Nitrogen-containing heteroaryl compound as well as preparation method, intermediate and application thereof

Abstract

The invention provides a nitrogen-containing heteroaryl compound as well as a preparation method, an intermediate and application thereof. In particular, the present invention relates to a nitrogen-containing heteroaryl compound represented by general formula I, a preparation method and an intermediate thereof, a pharmaceutical composition containing the nitrogen-containing heteroaryl compound, and an application of the nitrogen-containing heteroaryl compound or the pharmaceutical composition thereof as a GABBA receptor agonist in preparation of drugs in the field of central nervous systems. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a nitrogen-containing heteroaryl compound, a preparation method thereof, an intermediate and an application thereof. Background Art

[0002] Etomidate (CAS No.: 33125-97-2), with the chemical name of ethyl R-1-(1-phenylethyl)-1H-imidazole-5-carboxylate, is a non-barbiturate intravenous anesthetic. It is characterized by rapid onset, short action time, rapid recovery, and mild inhibition of cardiovascular and respiratory functions. Clinically, it is mainly used for induction anesthesia and outpatient surgical anesthesia. Its structure is shown as follows:

[0003]

[0004] However, studies have found that while etomidate exerts its anesthetic effect, it may inhibit 11β-hydroxylase, thereby reducing the secretion of cortisol and / or corticosterone, which limits its clinical application.

[0005] Therefore, developing more new anesthetic drugs with good anesthetic activity and better anesthetic characteristics has potential clinical significance. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a nitrogen-containing heteroaryl compound, a preparation method thereof, an intermediate and an application thereof. This nitrogen-containing heteroaryl compound not only has good anesthetic activity, rapid onset and short action time, but also has basically no inhibitory effect on the secretion of adrenal cortical hormones (steroid hormones) such as cortisol and corticosterone, thus having both good anesthetic effects and clinical safety.

[0007] On the one hand, the present invention provides a compound represented by Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Wherein,

[0010] R 1 is -L 1 C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-OT, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 - 8 - membered heterocyclic group, C 6-14 aryl or 5 - 14 - membered heteroaryl, and the above groups are optionally substituted by one or more Ra;

[0011] L 1 is a bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;

[0012] T is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 - 8 - membered heterocyclic group, C 6-14 aryl or 5 - 14 - membered heteroaryl;

[0013] R aa and R bb are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R aa and R bb together with the carbon to which they are attached form C 3-8 cycloalkyl;

[0014] R cc and R dd are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R cc and R dd together with the carbon to which they are attached form C 3-8 cycloalkyl;

[0015] q is 0 or 1;

[0016] Ra is hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, C 2-7 alkoxycarbonyl or C 6-14 aryl;

[0017] R2 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0018] R 3 each independently is hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-8 cycloalkyl;

[0019] p is 1, 2, 3, 4 or 5;

[0020] M is N or CH;

[0021] X and Y each independently are hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-8 cycloalkyl;

[0022] Ring A is C 6-14 aryl, 5 - 14 membered heteroaryl or C 6-10 aryl fused to a 3 - 8 membered heterocyclic ring.

[0023] On the other hand, the present invention provides a compound represented by formula III, its stereoisomers or its salts:

[0024]

[0025] wherein, R 4 is - OH or an - O - hydroxy protecting group; R 1 , R 2 , R 3 , p, M, X, Y and Ring A are as defined above;

[0026] The hydroxy protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert - butyldimethylsilyl, tert - butyldiphenylsilyl, methyl, tert - butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2 - tetrahydropyranyl, formyl, acetyl, propionyl, methanesulfonyl, ethanesulfonyl, benzoyl, p - nitrobenzoyl, p - toluoyl, p - chlorobenzoyl or p - toluenesulfonyl.

[0027] On the other hand, the present invention provides a method for preparing a compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts, which is characterized by comprising the following steps:

[0028] (1) The compound shown in formula (iii-1) undergoes a substitution reaction with the compound shown in formula (iii-2) to form the compound shown in formula IIIa.

[0029]

[0030] Optionally, the method further comprises the following step (2):

[0031] (2) Preparing the compound shown in formula I from the compound shown in formula IIIb.

[0032]

[0033] R 5 and R 5 ’ may be the same or different. When R 5 and R 5 ’ are different, optionally, the method further comprises the following step (3):

[0034] (3) The compound shown in formula IIIa undergoes a deprotection reaction of the hydroxyl protecting group and a further hydroxyl protection reaction to obtain the compound shown in formula IIIb.

[0035] wherein, R 5 and R 5 ’ are each independently -O-hydroxyl protecting group; R 1 , R 2 , R 3 , p, M, X, Y and ring A are as defined above;

[0036] The hydroxyl protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, methanesulfonyl, ethanesulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

[0037] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the compound shown herein, its stereoisomers or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers or excipients.

[0038] On the other hand, the present invention provides the use of the compound shown herein, its stereoisomers or its pharmaceutically acceptable salts or a pharmaceutical composition comprising the same in the preparation of a drug, preferably the drug is GABA AReceptor agonists, preferably the drug is a drug in the field of the central nervous system, preferably a drug for inducing and maintaining anesthesia in mammals, promoting sedation and hypnosis in mammals, treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy. Detailed implementation manners

[0039] Term

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of contradiction, the definitions provided in this application shall prevail. When trade names appear in this text, they are intended to refer to the corresponding products or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0041] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl preferably has an alkyl of 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl of 1 to 8 carbon atoms (i.e., C 1-8 alkyl), further preferably an alkyl of 1 to 6 carbon atoms (i.e., C 1-6 alkyl), and most preferably an alkyl of 1 to 3 carbon atoms (i.e., C 1-3alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. The alkyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0042] The term "alkylene" refers to a divalent alkyl group, where the alkyl group is as defined above and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene). The alkylene preferably has an alkylene group with 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group with 1 to 8 carbon atoms (i.e., C 1-8 alkylene), further preferably an alkylene group with 1 to 6 carbon atoms (i.e., C 1-6 alkylene), most preferably an alkylene group with 1 to 3 carbon atoms (i.e., C 1-3 alkylene). Non-limiting examples include: -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2-, -CH(CH 2 CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0043] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, where the alkyl group is as defined above and has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 alkenyl). The alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 alkenyl). Non-limiting examples include: vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0044] The term "alkenylene" refers to a divalent alkenyl group, where the alkenyl group is as defined above and has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 alkenylene). The alkenylene group preferably has 2 to 6 carbon atoms (i.e., C 2-6 alkenylene). Non-limiting examples include: -CH=CH-, -CH=CH-CH 2 -, -CH=C(CH 3 )-, -CH=CH-CH 2 -CH 2 -, -CH=CH-CH(CH 3) - etc. The alkenylene can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkenylene is substituted by a substituent, the substituent is not further substituted.

[0045] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, where the alkyl group is as defined above and has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 alkynyl). The alkynyl preferably has an alkynyl group with 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkynyl is substituted by a substituent, the substituent is not further substituted.

