 1-(2-Morpholinoethyl)-7-(2-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-2(1H)-one

[0088] 7-(2-(Methylthio)phenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0089] 1-(2-Morpholinoethyl)-7-(pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one

[0090] 7-(3,4-Dichlorophenyl)-1-[2-(piperidin-1-yl)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0091] 7-(Naphthalen-2-yl)-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0092] 7-[2-(Methylthio)phenyl]-1-[2-(piperidin-1-yl)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0093] 7-(Dibenzo[b,d]thiophen-3-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0094] 4-[1-(2-Morpholinoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]benzonitrile

[0095] 1'-(2-morpholinoethyl)-3',4'-dihydro-[-4,7'-biquinolinyl]-2'(1'H)-one

[0096] 1-(3-Morpholinoethyl)-7-(naphthalen-2-yl)-3,4-dihydroquinolin-2(1H)-one

[0097] 1-[2-(Azepan-1-yl)ethyl]-7-(2-methylthiophenyl)-3,4-dihydroquinolin-2(1H)-one

[0098] 1-[2-(Azepan-1-yl)ethyl]-6-methoxy-3,4-dihydroquinolin-2(1H)-one

[0099] 7-(2-Chlorophenyl)-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0100] 6-(3,4-Dichlorophenyl)-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0101] 7-(3-Hydroxypropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0102] 7-(3-Fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0103] 6-(3-Hydroxypropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0104] 6-(3-Fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0105] 7-([1,1'-biphenyl]-3-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0106] 7-([1,1'-biphenyl]-4-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0107] 1-(2-Morpholinoethyl)-7-(naphthalen-2-yl)-3,4-dihydroquinoline-2(1H)-thione.

[0108] Furthermore, the present invention relates to compounds of formula I, I', I", or pharmaceutically acceptable salts and isomers thereof, characterized in that the hydrogen in the compounds can be replaced by one or more deuterium.

[0109] Furthermore, the present invention relates to a method for preparing the compound of formula I, key intermediates and salts thereof.

[0110] Method 1:

[0111]

[0112] Compound II is reacted with organic boronic acid (III) or organic boronic ester (IV) in 1,4-dioxane, DMF, DMSO, DME, 1,4-dioxane / H2O and other solvents, under the catalysis of catalysts such as Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(Cy3)2Cl2, Pd(OAc)2, under the action of bases such as Na2CO3, K2CO3, Cs2CO3, CsF, at a temperature of 80-160°C for 8-16 hours to obtain key intermediate V. Key intermediate V is further reacted with compound VI in DMF, DMSO, CH3CN, THF solvents, with K2CO3, Cs2CO3, CsF, NaH at a temperature of 0-120°C, to obtain compound I after 4-16 hours.

[0113] Method 2:

[0114]

[0115] Compounds II and VI undergo substitution reaction with K2CO3, Cs2CO3, CsF, NaH in DMF, DMSO, CH3CN, THF solvents at 0-120°C to obtain compound VII after 4-16 hours. Compound VII is further reacted with organic boronic acid (III) or organic boronic ester (IV) in 1,4-dioxane, DMF, DMSO, DME, 1,4-dioxane / H2O solvents under the action of bases such as Na2CO3, K2CO3, Cs2CO3, CsF, etc., and under the catalysis of catalysts such as Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(Cy3)2Cl2, Pd(OAc)2, at 80-160°C for 8-16 hours to obtain compound I.

[0116] Where X is Br or Cl, Z is C or N, Y is O or S, and the dotted line represents that the C connected to Z forms a single bond or a double bond;

[0117] Furthermore, the present invention relates to the use of the compounds of formula I, I', and I" in the preparation of drugs for treating or preventing pain. DETAILED DESCRIPTION

[0118] The present invention will be further described in detail below in conjunction with embodiments and experimental examples. The embodiments and experimental examples of the present invention are only used to illustrate the technical scheme of the present invention, and are not intended to limit the present invention. Any equivalent substitutions in the art made in accordance with the contents disclosed in the present invention shall fall within the protection scope of the present invention.

[0119] The structure of the compound is determined by NMR ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0120] The liquid chromatography-mass spectrometer (LC-MS) was Agilent G6120B (used with Agilent 1260 liquid phase); the nuclear magnetic resonance instrument ( 1 HNMR) was Bruker AVANCE-400 or Bruker AVANCE-800, NMR ( 1 H NMR) shifts (δ) are given in parts per million (ppm) using CDCl3 as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed in 10 -6 (ppm) is given as the unit.

[0121] The term "room temperature" in the present invention means a temperature between 10 and 25°C.

[0122] Example 1: Preparation of 1-(2-morpholinoethyl)-7-(naphthalen-2-yl)quinolin-2(1H)-one

[0123]

[0124] Step 1: Add compound IIa (2.24 g, 10 mmol), compound VIa (2.24 g, 15 mmol), and Cs2CO3 (9.75 g, 30 mmol) to DMF (30 mL) at room temperature, heat to 100 ° C, react for 6 hours, and the raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3), the organic phase is washed with water and saturated brine in turn, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. The crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin-dried, and vacuum dried to obtain 2.87 g of a yellow oily product. Yield: 85%.

[0125] 1 H NMR (400MHz, CDCl3) 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).

[0126] Step 2, at room temperature, add compound VIIa (2.87 g, 8.5 mmol), compound naphthalene-2-ylboronic acid (1.76 g, 10.2 mmol), CsF (1.55 g, 10.2 mmol) to 1,4-dioxane / H2O (30 mL, V / V=5 / 1), after nitrogen replacement, add Pd(dppf)Cl2 (0.62 g, 0.85 mmol), nitrogen replacement again three times, heat to 100°C under nitrogen protection, react for 16 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, spin-dried, and vacuum dried to obtain 2.62 g of a yellow oily product: 1-(2-morpholinoethyl)-7-(naphthalene-2-yl)quinoline-2(1H)-one. Yield: 80%, purity 99.53%.

[0127] ESI-MS: m / z = 385.2 (M+H) + .

[0128] 1H NMR (400MHz, CDCl3) 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).

[0129] Example 2: Preparation of 1-(2-morpholinoethyl)-7-(naphthalen-2-yl)quinoxalin-2(1H)-one

[0130]

[0131] Step 1: At room temperature, compound IIa (2.25 g, 10 mmol), compound VIa (2.24 g, 15 mmol), and NaH (1.2 g, 30 mmol) were added to DMSO (30 mL), heated to 100 ° C, and reacted for 6 hours. The raw materials reacted completely. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin dried, and vacuum dried to obtain 2.74 g of a yellow oily product. Yield: 81%. ESI-MS: m / z = 339.2 (M+H) + .