[0046] The term "alkynylene" refers to a divalent alkynyl group, where the alkynyl group is as defined above and has 2 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 alkynylene). The alkynylene preferably has an alkynylene group with 2 to 6 carbon atoms (i.e., C 2-6 alkynylene). Non-limiting examples include: -C≡C-, -C≡C-CH 2 -, -C≡C-CH 2 -CH 2 -, -C≡C-CH(CH 3 ) - etc. The alkynylene can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkynylene is substituted by a substituent, the substituent is not further substituted.

[0047] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl preferably has a cycloalkyl having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), still more preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., C 3-5 cycloalkyl), or a cycloalkyl having 5 to 6 carbon atoms (i.e., C 3-5 cycloalkyl). Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc. Non-limiting examples of the polycyclic cycloalkyl include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0048] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic group) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n(wherein m and n are integers from 0 to 2) heteroatoms, but excluding the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclic group), containing 1 to 4 heteroatoms selected from N, O and S atoms, more preferably having 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclic group), containing 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms, further preferably having 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclic group), containing 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms, and most preferably having 5 to 6 ring atoms (i.e., 5- to 6-membered heterocyclic group), containing 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocyclic group include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azolanyl, etc. Non-limiting examples of the polycyclic heterocyclic group include: spiroheterocyclic group, fused heterocyclic group and bridged heterocyclic group. The heterocyclic group can be fused to an aryl, heteroaryl or cycloalkyl ring, such as C 6-10 aryl-fused 3- to 8-membered heterocyclic group, such as C 6-10 aryl-fused 5- to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S, such as benzo-5- to 6-membered nitrogen-containing heterocyclic group or benzo-5- to 6-membered oxygen-containing heterocyclic group, such as indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzodioxolenyl, benzodioxolanyl or dihydrobenzodioxinyl, etc.

[0049] The term "aryl" refers to a fully carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 aryl). The aryl preferably has an aryl with 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl with 6 to 10 carbon atoms (i.e., C 6-10 aryl), further preferably phenyl or naphthyl, and most preferably phenyl. The monocyclic aryl, such as phenyl. Non-limiting examples of the polycyclic aryl include: naphthyl, anthryl, phenanthryl, etc.

[0050] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) m and S(O) n (wherein m, n are integers from 0 to 2), preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. The heteroaryl preferably has a heteroaryl of 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl). The monocyclic heteroaryl, preferably has a heteroaryl of 5 to 6 ring atoms (i.e., 5-6 membered heteroaryl), non-limiting examples include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridone, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl, preferably 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-10 membered heteroaryl and C 6-10 aryl or C 6-10 aryl and 5-10 membered heteroaryl, more preferably 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienylphenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienylpyridyl, pyridylthienyl, pyridylpyrrolyl, etc. The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, which has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkoxy preferably has an alkoxy of 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably has an alkoxy of 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably has an alkoxy of 1 to 3 carbon atoms (i.e., C 1-3Alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkoxy is substituted by a substituent, the substituent is not further substituted.

[0051] The term "alkylamino" refers to -NH-(alkyl), -N-(alkyl) 2 , -NH-(unsubstituted cycloalkyl), -N-(unsubstituted cycloalkyl) 2 , where the alkyl and cycloalkyl are as defined above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 alkylamino). The alkylamino preferably has an alkylamino with 1 to 8 carbon atoms (i.e., C 1-8 alkylamino), more preferably an alkylamino with 1 to 6 carbon atoms (i.e., C 1-6 alkylamino), and most preferably an alkylamino with 1 to 3 carbon atoms (i.e., C 1-3 alkylamino). Non-limiting examples include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, dimethylamino, diethylamino, dipropylamino, etc. The alkylamino may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkylamino is substituted by a substituent, the substituent is not further substituted.

[0052] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where the alkyl and cycloalkyl are as defined above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio preferably has an alkylthio with 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio with 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), and most preferably an alkylthio with 1 to 3 carbon atoms (i.e., C 1-3(alkylthio). Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. The alkylthio group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkylthio group is substituted by a substituent, the substituent is not further substituted.

[0053] The term "carbonyl" refers to the organic functional group -C(=O)- formed by two atoms of carbon and oxygen connected by a double bond.

[0054] The term "alkoxycarbonyl" or "alkoxycarbonyl" refers to alkoxy -C(=O)-, that is, this group is connected to other parts of the compound through a carbonyl group. The term "C 2-7 alkoxycarbonyl" used herein refers to a C that is connected to the rest of the molecule through a carbonyl bond 1-6 alkoxy, where the term "C 1-6 alkoxy" is defined as above, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, n-hexyloxycarbonyl, etc.

[0055] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0056] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, where the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0057] The term "cyano" refers to -CN.

[0058] The term "hydroxy" refers to -OH.

[0059] The term "amino" refers to -NH 2 。

[0060] The term "nitro" refers to -NO 2 。

[0061] The term "mercapto" refers to -SH.

[0062] The term "hydroxy protecting group" refers to a group that is easily removable and introduced on the hydroxy group to block or protect the hydroxy group while reactions are carried out on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), optionally substituted alkyl acyl groups (such as formyl, acetyl, propionyl), optionally substituted alkyl sulfonyl groups (such as mesyl, ethylsulfonyl), optionally substituted aryl acyl groups (such as benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl), optionally substituted aryl sulfonyl groups (such as p-toluenesulfonyl), etc.

[0063] The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".

[0064] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0065] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range is specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0066] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0067] The expression mn used herein refers to a range from m to n and subranges consisting of individual point values ​​therein and individual point values. For example, the expression "C 2 -C 8 ” or “C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C 2 -C 5 , C 3 -C 4 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 4 -C 7 , C 4 -C 8 etc., and C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 For example, the expression “C 3 -C 10 " or "C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, for example, C 3 -C 9 , C 6 -C 9 , C 6-C 8 、C 6 -C 7 、C 7 -C 10 、C 7 -C 9 、C 7 -C 8 、C 8 -C 9 etc. and C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 etc. For another example, the expression "C 1 -C 6 " or "C 1-6 " covers the range of 1 to 6 carbon atoms and should be understood to also cover any sub - range and each point value therein. For example, C 2 -C 5 、C 3 -C 4 、C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 、C 1 -C 6 etc., and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 etc. For another example, the expression "from three to ten yuan" should be understood to cover any sub - range and each point value therein, such as from three to five yuan, from three to six yuan, from three to seven yuan, from three to eight yuan, from four to five yuan, from four to six yuan, from four to seven yuan, from four to eight yuan, from five to seven yuan, from five to eight yuan, from six to seven yuan, from six to eight yuan, from nine to ten yuan, etc., and three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should be understood in a similar way.

[0068] The different expressions such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. used in this article all express the same meaning, that is, it means that X can be any one or several of A, B, and C.

[0069] The term "optionally" or "optionally" means that the subsequently described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "a cycloalkyl group optionally (optionally) substituted by an alkyl group" means that the alkyl group may or may not be present, and this description includes the case where the cycloalkyl group is substituted by an alkyl group and the case where the cycloalkyl group is not substituted by an alkyl group.