[0132] Step 2, at room temperature, add compound Ⅶb (2.74 g, 8.1 mmol), compound naphthalene-2-ylboronic acid (1.67 g, 9.72 mmol), and Cs2CO3 (3.17 g, 9.72 mmol) to DMF (30 mL). After nitrogen substitution, add Pd(dppf)Cl2 (0.62 g, 0.85 mmol), and nitrogen substitution again three times. Heat to 100°C under nitrogen protection and react for 16 hours. The raw materials are reacted completely. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, spin-dried, and vacuum dried to obtain 2.56 g of a yellow oily product: 1-(2-morpholinoethyl)-7-(naphthalene-2-yl)quinoxaline-2(1H)-one. Yield: 82.0%, purity 99.42%.

[0133] ESI-MS: m / z = 386.2 (M+H) + .

[0134] 1H NMR (400MHz, CDCl3) 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).

[0135] Example 3: Preparation of 7-bromo-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0136]

[0137] Step 1: Add compound IIa (2.26 g, 10 mmol), compound VIa (2.24 g, 15 mmol), and CsF (4.56 g, 30 mmol) to THF (50 mL) at room temperature, heat to 100 ° C, react for 6 hours, and the raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3), the organic phase is washed with water and saturated brine in turn, the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is dried by spin drying. The crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin dried, and vacuum dried to obtain 2.92 g of a yellow oily product. Yield: 86%, purity 99.42%.

[0138] ESI-MS: m / z = 340.2 (M+H) + .

[0139] 1 H NMR (400MHz, CDCl3) δ7.32 (d, J=1.7Hz, 1H), 7.13 (dd, J=7.9, 1.8Hz, 1H), 7.03 (d, J=8.0 Hz, 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).

[0140] Example 4: Preparation of 7-(2-chlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0141]

[0142] Step 1: Prepare 7-bromo-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one (VIIc) by the method of Example 3;

[0143] Step 2, at room temperature, add compound Ⅶc (2.88 g, 8.5 mmol), compound 2-chlorophenylboronic acid (1.59 g, 10.2 mmol), Cs2CO3 (3.32 g, 10.2 mmol) to DMSO (30 mL), replace with nitrogen, then add Pd(dppf)Cl2 (0.62 g, 0.85 mmol), replace with nitrogen again three times, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, spin-dried, and dried in vacuo to obtain 2.57 g of white oil: 7-(2-chlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one, with a yield of 81.5% and a purity of 99.32%.

[0144] ESI-MS: m / z = 371.5 (M+H) + .

[0145] 1 H NMR (400MHz, CDCl3) 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).

[0146] Example 5: Preparation of 1-(2-morpholinoethyl)-7-(naphthalen-2-yl)-3,4-dihydroquinolin-2(1H)-one

[0147]

[0148] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 2-naphthaleneboric acid to obtain the title compound as a white oil with a yield of 81.2% and a purity of 99.60%.

[0149] ESI-MS: m / z = 387.2 (M+H) + .

[0150] 1H NMR (400MHz, CDCl3) 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).

[0151] Example 6: Preparation of 7-(4-fluorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0152]

[0153] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-fluorophenylboronic acid to obtain the title compound as a white oil with a yield of 83.1% and a purity of 99.51%.

[0154] ESI-MS: m / z = 455.2 (M+H) + .

[0155] 1 H NMR (400MHz, CDCl3) 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).

[0156] Example 7: Preparation of 7-(4-fluoro-2-methylphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0157]

[0158] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-fluoro-2-methylphenylboronic acid to obtain the title compound as a white oil with a yield of 82.2% and a purity of 99.75%.

[0159] ESI-MS: m / z = 369.2 (M+H) + .

[0160] 1 H NMR (400MHz, CDCl3) 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).

[0161] Example 8: Preparation of 1-(2-morpholinoethyl)-7-phenyl-3,4-dihydroquinolin-2(1H)-one

[0162]

[0163] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of phenylboronic acid to obtain the title compound as a white oil with a yield of 79.5% and a purity of 99.20%.

[0164] ESI-MS: m / z = 337.2 (M+H) + .

[0165] 1 H NMR (400MHz, CDCl3) 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).

[0166] Example 9: Preparation of 7-(3,5-difluorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0167]

[0168] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 3,5-difluorophenylboronic acid to obtain the title compound as a white oil with a yield of 81.6% and a purity of 99.47%.

[0169] ESI-MS: m / z = 373.2 (M+H) + .

[0170] 1H NMR (400MHz, CDCl3) 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).

[0171] Example 10: Preparation of 7-(3,4-dichlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0172]

[0173] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 3,4-dichlorophenylboronic acid to obtain the title compound as a white oil with a yield of 79.9% and a purity of 99.58%.

[0174] ESI-MS: m / z = 405.2 (M+H) + .

[0175] 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.3, 2.2 Hz, 1H), 7.29-7.22 (m, 2H), 7.18 (dd, J = 7.7, 1.6 Hz, 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

[0176]

[0177] According to the preparation method of Example 4, the 2-chlorophenylboric acid in step 2 was replaced with an equal molar amount of 3,4-difluorophenylboric acid to obtain the title compound as a white oil with a yield of 78.2% and a purity of 99.32%.

[0178] ESI-MS: m / z = 373.2 (M+H) + .

[0179] 1H NMR (400MHz, CDCl3) δ7.40–7.32 (m, 1H), 7.30–7.20 (m, 4H), 7.16 (dd, J=7.7, 1.6 Hz, 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).

[0180] Example 12: Preparation of 1-(2-morpholinoethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-2(1H)-one

[0181]

[0182] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-(trifluoromethoxy)phenylboronic acid to obtain the title compound as a white oil with a yield of 83.2% and a purity of 99.64%.

[0183] ESI-MS: m / z = 421.2 (M+H) + .

[0184] 1 H NMR (400MHz, CDCl3) 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).

[0185] Example 13: Preparation of 7-(4-methoxyphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0186]

[0187] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-methoxyphenylboronic acid to obtain the title compound as a white oil with a yield of 82.1% and a purity of 99.09%.

[0188] ESI-MS: m / z = 367.2 (M+H) + .

[0189] 1H NMR (400MHz, CDCl3) 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).

[0190] Example 14: Preparation of 7-(2-methoxyphenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0191]

[0192] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 2-methoxyphenylboronic acid to obtain the title compound as a white oil with a yield of 81.2% and a purity of 99.39%.

[0193] ESI-MS: m / z = 367.2 (M+H) + .

[0194] 1 H NMR (400MHz, CDCl3) 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).

[0195] Example 15: Preparation of 1-(2-morpholinoethyl)-7-(2-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-2(1H)-one

[0196]

[0197] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 2-(trifluoromethoxy)phenylboronic acid to obtain the title compound as a white oil with a yield of 80.7% and a purity of 99.10%.