[0070] The terms "substituted" and "substituted" mean that one or more (e.g., one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that the normal valence of the specified atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are only allowed when such combinations form a stable compound. When it is described that a certain substituent is absent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0071] If a substituent is described as "optionally... substituted", the substituent can be unsubstituted or can be substituted. If an atom or group is described as optionally being substituted by one or more of a list of substituents, one or more hydrogens on that atom or group can be replaced by independently selected optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is "unsubstituted" or "not substituted". Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0072] When the bond of a substituent is shown as passing through the bond connecting two atoms in a ring, such a substituent can be bonded to any ring-forming atom in the ring that can be substituted.

[0073] When any variable (e.g., R), and a variable with a label (e.g., R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 etc.) appears more than once in the composition or structure of a compound, its definition in each case at each occurrence is independent. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group can optionally be substituted by at most four R substituents, and the options for each R substituent in each case are independent of each other.

[0074] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all these mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0075] Any hydrogen atom described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the exemplified compounds of the present invention can also be replaced by a deuterium atom.

[0076] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the tissues of a patient without undue toxicity, irritation, allergic response, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0077] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0078] The term "pharmaceutical composition" refers to a composition containing one or more compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thus exert its biological activity.

[0079] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to an organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifying agents.

[0080] The terms "administer" or "administration", etc. refer to methods that can enable a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0081] As used herein, the term "treatment" includes alleviating, reducing or improving a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the development of a disease or symptom, alleviating a disease or symptom, promoting the remission of a disease or symptom, or arresting the signs of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to eradicating or improving the treated condition. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to a patient using a composition to prevent the risk of a certain disease, or taking it when the patient presents with one or more physiological conditions of the disease, although the disease has not been diagnosed.

[0082] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively prevent and / or treat a target disorder, disease or condition. The term "neuropsychiatric disease" refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0083] For a drug, drug unit or active ingredient, the terms "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refer to a sufficient amount of a drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also depends on the specific active substance. In a particular case, the appropriate effective amount can be determined by those skilled in the art through routine tests.

[0084] As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the diseases described herein) (referred to as patients) or normal individuals. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0085] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C to 25°C.

[0086] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the basic raw material used in each step (1 equivalent) according to the equivalent relationship of chemical reactions.

[0087] In the context of the present invention, when the words "about" or "approximate" are used, whether used or not, it means within 10% of the given value or range, preferably within 5%, especially within 1%. Alternatively, for those of ordinary skill in the art, the term "about" or "approximate" means within the acceptable standard error range of the average value. Whenever a number with a value of N is disclosed, any number within the value of N + / – 1%, N + / – 2%, N + / – 3%, N + / – 5%, N + / – 7%, N + / – 8% or N + / – 10% will be explicitly disclosed, where "+ / –" means plus or minus.

[0088] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other technicians in the art to more fully understand the technical solutions of the present invention, its principles and its practical applications, so that other technicians in the art can modify and implement the present invention in many forms to best meet the requirements of specific uses.

[0089] Compound

[0090] The present disclosure provides, on the one hand, a compound of formula I, its stereoisomers or its pharmaceutically acceptable salts:

[0091]

[0092] Wherein,

[0093] R 1 is -L 1 C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-OT, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, and the above groups are optionally substituted by one or more Ra; R 1 is preferably C 1-6 alkyl, C 2-6Alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl, the above groups optionally substituted by one or more Ra; R 1 is preferably C optionally substituted by one or more Ra 1-6 alkyl, preferably C 1-6 alkyl, preferably ethyl;

[0094] L 1 is a bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene;

[0095] T is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl;

[0096] R aa and R bb are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R aa and R bb together with the carbon to which they are attached form C 3-8 cycloalkyl;

[0097] R cc and R dd are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R cc and R dd together with the carbon to which they are attached form C 3-8 cycloalkyl;

[0098] q is 0 or 1;

[0099] Ra is hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8Cycloalkyl, C 2-7 Alkoxycarbonyl or C 6-14 Aryl, preferably hydrogen or halogen, preferably hydrogen;

[0100] R 2 Is hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, preferably hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, preferably hydrogen;

[0101] R 3 Are each independently hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-8 Cycloalkyl, preferably hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably hydrogen;

[0102] p is 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, preferably 1, 2 or 3, preferably 1 or 2;

[0103] M is N or CH;

[0104] X and Y are each independently hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-8 Cycloalkyl, preferably hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0105] Ring A is C 6-14 Aryl, 5- to 14-membered heteroaryl or C 6-10 Aryl and 3- to 8-membered heterocyclic group, preferably C 6-14 Aryl, 5- to 14-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S or C 6-10 Aryl and 1-3 heteroatoms selected from N, O or S in 3- to 8-membered heterocyclic group, preferably C 6-10 Aryl, 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S or C 6-10A 5- to 8-membered heterocyclic group having an aryl group and 1 to 3 heteroatoms selected from N, O, or S, preferably phenyl, naphthyl, benzothienyl, benzofuranyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, benzodioxolyl, or dihydrobenzodioxinyl, preferably phenyl, naphthyl,

[0106] preferably phenyl or naphthyl, preferably phenyl.

[0107] In some embodiments, R 1 is -L 1 C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-C(O)OT, -L 1 -[C(R aa R bb )]q-C(R cc R dd )-OT, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group, C 6-14 aryl, or a 5- to 14-membered heteroaryl, and the above groups are optionally substituted by one or more Ra; R 1 is preferably C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group, C 6-14 aryl, or a 5- to 14-membered heteroaryl, and the above groups are optionally substituted by one or more Ra; R 1 is preferably C 1-6 alkyl optionally substituted by one or more Ra, preferably C 1-6 alkyl, preferably ethyl.

[0108] In some embodiments, Ra is hydrogen, halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, C 2-7 alkoxycarbonyl, or C6-14 An aryl group, preferably hydrogen or a halogen, preferably hydrogen.

[0109] In some embodiments, R 2 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, preferably hydrogen or C 1-6 alkyl, preferably hydrogen or C 1-3 alkyl, preferably hydrogen.

[0110] In some embodiments, R 3 are each independently hydrogen, a halogen, a hydroxyl group, a mercapto group, a cyano group, an amino group, a nitro group, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-8 cycloalkyl, preferably hydrogen, a halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen.

[0111] In some embodiments, p is 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4, preferably 1, 2 or 3, preferably 1 or 2.

[0112] In some embodiments, X and Y are each independently hydrogen, a halogen, a hydroxyl group, a mercapto group, a cyano group, an amino group, a nitro group, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-8 cycloalkyl, preferably hydrogen, a halogen, C 1-6 alkyl or C 1-6 alkoxy. In some embodiments, X is hydrogen or a halogen, preferably hydrogen. In some embodiments, Y is hydrogen, a halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably a halogen, preferably fluorine.