[0198] ESI-MS: m / z = 421.2 (M+H) + .

[0199] 1H NMR (400MHz, CDCl3) 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).

[0200] Example 16: Preparation of 7-(2-(methylthio)phenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0201]

[0202] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 2-methylthiophenylboronic acid to obtain the title compound as a white oil with a yield of 80.7% and a purity of 99.28%.

[0203] ESI-MS: m / z = 383.2 (M+H) + .

[0204] 1 H NMR (400MHz, CDCl3) 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).

[0205] Example 17: Preparation of 1-(2-morpholinoethyl)-7-(pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one

[0206]

[0207] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 3-pyridineboronic acid to obtain the title compound as a white oil with a yield of 82.5% and a purity of 99.29%.

[0208] ESI-MS: m / z = 338.2 (M+H) + .

[0209] 1H NMR (400MHz, CDCl3) δ8.83 (d, J=1.9Hz, 1H), 8.62 (dd, J=4.8, 1.5Hz, 1H), 7.8 9–7.82(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).

[0210] Example 18: Preparation of 7-(3,4-dichlorophenyl)-1-[2-(piperidin-1-yl)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0211]

[0212] Step 1: Add compound IIc (2.26 g, 10 mmol), 3,4-dichlorophenylboronic acid (2.29 g, 12 mmol), and Cs2CO3 (3.91 g, 12 mmol) to 1,4-dioxane (30 mL) at room temperature. After nitrogen replacement, add Pd(Ph3P)4 (1.16 g, 1 mmol), replace the nitrogen three times again, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3). The organic phase is washed with water and saturated brine in turn, and the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. The crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin-dried, and vacuum dried to obtain 2.33 g of a yellow oily product. Yield: 80.1%. ESI-MS: m / z = 292.2 (M+H) + .

[0213] Step 2: At 0°C, compound Va (2.34 g, 9.31 mmol) and compound VIb (2.06 g, 13.96 mmol) were added to anhydrous THF (30 mL), and NaH (0.56 g, 13.96 mmol) was added in batches. The mixture was heated to room temperature and reacted for 6 h. The raw materials reacted completely. H2O (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, and dried by spin drying. The product was dried in vacuo to obtain 2.87 g of a yellow oily product. Yield: 76.3%, purity: 99.90%.

[0214] ESI-MS: m / z = 404.2 (M+H)+ .

[0215] 1 H NMR (400MHz, CDCl3) 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).

[0216] Example 19: Preparation of 7-[3-(naphthalen-2-yl)phenyl]-1-[2-(piperidin-1-yl)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0217]

[0218] According to the preparation method of Example 18, 3,4-dichlorobenzeneboric acid in step 1 was replaced with an equal molar amount of 2-naphthaleneboric acid to obtain the title compound as a light brown solid with a yield of 81.2% and a purity of 99.63%.

[0219] ESI-MS: m / z = 385.2 (M+H) + .

[0220] 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.96–7.84 (m, 3H), 7.75 (dd, J=8.5, 1.8Hz, 1 H), 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).

[0221] Example 20: Preparation of 7-[2-(methylthio)phenyl]-1-[2-(piperidin-1-yl)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0222]

[0223] According to the preparation method of Example 18, the 2-chlorophenylboronic acid in step 1 was replaced with an equal molar amount of 2-(methylthio)phenylboronic acid to obtain the title compound as a light yellow oil with a yield of 82.9% and a purity of 99.36%.

[0224] ESI-MS: m / z = 381.2 (M+H)+ .

[0225] 1 H NMR (400MHz, CDCl3) 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).

[0226] Example 21: Preparation of 7-(dibenzo[b,d]thiophen-4-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0227]

[0228] According to the preparation method of Example 4, the 2-chlorophenylboric acid in step 2 was replaced with an equal molar amount of dibenzothiophene-4-boric acid to obtain the title compound as a light yellow oil with a yield of 76.2% and a purity of 99.23%.

[0229] ESI-MS: m / z = 443.2 (M+H) + .

[0230] 1 H NMR (400MHz, CDCl3) δ8.24–8.11 (m, 2H), 7.86–7.78 (m, 1H), 7.57 (t, J=7.6Hz, 1 H), 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).

[0231] Example 22: Preparation of 4-[1-(2-morpholinoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]benzonitrile

[0232]

[0233] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-cyanophenylboronic acid to obtain the title compound as a light yellow oil with a yield of 80.2% and a purity of 99.30%.

[0234] ESI-MS: m / z = 362.2 (M+H)+ .

[0235] 1 H NMR (400MHz, CDCl3) 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).

[0236] Example 23: Preparation of 1'-(2-morpholinoethyl)-3',4'-dihydro-[-4,7'-bisquinolinyl]-2'(1'H)-one

[0237]

[0238] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-quinolineboric acid to obtain the title compound as a light yellow oil with a yield of 78.9% and a purity of 98.71%.

[0239] ESI-MS: m / z = 388.2 (M+H) + .

[0240] 1 H NMR (400MHz, CDCl3) 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).

[0241] Example 24: Preparation of 1-(3-morpholinopropyl)-7-(naphthalen-2-yl)-3,4-dihydroquinolin-2(1H)-one

[0242] Step 1: Add compound IIc (2.26 g, 10 mmol), naphthalene-2-boronate (3.05 g, 12 mmol), and CsF (1.82 g, 12 mmol) to 1,4-dioxane (30 mL) at room temperature. After nitrogen replacement, add Pd(dppf)Cl2 (0.73 g, 1 mmol), replace the nitrogen three times again, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3). The organic phase is washed with water and saturated brine in turn, and the organic phase is dried and filtered with anhydrous sodium sulfate. The filtrate is spin-dried, and the crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin-dried, and vacuum dried to obtain 2.18 g of yellow oily product Ⅴb. Yield: 79.6%. ESI-MS: m / z = 274.2 (M+H) + .

[0243] Step 2: At 0°C, compound Vb (2.18 g, 8.0 mmol) and compound VIc (2.16 g, 11.7 mmol) were added to anhydrous DMF (30 mL), and CsF (1.78 g, 11.7 mmol) was added. The mixture was heated to room temperature and reacted for 6 h. The raw materials reacted completely. H2O (30 mL) was added and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, and dried by spin drying. The product was dried under vacuum to obtain 2.43 g of a yellow oily product: 1-(3-morpholinoethyl)-7-(naphthalene-2-yl)-3,4-dihydroquinolin-2(1H)-one. Yield: 76.4%, purity: 98.11%.

[0244] ESI-MS: m / z = 401.2 (M+H) + .

[0245] 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.95–7.85 (m, 3H), 7.70 (dd, J=8.5, 1.8Hz, 1 H), 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).

[0246] Example 25: Preparation of 1-[2-(azepan-1-yl)ethyl]-7-(2-methylthiophenyl)-3,4-dihydroquinolin-2(1H)-one

[0247]

[0248] Step 1: At room temperature, compound IIc (2.26 g, 10 mmol), 2-methylthiophenyl borate (3.00 g, 12 mmol), K2CO3 (1.66 g, 12 mmol) were added to DMSO (30 mL). After nitrogen replacement, Pd(dppf)Cl2 (0.73 g, 1 mmol) was added, and nitrogen replacement was performed three times again. The mixture was heated to 100°C under nitrogen protection, and the reaction was carried out for 16 hours. The raw materials reacted completely. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, and dried by spin drying. The product was dried in vacuo to obtain 2.10 g of a yellow oily product Vc, with a yield of 78%. ESI-MS: m / z = 270.2 (M+H) + .

[0249] Step 2: At 0°C, compound Ⅴc (2.10 g, 7.8 mmol) and compound Ⅵd (1.89 g, 11.7 mmol) were added to anhydrous CH3CN (50 mL), and Cs2CO3 (3.89 g, 11.7 mmol) was added. The mixture was heated to room temperature and reacted for 6 h. The raw materials reacted completely. H2O (30 mL) was added and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, and dried by spin drying. The product was dried under vacuum to obtain 2.33 g of a yellow oily product: 1-[2-(azepan-1-yl)ethyl]-7-(2-methylthiophenyl)-3,4-dihydroquinolin-2(1H)-one. Yield: 75%, purity: 98.11%.

[0250] ESI-MS: m / z = 395.2 (M+H) + .

[0251] 1H NMR (400MHz, CDCl3) 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).

[0252] Example 26: Preparation of 1-[2-(azepan-1-yl)ethyl]-6-methoxy-3,4-dihydroquinolin-2(1H)-one

[0253]

[0254] At 0°C, compound IId (1.77 g, 10 mmol) and compound VIa (2.42 g, 15 mmol) were added to anhydrous DMSO (30 mL), K2CO3 (2.07 g, 15 mmol) was added, the mixture was heated to room temperature, and the reaction was continued for 6 h. The raw materials were completely reacted. H2O (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, and dried by spin drying. The product was dried in vacuo to obtain 2.42 g of a yellow oily product VIId. The yield was 80.2%, and the purity was 98.11%.

[0255] ESI-MS: m / z = 303.2 (M+H) + .

[0256] 1 H NMR (400MHz, CDCl3) 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).

[0257] Example 27: Preparation of 7-(3,4-dichlorophenyl)-1-(2-morpholinoethyl)-3,4-dihydroquinoline-2(1H)-thione

[0258]

[0259] Step 1: Prepare the intermediate 7-bromo-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one (VIIc) according to the preparation method of Example 3

[0260] Step 2, the compound 7-bromo-1-(2-morpholinomorphinone)-3,4-dihydroquinoline-2(1H)-one (2.72 g, 8 mmol) was dissolved in toluene (40 mL), Lawesson's reagent (1.64 g, 2 mmol) was added, the suspension was heated to 120°C, reacted for 4 hours, then the system was cooled to 10°C and a solid plate was produced, the solid was collected by filtration using a Buchner funnel, washed with a small amount of dichloromethane, and dried to obtain 7-bromo-1-(2-morpholinomorphinone)-3,4-dihydroquinoline-2(1H)-thione (2.08 g) with a yield of 73%.

[0261] Step three, at room temperature, add compound IXc (7-bromo-1-(2-morpholinomorphinone)-3,4-dihydroquinoline-2(1H)-thione) (2.08 g, 5.85 mmol), compound 3,4-dichlorophenylboronic acid (1.42 g, 7.44 mmol), CsF (1.13 g, 10.2 mmol) to DME (50 mL), replace with nitrogen, and then add Pd(PPh3)2Cl2 (0.44 g, 0.85 mmol), replace with nitrogen again three times, heat to 100°C under nitrogen protection, react for 16 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 2:1, spin-dried, and vacuum dried to obtain 1.90 g of a yellow oily product. Yield: 79.3%, purity: 98.71%.

[0262] ESI-MS: m / z = 387.3 (M+H) + .

[0263] 1 H NMR (800MHz, CDCl3) 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).

[0264] Example 28: Preparation of 7-(2-chlorophenyl)-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one

[0265] Step 1: Add compound IIc (2.26 g, 10 mmol), compound VIe (1.61 g, 15 mmol), and K2CO3 (4.14 g, 30 mmol) to CH3CN (50 mL) at room temperature, heat to 100°C, and react for 6 h. The raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3). The organic phase is washed with water and saturated brine in turn, and the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is dried by spin drying. The crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin dried, and vacuum dried to obtain 2.49 g of a yellow oily product VIIe. Yield: 83.8%. ESI-MS: m / z = 297.2 (M+H) + .

[0266] Step 2, at room temperature, add compound VIIe (2.49 g, 8.4 mmol), compound 2-chlorophenylboronic acid (1.58 g, 10.1 mmol), CsF (1.53 g, 10.2 mmol) to DMSO (30 mL), replace with nitrogen, then add Pd(PPh3)4 (0.97 g, 0.84 mmol), replace with nitrogen again three times, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials react completely. The reaction solution was cooled to room temperature, H2O (30 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was eluented with petroleum ether: ethyl acetate = 2:1, spin-dried, and vacuum dried to obtain 2.25 g of yellow oily product 7-(2-chlorophenyl)-1-[2-(dimethylamino)ethyl]-3,4-dihydroquinolin-2(1H)-one. Yield: 81.3%, purity 98.85%.

[0267] ESI-MS: m / z = 329.2 (M+H) + .

[0268] 1 H NMR (400MHz, CDCl3) 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).

[0269] Example 29: Preparation of 6-(3,4-dichlorophenyl)-1-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinolin-2(1H)-one

[0270]

[0271] Step 1: At room temperature, 6-bromo-3,4-dihydroquinolin-2(1H)-one (2.26g, 10mmol), 3,4-dichlorophenylboronic acid (2.29g, 12mmol), and Cs2CO3 (3.91g, 12mmol) were added to 1,4-dioxane (30mL). After nitrogen replacement, Pd(Ph3P)4 (1.16g, 1mmol) was added, and nitrogen replacement was performed three times. The reaction was heated to 100°C under nitrogen protection for 16h, and the raw materials reacted completely. The reaction solution was cooled to room temperature, H2O (30mL) was added, and extracted three times with ethyl acetate (50mL*3). The organic phase was washed with water and saturated brine in turn, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin dried, and vacuum dried to obtain 2.34g of a yellow oily product. Yield: 82.8%. ESI-MS: m / z = 392.2 (M+H) + .