[0113] In some embodiments, ring A is C 6-14 aryl, a 5- to 14-membered heteroaryl or C 6-10 aryl-fused 3- to 8-membered heterocyclic group, preferably C 6-14 aryl, a 5- to 14-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S or C 6-10 aryl-fused 3- to 8-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S, preferably C 6-10 aryl, a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O or S or C6-10 A 5- to 8-membered heterocyclic group having an aryl group and 1 to 3 heteroatoms selected from N, O, or S, preferably phenyl, naphthyl, benzothienyl, benzofuranyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, benzodioxolanyl, or dihydrobenzodioxinyl, preferably phenyl, naphthyl,

[0114] preferably phenyl or naphthyl, more preferably phenyl.

[0115] In some embodiments, Formula I is further as shown in Formula II:

[0116]

[0117] In some embodiments, in Formula II, R 1 is C 1-6 alkyl, R 2 is hydrogen, R 3 is hydrogen, p is 1 or 2, M is N, X is hydrogen, and Y is fluorine.

[0118] In some embodiments, the compounds of Formula I are selected from the following compounds:

[0119]

[0120] Preparation method

[0121] The present invention also provides a method for preparing the compound shown in Formula I, its stereoisomers, or its pharmaceutically acceptable salts. The said preparation method can be synthesized from commercially available raw materials through known reaction principles.

[0122] In some embodiments, the preparation method includes the following step (1):

[0123] (1) The compound shown in Formula iii-1 reacts with the compound shown in Formula iii-2 through a substitution reaction to generate the compound shown in Formula IIIa,

[0124]

[0125] wherein, R 5 is -O-hydroxy protecting group; R 1 , R 2 , R 3 , p, M, X, Y, and ring A are as defined above,

[0126] The hydroxyl protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, mesyl, ethylsulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

[0127] In some embodiments, the substitution reaction conditions can be the conventional conditions for such reactions in the art.

[0128] In some embodiments, R 5 is tert-butyldimethylsilyl-O-.

[0129] In some embodiments, the method further comprises the following step (2):

[0130] (2) Preparing the compound shown in Formula I from the compound shown in Formula IIIb,

[0131]

[0132] wherein R 5 ’ is -O-hydroxyl protecting group; R 1 , R 2 , R 3 , p, M, X, Y and ring A are as defined above;

[0133] The hydroxyl protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, mesyl, ethylsulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

[0134] In some embodiments, R 5 ’ is mesyl-O-.

[0135] In some embodiments, the reaction conditions for forming the alkenyl group can be the conventional conditions for such reactions in the art.

[0136] In some embodiments, R 5 is the same as R 5 ’.

[0137] In some embodiments, R 5 is the same as R 5If they are not the same, the method further includes obtaining the compound shown in formula IIIb by subjecting the compound shown in formula IIIa to a hydroxy protecting group removal reaction and a further hydroxy protection reaction. In some embodiments, the reaction conditions of the hydroxy protecting group removal reaction and the hydroxy protection reaction may be conventional conditions for such reactions in the art.

[0138] Intermediate

[0139] The present invention further provides a compound shown in formula III, its stereoisomer or its salt:

[0140]

[0141] wherein, R 4 is -OH or -O-hydroxy protecting group; R 1 , R 2 , R 3 , p, M, X, Y and ring A are as defined above;

[0142] The hydroxy protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, methanesulfonyl, ethanesulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

[0143] In some embodiments, formula III is further as shown in formula IIIa or formula IIIb.

[0144] In some embodiments, the compound shown in formula I is prepared from the compound shown in formula IIIa or formula IIIb.

[0145] Pharmaceutical composition

[0146] The present invention further relates to a pharmaceutical composition, which comprises a therapeutically effective dose of any of the shown compounds, its stereoisomer or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers or excipients.

[0147] In some embodiments, the above pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The carrier refers to a conventional carrier in the pharmaceutical field, for example: diluents such as water; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch, etc.; disintegrants such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate, etc. Additionally, other adjuvants such as sweeteners, fragrances or colorants can be added to the composition.

[0148] In some embodiments, the pharmaceutical composition can be administered in any of the following ways: oral administration, inhalation spray, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intracardiac, intrasternal or intracranial injection or infusion, or administration by means of an implantable reservoir.

[0149] Application

[0150] The present invention further relates to the use of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of a medicament. In some embodiments, the medicament is a GABA A receptor agonist. In some embodiments, the medicament is a medicament in the field of the central nervous system, preferably a medicament for inducing and maintaining anesthesia in mammals, promoting sedative hypnosis in mammals, treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion or epilepsy.

[0151] The present invention also relates to a method for inducing and maintaining anesthesia in mammals, promoting sedative hypnosis in mammals, treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion or epilepsy, which comprises administering to a subject a therapeutically effective dose of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, or their pharmaceutical compositions.

[0152] The present invention further relates to the use of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of a medicament for treating adrenocortical insufficiency. The adrenocortical insufficiency may be a primary disease caused by the adrenal gland, a secondary disease caused by the pituitary gland or a tertiary disease caused by the hypothalamus. The diseases causing adrenocortical insufficiency are adrenal tuberculosis, lymphoma, leukemia, diabetes, rheumatoid arthritis, systemic lupus erythematosus, etc. Beneficial effect

[0153] The present invention relates to a class of novel-structured nitrogen-containing heteroaryl compounds, further etomidate derivatives, which have good sedative and anesthetic effects. In some embodiments, the compounds of this class have strong anesthetic potency. In some embodiments, the compounds of this class have good anesthetic characteristics, that is, they have a rapid onset, a short anesthetic time and a rapid recovery. In some embodiments, the compounds of this class have high safety, for example, have low toxicity. In some embodiments, the compounds of this class have little or no inhibitory effect on 11β-hydroxylase or have a promoting effect, and thus have little effect on the secretion of adrenocortical hormones (such as cortisol and / or corticosterone), or can further promote the secretion of adrenocortical hormones (such as cortisol and / or corticosterone).

[0154] Example

[0155] The embodiments of the present invention will be described in detail below in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0156] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS).

[0157] The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker Advanced 400 nuclear magnetic resonance instrument, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is tetramethylsilane (TMS).

[0158] The liquid chromatography-mass spectrometry (LC-MS) measurement is performed using a Shimadzu LCMS2020 liquid chromatography-mass spectrometer in Japan.

[0159] The HPLC measurement is performed using an Agilent 1260 liquid chromatography instrument.

[0160] The thin-layer chromatography silica gel plate uses a Qingdao Marine silica gel plate. The TLC specification is 0.2 mm - 0.25 mm, and the specification for separating and purifying products by thin-layer chromatography is 0.2 mm - 0.25 mm.

[0161] General synthetic route of the compounds in the examples of the present invention:

[0162]

[0163] Among them, R 1 、R 2 、R 3 、p, M, X, Y and ring A are as defined above.