[0272] Step 2: At 0°C, add compound Va (2.34 g, 9.31 mmol) and compound VIb (2.06 g, 13.96 mmol) to anhydrous THF (30 mL), add NaH (0.56 g, 13.96 mmol) in batches, warm to room temperature, react for 6 hours, and the raw materials react completely. Add H2O (30 mL), extract three times with ethyl acetate (50 mL*3), wash the organic phase with water and saturated brine in turn, dry the organic phase with anhydrous sodium sulfate, filter, spin-dry the filtrate, pass the crude product with eluent petroleum ether: ethyl acetate = 2:1, spin-dry, and vacuum dry to obtain 2.87 g of yellow oily product. Yield: 76.3%, purity 96.24%.

[0273] ESI-MS: m / z = 404.2 (M+H) + .

[0274] 1 H NMR (400MHz, CDCl3) 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).

[0275] Example 30: Preparation of 7-(3-hydroxypropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0276]

[0277] Step 1: Prepare the intermediate 7-bromo-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one (VIIc) according to the preparation method of Example 3

[0278] Step 2, at room temperature, add compound Ⅶc (3 g, 8.8 mmol), allylboronic acid (0.91 g, 10.6 mmol), CsF (4.01 g, 26.4 mmol) to 1,4-dioxane / H2O (60 ml, V / V = 5 / 1), after nitrogen substitution, add Pd(dppf)Cl2 (0.64 g, 0.88 mmol), nitrogen substitution again three times, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, H2O (30 ml) was added, and extracted three times with ethyl acetate (50 ml*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin-dried, and vacuum dried to obtain 2.5 g of the title compound 7-allyl-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one as a yellow oil. Yield: 95%, purity 99.19%.

[0279] ESI-MS: m / z = 301.2 (M+H) + .

[0280] 1 H NMR (800MHz, CDCl3) 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).

[0281] Step 3, at room temperature, Ⅺa (1g, 3.3mmol) was dissolved in anhydrous THF (20ml), and after nitrogen replacement protection, it was cooled to -40°C, and 1M BH3.THF (10ml) was added dropwise. After the addition was completed, the reaction solution was slowly heated to room temperature and reacted for 2h. The reaction solution was cooled to 0°C again, H2O (10ml) was added dropwise to quench the excess BH3.THF, and then 0.5M NaOH (10ml) and 35% H2O2 (2ml) were added dropwise, and the reaction was continued at 0°C for 1h. H2O (30ml) was added, and the mixture was extracted three times with ethyl acetate (50ml*3). The organic phase was washed with water, saturated NaHCO3 solution, and saturated brine in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin-dried, and vacuum-dried to obtain 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%, purity 99.70%.

[0282] ESI-MS: m / z = 319.2 (M+H) + .

[0283] 1 H NMR (800MHz, CDCl3) 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).

[0284] Example 31: Preparation of 7-(3-fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0285]

[0286] Step 1, at room temperature, Example Compound 30 (0.9 g, 2.8 mmol) was dissolved in anhydrous dichloromethane (20 ml), and after nitrogen replacement protection, cooled to -78 ° C, and diethylamino sulfur trifluoride (0.68 g, 4.2 mmol) was added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was cooled to 0 ° C, quenched with a saturated NaHCO3 solution, H2O (30 ml) was added, and extracted three times with dichloromethane (50 ml * 3), and the organic phase was washed with water, saturated NaHCO3 solution, and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin dried, and vacuum dried to obtain 0.4 g of the title compound 7-(3-fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one as a yellow oil. Yield: 44.6%, purity 99.35%.

[0287] ESI-MS: m / z = 321.2 (M+H) + .

[0288] 1 H NMR (800MHz, CDCl3) δ7.09 (d, J=7.5Hz, 1H), 6.92 (s, 1H), 6.86–6.83 (m, 1H), 4.5 1–4.43 (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).

[0289] Example 32: Preparation of 6-(3-hydroxypropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0290]

[0291] Step 1: Add compound IId (2.26 g, 10 mmol), compound VIa (2.24 g, 15 mmol), and Cs2CO3 (9.75 g, 30 mmol) to DMF (30 mL) at room temperature, heat to 100 ° C, react for 6 h, and the raw materials react completely. The reaction solution is cooled to room temperature, H2O (30 mL) is added, and extracted three times with ethyl acetate (50 mL*3), the organic phase is washed with water and saturated brine in turn, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried. The crude product is passed through a column with an eluent of petroleum ether: ethyl acetate = 3:1, spin-dried, and vacuum dried to obtain 2.86 g of yellow oily compound VIIf. Yield: 85%.

[0292] Step 2, at room temperature, add compound VIIf (3 g, 8.8 mmol), allylboronic acid (0.91 g, 10.6 mmol), CsF (4.01 g, 26.4 mmol) to 1,4-dioxane / H2O (60 ml, V / V = 5 / 1), after nitrogen replacement, add Pd(dppf)Cl2 (0.64 g, 0.88 mmol), nitrogen replacement again three times, heat to 100 ° C under nitrogen protection, react for 16 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, H2O (30 ml) was added, and extracted three times with ethyl acetate (50 ml*3). The organic phase was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin-dried, and vacuum dried to obtain 2.4 g of the title compound 6-allyl-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one as a yellow oil. Yield: 90.9%, purity 99.23%.

[0293] ESI-MS: m / z = 301.2 (M+H) + .

[0294] 1 H NMR (800MHz, CDCl3) 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).

[0295] Step 3, at room temperature, Ⅺb (1 g, 3.3 mmol) was dissolved in anhydrous THF (20 ml), and after nitrogen replacement protection, it was cooled to -40°C, and 1M BH3.THF (10 ml) was added dropwise. After the addition was completed, the reaction solution was slowly heated to room temperature and reacted for 2 h. The reaction solution was cooled to 0°C again, H2O (10 ml) was added dropwise to quench the excess BH3.THF, and then 0.5M NaOH (10 ml) and 35% H2O2 (2 ml) were added dropwise, and the reaction was continued at 0°C for 1 h. H2O (30ml) was added, and the mixture was extracted three times with ethyl acetate (50ml*3). The organic phase was washed with water, saturated NaHCO3 solution, and saturated brine in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin-dried, and vacuum dried to obtain 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%, purity 99.16%.

[0296] ESI-MS: m / z = 319.2 (M+H) + .

[0297] 1 H NMR (800MHz, CDCl3) δ7.07 (dd, J=8.2, 1.8Hz, 1H), 7.01 (s, 1H), 6.98 (d, J=8.3H z, 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).

[0298] Example 33: Preparation of 6-(3-fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0299]

[0300] Step 1, at room temperature, Example compound 32 (0.9 g, 2.8 mmol) was dissolved in anhydrous dichloromethane (20 ml), and after nitrogen replacement protection, it was cooled to -78 ° C, and DAST (0.68 g, 4.2 mmol) was added dropwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was cooled to 0 ° C, quenched with a saturated NaHCO3 solution, H2O (30 ml) was added, and extracted three times with dichloromethane (50 ml * 3), and the organic phase was washed with water, saturated NaHCO3 solution, and saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The crude product was passed through a column with an eluent of methanol: dichloromethane = 20:1, spin dried, and vacuum dried to obtain 0.43 g of the title compound 6-(3-fluoropropyl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one as a yellow oil. Yield: 48.2%, purity 98.99%.

[0301] ESI-MS: m / z = 321.2 (M+H) + .

[0302] 1 H NMR (800MHz, CDCl3) 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).

[0303] Example 34: Preparation of 7-([1,1'-biphenyl]-3-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0304]

[0305] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 3-biphenylboronic acid to obtain the title compound as a light yellow oil with a yield of 83.2% and a purity of 99.77%.

[0306] ESI-MS: m / z = 413.2 (M+H) + .

[0307] 1H NMR (800MHz, CDCl3) 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).

[0308] Example 35: Preparation of 7-([1,1'-biphenyl]-4-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinolin-2(1H)-one

[0309]

[0310] According to the preparation method of Example 4, the 2-chlorophenylboronic acid in step 2 was replaced with an equal molar amount of 4-biphenylboronic acid to obtain the title compound as a light yellow oil with a yield of 81.1% and a purity of 99.93%.

[0311] ESI-MS: m / z = 413.2 (M+H) + .

[0312] 1 H NMR (800MHz, CDCl3) 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).

[0313] Example 36: Preparation of 1-(2-morpholinoethyl)-7-(naphthalen-2-yl)-3,4-dihydroquinoline-2(1H)-thione

[0314]

[0315] According to the preparation method of Example 27, the 3,4-dichlorophenylboronic acid in step 3 was replaced with an equal molar amount of 2-naphthaleneboric acid to obtain the title compound as a light yellow oil with a yield of 80.1% and a purity of 98.57%.

[0316] ESI-MS: m / z = 403.2 (M+H) + .

[0317] 1 H NMR (800MHz, CDCl3) 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).

[0318] Preparation Example 1: Preparation of 4-{2-[[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yl]oxy]ethyl}morpholine

[0319]

[0320] Step 1, dissolve compound 1h (10g, 61mmol) in 100mL toluene, and then add 100mL ethyl acetate to the reaction solution. The reaction solution is cooled to 0°C in an ice bath, and acetic anhydride (7.74g, 75mmol) is slowly added dropwise to the reaction solution. After the dropwise addition, the temperature is naturally raised to room temperature and the reaction is allowed to proceed overnight. The reaction of the raw materials is detected by TLC (dichloromethane: methanol = 10:1). 100mL of water is added to the reaction solution, and the pH is adjusted to 9-10 with a saturated Na2CO3 solution. The reaction solution is extracted with ethyl acetate (100mL* 3), and the organic phase is washed with a saturated NaHCO3 solution, water, and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase is filtered, and the filtrate is concentrated to obtain a crude product, which is purified by column chromatography (petroleum ether: ethyl acetate = 5:1-2:1) to obtain compound 2h (7.6 g, light yellow oil). Yield: 62.3%. ESI-MS: m / z = 201.2 (M+H) + .

[0321] Step 2, compound 2h (6g, 30mmol), ethyl acetoacetate (4.85g, 45mmol), under nitrogen protection, slowly added to phosphorus tribromide (10mL), the reaction solution was heated to 50°C, and the reaction was kept warm for 2 hours. The reaction of the raw materials was detected by TLC (petroleum ether: ethyl acetate = 1:1). The reaction solution was cooled to room temperature, poured into 100mL of dichloromethane, 50mL of ice water was added, and extracted with dichloromethane (100mL*3), and the organic phase was washed with saturated NaHCO3 solution, water, and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5:1~2:1) to obtain compound 3h (2.2g, white solid). Yield: 32.7%. ESI-MS: m / z = 225.2 (M+H) + .

[0322] Step 3, under nitrogen protection, compound 3h (2g, 8.9mmol), N-(2-chloroethyl)morpholine hydrochloride (1.6g, 10.7mmol) were added to 10mL DMF, and NaH (0.72g, 17.8mmol) was added in batches under ice bath. The reaction solution was heated to 60°C for 4 hours. TLC (petroleum ether: ethyl acetate = 1:1) was used to detect that the raw material had reacted. The reaction solution was cooled to room temperature, poured into 100mL ethyl acetate, 50mL ice water was added, extracted with ethyl acetate (100mL*3), the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain compound 4h (2.3g, white solid). Yield: 76.6%. ESI-MS: m / z = 338.2 (M+H) + .

[0323] Step 4: Dissolve compound 4h (2.3 g, 6.8 mmol) in 3 mL of anhydrous ethyl acetate, add ethyl acetate / HCl (2.5 N, 3 mL) dropwise under an ice bath, return to room temperature naturally after addition, and react overnight. Filter the reaction solution, wash the filter residue three times with anhydrous ethyl acetate, and dry the solid to obtain the title compound of Preparation Example 1 (2.1 g, white solid). Yield: 82.7%. Purity: 98.47%.

[0324] 1H NMR (400MHz, CDCl3) 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).

[0325] Test Example 1: Acetic acid writhing test in mice

[0326] 1. Test materials

[0327] 1.1 Test reagents

[0328]

[0329] 1.2 Test equipment

[0330] 1mL syringe, stopwatch, micropipette, electronic balance, 15mL centrifuge tube, 50mL centrifuge tube, etc.

[0331] 2. Experimental Animals

[0332] Kunming mice, half male and half female, weighing 22-25 g, were provided by Chengdu Dashuo Biotechnology Co., Ltd.

[0333] 3. Test methods

[0334] 3.1 Preparation of test products

[0335] HCl was added to the saline to adjust the pH to 4.5 for later use.

[0336] Weigh each compound, add 100 μL DMSO and shake to dissolve, then add the above-mentioned saline hydrochloric acid solution to prepare a 2 mg / mL test solution. If there is still insoluble matter, heat it until it dissolves.

[0337] 3.2 Preparation of 0.8% acetic acid solution

[0338] Take 0.2mL of glacial acetic acid in a 50mL centrifuge tube, add 1.8mL of normal saline and shake thoroughly to mix, then add 23mL of normal saline and shake to mix to obtain the acetic acid solution of the required concentration. The solution should be prepared before use, and the centrifuge tube cap should be tightened after each use to prevent acetic acid from volatilizing and affecting the test results.