[0164] Specifically: First, the substituted 1,2-ethylene glycol undergoes a substitution reaction with tert-butyldimethylchlorosilane to obtain 2-((tert-butyldimethylsilyl)oxy)-1-substituted ethan-1-ol; second, it undergoes a condensation reaction with an imidazole / pyrrole ester derivative under the action of triphenylphosphine and DIAD to obtain 1-(2-((tert-butyldimethylsilyl)oxy)-1-substituted ethyl)-imidazole / pyrrole ester derivative; then, it generates 1-(2-hydroxy-1-substituted ethyl)-imidazole / pyrrole ester derivative under the action of TBAF, and then reacts with methanesulfonyl chloride to obtain 1-(2-(methylsulfonyloxy))-1-(substituted ethyl)-imidazole / pyrrole ester derivative, and finally obtains the target compound under the action of DBU.

[0165] Example 1, Ethyl 4-fluoro-1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (1)

[0166]

[0167] 1.1 Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-ol

[0168] Phenyl-1,2-ethylene glycol (50.0 g, 0.36 mol) and dichloromethane (300 mL) were successively added to a 500 mL three-necked flask, stirred magnetically, DMAP (4.4 g, 0.036 mol) and TEA (73.0 g, 0.72 mol) were added, the temperature was lowered in an ice bath, and tert-butyldimethylchlorosilane (54.5 g, 0.36 mol) was added dropwise at 0 °C. After addition, it was transferred to room temperature and reacted for 8 h. 300 mL of water was added, and the mixture was extracted with dichloromethane 3 times (3 × 150 mL). The organic phase was washed with saturated sodium chloride solution 2 times (2 × 150 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated to obtain 69.17 g of a colorless oily liquid with a yield of 76.2%.

[0169] 1.2 Preparation of Ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-4-fluoro-1H-imidazole-5-carboxylate

[0170] Triphenylphosphine (6.86 g, 0.03 mol), tetrahydrofuran (300 mL), and ethyl 4-fluoro-1H-imidazole-5-carboxylate (3.16 g, 0.02 mol) were successively added to a 500 mL four-necked flask and stirred until dissolved. N 2After adding the substitution three times, the temperature was lowered by 0 °C, and DIAD (5.37 g, 0.03 mol) was added. After reacting for 1 h, 2-((tert-butyldimethylsilyl)oxy)-1-phenylethan-1-ol (5.8 g, 0.02 mol) was added dropwise. After the addition, the temperature was slowly raised to room temperature and the reaction was carried out for 5 h. After the reaction was completed, tetrahydrofuran was evaporated to dryness, DCM (100 mL) was added, the organic phase was washed twice with saturated sodium chloride solution (2×50 mL), dried over anhydrous magnesium sulfate, filtered by suction, concentrated, and separated by silica gel column chromatography (PE / EA = 10:1) to obtain 6.47 g of a light yellow oily liquid with a yield of 82.5%.

[0171] 1.3 Preparation of ethyl 4-fluoro-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate

[0172] Ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-4-fluoro-1H-imidazole-5-carboxylate (5.88 g, 0.015 mol) and THF (150 mL) were successively added to a 250 mL three-necked flask, stirred magnetically, and TBAF (5.99 g, 0.03 mol) was added dropwise at room temperature. The reaction was carried out at room temperature for 8 h. After the reaction was completed, THF was evaporated to dryness, 50 mL of saturated sodium chloride solution was added, and the mixture was extracted twice with ethyl acetate (2×30 mL), dried over anhydrous magnesium sulfate, filtered by suction, concentrated, and separated by silica gel column chromatography to obtain 2.96 g of an oily liquid with a yield of 71.1%.

[0173] 1.4 Preparation of ethyl 4-fluoro-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate

[0174] Ethyl 4-fluoro-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate (2.90 g, 0.01 mol), TEA (20 mL), and THF (50 mL) were successively added to a 100 mL single-necked flask, stirred magnetically, the temperature was lowered to 0 °C, and MsCl (1.83 g, 0.015 mol) was added. The reaction was carried out for 4 h and the reaction was stopped. THF was concentrated until no distillate came out, 50 mL of saturated sodium chloride solution was added, and the mixture was extracted twice with ethyl acetate (2×30 mL), dried over anhydrous magnesium sulfate, filtered by suction, concentrated and directly used for the next step of the reaction to obtain 2.85 g of an oil with a yield of 80.0%.

[0175] 1.5 Preparation of ethyl 4-fluoro-1-(1-phenylvinyl)-1H-imidazole-5-carboxylate

[0176] Ethyl 4-fluoro-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate (2.85 g, 0.008 mol), DBU (11.97 g, 0.08 mol), and THF (50 mL) were successively added to a 100 mL single-necked flask, stirred magnetically, cooled to 0 °C, reacted for 5 h, and the reaction was stopped. Concentrated until no distillate was obtained, 50 mL of saturated sodium chloride solution was added, extracted twice with ethyl acetate (2 × 30 mL), dried over anhydrous magnesium sulfate, filtered by suction, concentrated, and separated by silica gel column chromatography to obtain 758.6 mg of the target compound with a yield of 60.1%. 1 H NMR(400MHz,DMSO-d 6 )δ7.99(s,1H),7.38(t,J=3.5Hz,3H),7.20(dd,J=7.0,2.7Hz,2H),6.06(s,1H),5.60(s,1H),3.99(q,J=7.1Hz,2H),0.99(td,J=7.1,1.3Hz,3H);MS(ESI,m / z):261.3(M+H) + 。

[0177] Example 2, Ethyl 1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (2)

[0178]

[0179] 2.1 According to the method of 1.2 in Example 1, ethyl 1H-imidazole-5-carboxylate was used instead of ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, and 6.30 g of a light yellow oily liquid was obtained with a yield of 80.5%.

[0180] 2.2 According to the method of 1.3 in Example 1, ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 5.7 g of a colorless oily liquid was obtained with a yield of 70.1%.

[0181] 2.3 According to the method of 1.4 in Example 1, ethyl 1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 3.8 g of a light yellow oily liquid was obtained with a yield of 68.04%.

[0182] 2.4 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 0.98 g of the target compound was obtained with a yield of 58.9%. 1 H NMR(400MHz,DMSO-d 6) δ 7.93 (s, 2H), 7.49 (dd, J = 17.7, 6.3 Hz, 3H), 7.41–7.28 (m, 2H), 5.63 (d, J = 17.6 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); MS(ESI, m / z): 243.3 (M + H) + 。

[0183] Example 3, Ethyl 1-(1-phenylethenyl)-1H-pyrrole-2-carboxylate (3)

[0184]

[0185] 3.1 According to the method of 1.2 in Example 1, use ethyl 1H-pyrrole-2-carboxylate to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, and obtain 6.27 g of a light yellow oily liquid, with a yield of 81.5%.

[0186] 3.2 According to the method of 1.3 in Example 1, use ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-pyrrole-2-carboxylate to participate in the reaction, and obtain 5.0 g of a colorless oily liquid, with a yield of 76.1%.

[0187] 3.3 According to the method of 1.4 in Example 1, use ethyl 1-(2-hydroxy-1-phenylethyl)-1H-pyrrole-2-carboxylate to participate in the reaction, and obtain 2.7 g of a light yellow oily liquid, with a yield of 63.04%.