[0339] 3.3 Administer medication and observe the number of writhing times

[0340] The test was conducted in a quiet environment at room temperature of 23-25°C. The mice were numbered before administration and placed in the corresponding numbered cages to adapt for 15 minutes. After the adaptation was completed, the mice were intraperitoneally injected with 10mL / kg, and the final doses were 20mg / kg, 5mg / kg, 2.5mg / kg, 1mg / kg, and 0.5mg / kg, respectively. The negative control group was given the same volume of normal saline. 10 minutes after administration, the mice were intraperitoneally injected with 10mL / kg of the above acetic acid solution and immediately placed in a cage to observe the number of twists of the mice within 15 minutes. The indicators of twisting are: when the mouse has a typical concave abdomen, accompanied by characteristic reactions such as twisting of the trunk, raising of the hips, and extension of the hind limbs, it is considered to be a twisting occurrence.

[0341] 4. Results Analysis

[0342] The average number of writhings of 10 mice within 15 minutes was used as the criterion for judging the analgesic effect of the example compound. The smaller the average number of writhings in each group, the stronger the analgesic effect of the example compound. The following is the average number of writhings of mice in each group:

[0343] Table 1-1: Average number of writhing times of mice when 20 mg / kg of the experimental compound was intraperitoneally injected

[0344] serial number Average number of writhing times of 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

[0345] As shown in the table above, compared with the blank group, Examples 2 and 3 showed certain analgesic effects; the compounds of Examples 4, 5, 6 and 7 all had strong analgesic effects in the 20 mg / kg group. When the dosage of Preparation Example 1 was as high as 20 mg / kg, it still did not show statistically significant analgesic activity in the mouse acetic acid writhing test compared with the blank group.

[0346] Table 1-2: Average number of writhing times of mice when 5 mg / kg of the experimental compound was intraperitoneally injected

[0347] serial number Average number of writhing times 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 Embodiment 11 11.9 Example 12 16.6 Embodiment 13 12.6 Embodiment 14 2.4 Embodiment 15 0.0 Example 16 7.8 Embodiment 17 17.9 Embodiment 18 2.1 Embodiment 19 0.5 Embodiment 20 1.3 Embodiment 21 15.6 Embodiment 22 9.5 Embodiment 23 0.2 Embodiment 24 2.9 Embodiment 25 1.6 Embodiment 26 2.5 Embodiment 36 4.1

[0348] As shown in the table above, after intraperitoneal injection of 5 mg / kg of the example compounds, compared with the blank group, Example compounds 4 to Example 27 all showed strong analgesic effects in the mouse acetic acid writhing test, especially Example 5, Example 7, Example 10, Example 14, Example 15, Example 19, Example 20, Example 23, Example 24, Example 25, Example 26, and Example 27; Preparation Example 1 did not show statistically significant analgesic activity in the mouse acetic acid writhing test under these conditions compared with the blank group.

[0349] Table 1-3: Average number of writhing times of mice when 2.5 mg / kg of the experimental compound was intraperitoneally injected

[0350] serial number The average number of writhing times of 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 Embodiment 11 18.1 Example 12 25.6 Embodiment 13 5.4 Embodiment 14 0.2 Embodiment 15 0.0 Example 16 1.4 Embodiment 17 24.8 Embodiment 18 12 Embodiment 19 5.6 Embodiment 20 4.4 Embodiment 22 19.7 Embodiment 23 3.8 Embodiment 24 13.6 Embodiment 25 12.5 Embodiment 26 11.5 Embodiment 28 20.8 Embodiment 29 18.3 Embodiment 36 15.3

[0351] As shown in the table above, after intraperitoneal administration of 2.5 mg / kg of the example compounds, compared with the blank group, Example 4, Example 5, Example 7, Example 10, Example 13, Example 14, Example 15, Example 16, Example 20, Example 24, and Example 26 also showed strong analgesic effects in the mouse acetic acid writhing test. Preparation Example 1 did not show statistically significant analgesic activity in the mouse acetic acid writhing test conducted under these conditions compared with the blank group.

[0352] Table 1-4: Average number of writhing times of mice when 1 mg / kg of the experimental compound was intraperitoneally injected

[0353]

[0354]

[0355] As shown in the table above, after intraperitoneal administration of 1 mg / kg of the example compounds, Example compounds 5, 10, 15, and 16 also showed significant analgesic effects in the mouse acetic acid writhing test. Preparation Example 1 did not show statistically significant analgesic activity compared with the blank group in the mouse acetic acid writhing test under these conditions.

[0356] Table 1-5: Average number of writhing times of mice when 0.5 mg / kg of the experimental compound was intraperitoneally injected

[0357] serial number The average number of writhing times of mice DMSO 29.6 Preparation Example 1 31.2 Example 5 10.3 Example 10 15.2 Embodiment 15 18.9 Example 16 20.1

[0358] As shown in the table above, after intraperitoneal administration of 0.5 mg / kg of the example compounds, compared with the blank group, the compounds of Example 5, Example 10, Example 15, and Example 16 also showed analgesic effects in the mouse acetic acid writhing test, especially the compound of Example 5. Preparation Example 1 did not show statistically significant analgesic activity in the mouse acetic acid writhing test conducted under these conditions compared with the blank group.

[0359] Test Example 2: Test on the effect of heat conduction on the pseudo-pain response of mice (hot plate method test)

[0360] 1. Test materials

[0361] 1.1 Test reagents

[0362] Reagent name batch number source Kolliphor HS-15 48328768E0 Produced by BASF Applied Chemicals Co., Ltd. 0.9% Sodium Chloride Injection w215080801 Produced by Sichuan Kelun Pharmaceutical Co., Ltd. Carboxymethyl cellulose #G1226001 Aladdin High-grade carbon ink 201604285 Guizhou Boshi Chemical Co., Ltd. Medical carbon sheet 48160118 Hebei Changtian Pharmaceutical Co., Ltd.

[0363] 1.2 Test equipment

[0364] Pipette, centrifuge tube, electronic balance, syringe, mouse holder, intelligent hot plate instrument, ruler, scissors, tweezers, gavage needle, etc.

[0365] 2. Experimental Animals

[0366] Kunming mice, all female mice, 18-22 g, were provided by Chengdu Dashuo Experimental Animal Co., Ltd.

[0367] 3. Test methods

[0368] 3.1 Preparation of test products

[0369] HCl was added to the saline to adjust the pH to 4.5 for later use.

[0370] Accurately weigh 2 mg of the test sample, i.e., the compounds of Preparation Example 1, Example 5, and Example 10, respectively, add 1 mL of 50% HS-15 solution, mix well, then add 1 mL of saline hydrochloric acid solution, fully dissolve and mix well to obtain a 1 mg / mL test sample solution.