[0188] 3.4 According to the method of 1.5 in Example 1, use ethyl 1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-pyrrole-2-carboxylate to participate in the reaction, and obtain 0.68 g of the target compound, with a yield of 61.3%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (d, J = 6.3 Hz, 3H), 7.20 (d, J = 2.2 Hz, 1H), 7.11–7.05 (m, 2H), 7.02 (dd, J = 3.9, 2.1 Hz, 1H), 6.36–6.30 (m, 1H), 5.86 (s, 1H), 5.36 (s, 1H), 3.94 (q, J = 7.0 Hz, 2H), 1.01 (t, J = 7.0 Hz, 3H); MS(ESI, m / z): 242.3 (M + H) + 。

[0189] Example 4, Ethyl 4-chloro-1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (4)

[0190]

[0191] 4.1 According to the method of 1.2 in Example 1, ethyl 4-chloro-1H-imidazole-5-carboxylate was used to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, and 7.21 g of a light yellow oily liquid was obtained with a yield of 76.2%.

[0192] 4.2 According to the method of 1.3 in Example 1, ethyl 4-chloro-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 6.24 g of a colorless oily liquid was obtained with a yield of 68.4%.

[0193] 4.3 According to the method of 1.4 in Example 1, ethyl 4-chloro-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 2.92 g of a light yellow oily liquid was obtained with a yield of 65.26%.

[0194] 4.4 According to the method of 1.5 in Example 1, ethyl 4-chloro-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 0.62 g of the target compound was obtained with a yield of 59.69%. 1 H NMR(400MHz,DMSO-d 6 )δ8.45(s,1H),7.53(d,J=7.6Hz,2H),7.46–7.40(m,2H),7.38–7.33(m,1H),5.68(d,J=8.2Hz,2H),4.36–4.29(m,2H),1.36–1.28(m,3H);MS(ESI,m / z):277.7(M+H) + 。

[0195] Example 5, Ethyl 1-(1-(p-tolyl)vinyl)-1H-imidazole-5-carboxylate (5)

[0196]

[0197] 5.1 According to the method of 1.1 in Example 1, (4-tolyl)-1,2-ethanediol was used to replace phenyl-1,2-ethanediol to participate in the reaction, and 8.95 g of a light yellow oily liquid was obtained with a yield of 82.6%.

[0198] 5.2 According to the method of 1.2 in Example 1, ethyl 1H-imidazole-5-carboxylate was used to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to react with 2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol, and 6.54 g of a light yellow oily liquid was obtained with a yield of 78.94%.

[0199] 5.3 According to the method of 1.3 in Example 1, ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 5.67 g of colorless oily liquid was obtained with a yield of 71.92%.

[0200] 5.4 According to the method of 1.4 in Example 1, ethyl 1-(2-hydroxy-1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 3.05 g of light yellow oily liquid was obtained with a yield of 70.57%.

[0201] 5.5 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 0.59 g of the target compound was obtained with a yield of 62.31%. 1 H NMR(400MHz,DMSO-d 6 )δ8.44(s,1H),8.26(s,1H),7.49–7.43(m,2H),7.23–7.18(m,2H),

[0202] 5.30(s,1H),5.17(s,1H),4.31(q,J=8.0Hz,2H),2.37(d,J=0.9Hz,3H),1.34(t,J=8.0Hz,3H);MS(ESI,m / z):257.3(M+H) + 。

[0203] Example 6, Ethyl 2-fluoro-1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (6)

[0204]

[0205] 6.1 According to the method of 1.2 in Example 1, ethyl 2-fluoro-1H-imidazole-5-carboxylate was used instead of ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, and 7.89 g of light yellow oily liquid was obtained with a yield of 72.4%.

[0206] 6.2 According to the method of 1.3 in Example 1, ethyl 2-fluoro-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 6.58 g of colorless oily liquid was obtained with a yield of 63.81%.

[0207] 6.3 According to the method of 1.4 in Example 1, ethyl 2-fluoro-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 2.53 g of light yellow oily liquid was obtained with a yield of 64.97%.

[0208] 6.4 According to the method in 1.5 of Example 1, ethyl 2-fluoro-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 0.53 g of the target compound was obtained with a yield of 57.59%. 1 H NMR(400MHz,DMSO-d 6 )δ8.19(s,1H),7.56–7.50(m,2H),7.47–7.42(m,1H),7.42–7.35(m,2H),5.19(s,1H),5.11(s,1H),4.29(q,J=8.0Hz,2H),1.35(t,J=8.0Hz,3H);MS(ESI,m / z):261.3(M+H) + 。

[0209] Example 7, Ethyl 4-ethoxy-1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (7)

[0210]

[0211] 7.1 According to the method in 1.2 of Example 1, ethyl 4-ethoxy-1H-imidazole-5-carboxylate was used to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, and 8.89 g of a light yellow oily liquid was obtained with a yield of 71.54%.

[0212] 7.2 According to the method in 1.3 of Example 1, ethyl 4-ethoxy-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 7.01 g of a colorless oily liquid was obtained with a yield of 78.52%.

[0213] 7.3 According to the method in 1.4 of Example 1, ethyl 4-ethoxy-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 3.13 g of a light yellow oily liquid was obtained with a yield of 66.39%.

[0214] 7.4 According to the method in 1.5 of Example 1, ethyl 4-ethoxy-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 0.71 g of the target compound was obtained with a yield of 62.60%. 1 H NMR(400MHz,DMSO-d 6)δ8.40(s,1H),7.54–7.48(m,2H),7.43–7.36(m,3H),5.35(s,1H),5.24(s,1H),4.35-4.29(m,4H),1.47(t,J=8.0Hz,3H),1.38(t,J=8.0Hz,3H);MS(ESI,m / z):287.3(M+H) + 。

[0215] Example 8, Ethyl 4-methyl-1-(1-phenylethenyl)-1H-imidazole-5-carboxylate (8)

[0216]

[0217] 8.1 According to the method of 1.2 in Example 1, using ethyl 4-methyl-1H-imidazole-5-carboxylate to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to participate in the reaction, 7.89 g of a light yellow oily liquid was obtained, with a yield of 72.4%.

[0218] 8.2 According to the method of 1.3 in Example 1, using ethyl 4-methyl-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate to participate in the reaction, 6.58 g of a colorless oily liquid was obtained, with a yield of 63.81%.

[0219] 8.3 According to the method of 1.4 in Example 1, using ethyl 4-methyl-1-(2-hydroxy-1-phenylethyl)-1H-imidazole-5-carboxylate to participate in the reaction, 2.53 g of a light yellow oily liquid was obtained, with a yield of 64.97%.