[0371] 3.2 Test operation

[0372] 90 KM all-female mice, 18-22g, were taken, and the basic pain threshold was measured on a hot plate at 55±0.5℃, and 40 mice with a pain threshold of 5-30s were selected for the experiment. The pain threshold of the 40 qualified mice was measured twice before administration, with an interval of 5min, and the average value was taken as the basic pain threshold. They were randomly divided into 4 groups, namely the blank control group, the compound group of Preparation Example 1, Example 5, and Example 10, with 10 mice in each group, and each group was administered by tail vein (the control group was given an equal amount of 0.9% saline), and the administration volume was 1mL / kg. The pain threshold of the mice was measured at 30, 60, and 120min after administration. Those with a pain threshold exceeding 60s were counted as 60s, and the difference in pain threshold between each drug group and the blank control group was statistically compared.

[0373] 4. Experimental results and discussion

[0374] Table 2-1, Effects of the compounds of Preparation Example 1, Example 5, and Example 10 on the pain threshold of mice induced by hot plate

[0375]

[0376]

[0377] Note: “*” compared with the blank group, P < 0.05; “**” compared with the blank group, P < 0.01.

[0378] As can be seen from the above table, the compounds of Example 5 and Example 10 can increase the pain threshold of mice at 30 minutes and 60 minutes after administration, which is statistically different from the blank group; the compound of Preparation Example 1 has no obvious effect on improving the pain threshold of mice at 30 minutes, 60 minutes and 120 minutes after administration, and there is no statistical difference compared with the blank group.

[0379] Test Example 3: Thermal Radiation Tail Flick Test in Rats

[0380] 3.1 Test materials

[0381] 3.1.1 Basic information of test product

[0382] Compound No. Traits batch number source Preparation Example 1 White oily 20180314 self made Example 5 Light yellow oil 20180813 self made Example 10 Light yellow oil 20180802 self made

[0383] 3.1.2 Test reagents

[0384] Reagent name batch number source Kolliphor HS-15 69889088Q0 Beijing Fengli Jingqiu Pharmaceutical Co., Ltd. 0.9% Sodium Chloride Injection w214011102 Produced by Sichuan Kelun Pharmaceutical Co., Ltd.

[0385] 3.1.3 Test instruments

[0386] 1mL syringe, timer, micropipette, electronic balance, 15mL centrifuge tube, 50mL centrifuge tube, rat tail light analgesia meter, etc.

[0387] 3.2 Experimental animals

[0388] SD rats, all female, weighing 160-180 g, were provided by Chengdu Dashuo Biotechnology Co., Ltd.

[0389] 3.3 Test methods

[0390] 3.3.1 Preparation of test products

[0391] HCl was added to the saline to adjust the pH to 4.5 for later use.

[0392] Weigh about 20 mg of each compound into a 50 mL centrifuge tube, add physiological saline hydrochloric acid solution to prepare a 1 mg / mL test solution, and heat to dissolve poorly soluble compounds. Preparation Example 1 Add 100 μL of 50% HS-15 to assist dissolution and then add physiological saline to prepare a 1 mg / mL test solution.

[0393] 3.3.2 Drug administration and testing

[0394] After the adaptation period, the pain threshold of rats was measured one day before drug administration. The lower 1 / 3 of the tail was selected as the pain measurement point, and the measurement was performed 3 times, with a test interval of no less than 5 minutes. The average of the 3 measurements was taken as the basic pain threshold of each rat. The latency from the start of irradiation to the tail flick reaction (tail flick latency, TFL) was used as the pain threshold, and the power of the pain meter was adjusted to 99%. Animals with a basic pain threshold of less than 2s or greater than 10s were eliminated. According to the basic pain threshold, 24 animals were selected and randomly divided into 4 groups, with 6 animals in each group:

[0395]

[0396] The drugs were administered according to the above table, and the pain threshold was tested at 30, 60, and 120 minutes after administration.

[0397] 3.4 Experimental results and discussion

[0398] The maximum analgesic effect percentage (MPE%) and pain threshold increase rate were calculated according to the following formula:

[0399] Maximum analgesic effect percentage (MPE%) = (TFL after administration - basic TFL) / (15 - basic TFL) × 100%

[0400] Pain threshold enhancement rate (%) = (TFL after administration - basic TFL) / basic TFL × 100%

[0401] This experiment completed the rat thermal radiation tail flick test of 3 compounds. The test results are as follows:

[0402] Table 3-1: Results of thermal radiation tail flick test of test compounds

[0403]

[0404]

[0405] Note: “*” compared with the normal saline group, P < 0.05; “**” compared with the normal saline group, P < 0.01;

[0406] From the table above, we can see that:

[0407] ① Under the conditions of this experiment, when the dosage was 4 mg / kg, 30 minutes after administration to rats, Example 5 (maximum analgesic effect 100%, pain threshold increase rate 92.87%) and Example 10 (maximum analgesic effect 73.65%, pain threshold increase rate 82.12%) had the best analgesic effect; no analgesic effect was observed in Preparation Example 1;

[0408] ② Under the conditions of this experiment, when the dosage was 4 mg / kg, 60 minutes after administration to rats, Example 5 (maximum analgesic effect 87.41%, pain threshold increase rate 82.23%) still had a good analgesic effect; Example 10 (maximum analgesic effect 31.54%, pain threshold increase rate 35.87%) had a significantly reduced analgesic effect; no analgesic effect was observed in Preparation Example 1;

[0409] ③ Under the conditions of this experiment, when the dosage was 4 mg / kg, 120 minutes after administration to rats, Example 5 (maximum analgesic effect 59.85%, pain threshold increase rate 52.02%) still had a good analgesic effect, but the analgesic effect was significantly reduced; the analgesic effect of Example 10 (maximum analgesic effect 10.81%, pain threshold increase rate 16.99%) was further significantly reduced, and the analgesic effect was weak; no analgesic effect was observed in Preparation Example 1;

[0410] Therefore, the analgesic effects of the compounds of Examples 5 and 10 were detected by the rat thermal radiation tail flick test, and the results showed that: under the experimental conditions, the compound of Example 5 had the best analgesic effect, and there were significant statistical differences compared with normal saline at 30min, 60min, and 120min (P<0.01); the analgesic effect of the compound of Example 10 was second, and it had a better analgesic effect at 30min of administration, and there was a significant statistical difference compared with normal saline (P<0.01), and there was a statistical difference compared with normal saline at 60min of administration (P<0.05), and then the analgesic effect gradually decreased; no analgesic effect was observed for the compound of Preparation Example 1, and there was no statistical difference compared with normal saline at 30min, 60min, and 120min (P>0.05), and it had no effect on the pain threshold of rats.

[0411] In summary, the present invention provides novel alkylamine compounds, which exhibit excellent analgesic effects in the mouse acetic acid writhing test, the test on the effect of thermal conduction on the pseudo-pain response of mice, and the rat thermal radiation tail-flick test.

Claims

1. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

2. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing pain.

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