[0220] 8.4 According to the method of 1.5 in Example 1, using ethyl 4-methyl-1-(2-((methylsulfonyl)oxy)-1-phenylethyl)-1H-imidazole-5-carboxylate to participate in the reaction, 0.53 g of the target compound was obtained, with a yield of 57.59%. 1 H NMR(400MHz,DMSO-d 6 )δ8.08(s,1H),7.55–7.49(m,2H),7.47–7.36(m,3H),5.31(s,1H),5.18(s,1H),4.34(q,J=8.0Hz,2H),2.47(s,3H),1.35(t,J=8.0Hz,3H);MS(ESI,m / z):257.3(M+H) + 。

[0221] Example 9, Ethyl 1-(1-(4-fluorophenyl)ethenyl)-1H-imidazole-5-carboxylate (9)

[0222]

[0223] 9.1 According to the method of 1.1 in Example 1, 4-fluorophenyl-1,2-ethanediol was used to replace phenyl-1,2-ethanediol to participate in the reaction, and 12.8 g of a light yellow oily liquid was obtained, with a yield of 79.14%.

[0224] 9.2 According to the method of 1.2 in Example 1, ethyl 1H-imidazole-5-carboxylate was used to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate to react with 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenylethyl)-1-ol, and 8.32 g of a light yellow oily liquid was obtained, with a yield of 71.35%.

[0225] 9.3 According to the method of 1.3 in Example 1, 1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenylethyl))-1H-imidazole-5-carboxylate was used to participate in the reaction, and 6.67 g of a colorless oily liquid was obtained, with a yield of 73.26%.

[0226] 9.4 According to the method of 1.4 in Example 1, ethyl 1-(2-hydroxy-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate was used to participate in the reaction, and 4.12 g of a light yellow oily liquid was obtained, with a yield of 68.57%.

[0227] 9.5 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(4-fluorophenylethyl))-1H-imidazole-5-carboxylate was used to participate in the reaction, and 1.23 g of the target compound was obtained, with a yield of 52.35%. 1 H NMR(400MHz,DMSO-d 6 )δ7.95(s,2H),7.50–7.36(m,2H),7.30(td,J=8.9,2.0Hz,2H),5.62(d,J=12.2Hz,2H),4.34–4.13(m,2H),1.27(td,J=7.1,1.8Hz,3H);MS(ESI,m / z):260.3(M+H) + 。

[0228] Example 10, Ethyl 1-(1-(4-methoxyphenyl)vinyl)-1H-imidazole-5-carboxylate (10)

[0229]

[0230] 10.1 According to the method of 1.1 in Example 1, 4-methoxyphenyl-1,2-ethanediol was used to replace phenyl-1,2-ethanediol to participate in the reaction, and 12.8 g of a light yellow oily liquid was obtained, with a yield of 79.14%.

[0231] 10.2 According to the method of 1.2 in Example 1, ethyl 1H-imidazole-5-carboxylate was used to replace ethyl 4-fluoro-1H-imidazole-5-carboxylate and react with 2-((tert-butyldimethylsilyl)oxy)-1-(4-methoxyphenylethyl)-1-ol to obtain 8.32 g of a light yellow oily liquid with a yield of 71.35%.

[0232] 10.3 According to the method of 1.3 in Example 1, 1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-methoxyphenylethyl)-1H-imidazole-5-carboxylate was involved in the reaction to obtain 6.67 g of a colorless oily liquid with a yield of 73.26%.

[0233] 10.4 According to the method of 1.4 in Example 1, ethyl 1-(2-hydroxy-1-(4-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate was involved in the reaction to obtain 4.12 g of a light yellow oily liquid with a yield of 68.57%.

[0234] 10.5 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(4-methoxyphenylethyl))-1H-imidazole-5-carboxylate was involved in the reaction to obtain 1.23 g of the target compound with a yield of 52.35%. 1 H NMR(400MHz,DMSO-d 6 )δ7.91(d,J=7.6Hz,2H),7.28(d,J=7.8Hz,2H),7.01(d,J=7.8Hz,2H),5.52(s,1H),5.47(s,1H),4.24(q,J=6.9Hz,2H),3.80(d,J=1.9Hz,3H),1.27(t,J=6.9Hz,3H);MS(ESI,m / z):273.3(M+H) + 。

[0235] Example 11, Ethyl 4-fluoro-1-(1-p-tolylvinyl)-1H-imidazole-5-carboxylate (11)

[0236]

[0237] 11.1 According to the method of 1.1 in Example 1, (4-tolyl)-1,2-ethanediol was used to replace phenyl-1,2-ethanediol and react to obtain 12.95 g of a light yellow oily liquid with a yield of 80.61%.

[0238] 11.2 According to the method of 1.2 in Example 1, it was reacted with 2-(tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethan-1-ol to obtain 7.54 g of a light yellow oily liquid with a yield of 75.67%.

[0239] 11.3 According to the method of 1.3 in Example 1, ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-(p-tolyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 6.07 g of a colorless oily liquid with a yield of 79.52%.

[0240] 11.4 According to the method of 1.4 in Example 1, ethyl 1-(2-hydroxy-1-(p-tolyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 3.26 g of a light yellow oily liquid with a yield of 74.68%.

[0241] 11.5 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(p-tolyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 1.20 g of the target compound with a yield of 52.11%. 1 H NMR(400MHz,DMSO-d 6 )δ8.46(s,1H),7.47–7.41(m,2H),7.23–7.17(m,2H),5.24(s,1H),5.12(s,1H),4.37(q,J=8.0Hz,2H),2.39(d,J=0.9Hz,3H),1.37(t,J=8.0Hz,3H);MS(ESI,m / z):275.3(M+H) + 。

[0242] Example 12、Ethyl 4-fluoro-1-(1-(4-fluorophenyl)vinyl)-1H-imidazole-5-carboxylate(12)

[0243]

[0244] 12.1 According to the method of 1.1 in Example 1, 4-fluorophenyl-1,2-ethanediol was used instead of phenyl-1,2-ethanediol in the reaction to obtain 11.8 g of a light yellow oily liquid with a yield of 78.27%.

[0245] 12.2 According to the method of 1.2 in Example 1, it was reacted with 2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenylethyl)-1-ol to obtain 7.91 g of a light yellow oily liquid with a yield of 70.45%.

[0246] 12.3 According to the method of 1.3 in Example 1, ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-fluorophenylethyl))-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 6.67 g of a colorless oily liquid with a yield of 73.26%.

[0247] 12.4 According to the method in 1.4 of Example 1, ethyl 1-(2-hydroxy-1-(4-fluorophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 4.12 g of a light yellow oily liquid with a yield of 68.57%.

[0248] 12.5 According to the method in 1.5 of Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(4-fluorophenylethyl))-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 1.21 g of the target compound with a yield of 54.01%. 1 H NMR(400MHz,DMSO-d 6 )δ8.46(s,1H),7.62–7.55(m,2H),7.18–7.11(m,2H),5.31(s,1H),5.12(s,1H),4.37(q,J=8.0Hz,2H),1.35(t,J=8.0Hz,3H);MS(ESI,m / z):279.3(M+H) + 。

[0249] Example 13, Ethyl 4-fluoro-1-(1-(4-methoxyphenyl)vinyl)-1H-imidazole-5-carboxylate (13)

[0250]

[0251] 13.1 According to the method in 1.1 of Example 1, 4-methoxyphenyl-1,2-ethanediol was used instead of phenyl-1,2-ethanediol in the reaction to obtain 9.18 g of a light yellow oily liquid with a yield of 77.63%.

[0252] 13.2 According to the method in 1.2 of Example 1, it was reacted with 2-((tert-butyldimethylsilyl)oxy)-1-(4-methoxyphenylethyl)-1-ol to obtain 7.13 g of a light yellow oily liquid with a yield of 75.38%.

[0253] 13.3 According to the method in 1.3 of Example 1, ethyl 1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-methoxyphenylethyl))-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 5.67 g of a colorless oily liquid with a yield of 69.86%.

[0254] 13.4 According to the method in 1.4 of Example 1, ethyl 1-(2-hydroxy-1-(4-methoxyphenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate was used in the reaction to obtain 3.01 g of a light yellow oily liquid with a yield of 60.92%.

[0255] 13.5 According to the method of 1.5 in Example 1, ethyl 1-(2-((methylsulfonyl)oxy)-1-(4-methoxyethyl))-4-fluoro-1H-imidazole-5-carboxylate was used to participate in the reaction to obtain 0.81 g of the target compound, with a yield of 50.51%. 1 H NMR(400MHz,DMSO-d 6 )δ8.45(s,1H),7.57–7.51(m,2H),6.95–6.89(m,2H),5.31(s,1H),5.12(s,1H),4.36(q,J=8.0Hz,2H),3.83(s,3H),1.35(t,J=8.0Hz,3H);MS(ESI,m / z):291.3(M+H) + 。

[0256] Biological test evaluation

[0257] The present invention will be further described and explained with reference to test examples below, but these examples do not mean to limit the scope of the present invention.

[0258] The compound of Comparative Example 1 in the present application is etomidate; the structure of the compound of Comparative Example 2 below is shown as follows, and it was prepared by referring to the method of Example 9 of Patent Application PCT / CN2016 / 101696.

[0259]

[0260] Test Example 1, Hypnosis Test on Mice

[0261] 1.1 Experimental Method

[0262] 1.1.1 Test Animals

[0263] ICR mice, SPF grade, weighing 20 - 40 g, source of animals: Beijing SPF Biotechnology Co., Ltd., animal use license: SYXK (Su) 2019 - 0053.

[0264] 1.1.2 Test Compounds

[0265] For the compound of Comparative Example 1, an emulsion injection was used for the experiment, namely etomidate injection, commercially available (2 mg / ml), from Jiangsu Nhwa Pharmaceutical Co., Ltd.

[0266] For the compound of the Example and the compound of Comparative Example 2, 20% blank lipid emulsion (Sichuan Kelun Pharmaceutical Co., Ltd.) was used to prepare an emulsion with a compound concentration of 2 mg / ml for the experiment.

[0267] 1.1.3 Test Environment:

[0268] Animals need to be transferred from the breeding room to the laboratory 1 hour in advance to adapt to the environment. The laboratory environment is generally: temperature 16 - 26 °C, relative humidity 40% - 70%, illuminance is adjusted according to the test requirements, and keep quiet during the test.

[0269] 1.1.4 Test procedures:

[0270] Administer the compound through the tail vein of the mouse, and observe whether the righting reflex disappears to determine whether the compound has an anesthetic effect. The preliminary test of the anesthetic efficacy of the test compound in mice was carried out by the sequential method.

[0271] (1) Administer the compound to the mouse through the tail vein. First, administer the compound with a dosing volume of 10 mL / kg respectively, and inject it evenly within 10 seconds. Observe whether the righting reflex of the mouse disappears after administration.

[0272] (2) Judgment criteria for the disappearance of the righting reflex: Observe the state of the animal. After the animal enters a quiet state, gently place the mouse on its back in the cage. If the mouse can recover to all four feet on the ground within 30 seconds, it is determined that the righting reflex exists; after the mouse returns to a quiet state again, repeat the above operation until the righting reflex disappears.

[0273] (3) Adjust the dosing dose up and down according to the dosing volume / dose ratio of 1:0.8. That is, when the compound does not exert an anesthetic effect at a dosing volume of 10 mL / kg, the next mouse is given a higher dose, and the compound with a dosing volume of 12.5 mL / kg is injected; when the compound shows anesthetic efficacy at a dosing volume of 10 mL / kg, the next mouse is given a lower dose, and the drug with a dosing volume of 8 mL / kg is injected; and so on, until the ED 50 is calculated by the AOT425 Statpgm software.

[0274] 1.2 Experimental results

[0275] The experimental results are shown in the following table.

[0276] Compound number <![CDATA[ED 50 (mg / kg)]]> Comparative example 1 2.5 Comparative example 2 2.0 Example 1 2.5

[0277] 1.3 Experimental conclusion

[0278] The experimental results exemplarily show that the compound of the present invention has good sedative and anesthetic effects.

[0279] Test example 2: Determination of the anesthetic latency and duration in mice

[0280] 2.1 Experimental method

[0281] Use the test mice as described in Test example 1, divide them into groups of 10 each, and administer the compound through the tail vein of the mouse. The test compound is formulated similarly to Test example 1, and the dosing dose is 2*ED 50. Record the disappearance time of the righting reflex in mice and continuously observe. If the animal wakes up and stands on all four limbs, it is determined that the animal has woken up, record the corresponding time and continue to observe. If the animal can walk independently, record the corresponding time.

[0282] Latency = Disappearance time of righting reflex – Administration start time

[0283] Duration = Awakening time – Disappearance time of righting reflex

[0284] Walking time = Independent walking time – Awakening time

[0285] 2.2 Experimental results

[0286] The experimental results are shown in the following table.

[0287]

[0288] 2.3 Experimental conclusions

[0289] The experimental results exemplarily show that the compounds of the present invention have a short latency, indicating a rapid onset of anesthesia; have a short duration, indicating a short anesthesia time; and have a short walking time, indicating a rapid recovery after anesthesia.

[0290] Test Example 3. Experiment on the effect of NCI-H295R cell cortisol secretion

[0291] 3.1 Experimental method

[0292] Culture NCI-H295R cells to the logarithmic growth phase, prepare a cell suspension, inoculate it into a 24-well plate and culture overnight; prepare the compound (dissolve the test compound in DMSO (the blank control group is only the same amount of solvent DMSO), and then dilute it to a final concentration of 1 μM in the cell culture medium), co-incubate with the cells and then place them in an incubator, and continue to culture at 37 °C and 5% CO 2 for 48 h under the conditions; collect the culture supernatant, centrifuge at 1000 rpm for 5 min, take the supernatant, and detect the cortisol level using a cortisol detection kit (R&D, catalog number: KGE008B), and calculate the inhibition rate of the test compound on the cortisol secretion of NCI-H295R cells.

[0293] 3.2 Experimental results

[0294] The experimental results are shown in the following table.

[0295] Compound number Inhibition rate (%) Example 1 -6.85 Example 2 -16.03 Example 3 -18.70 Example 4 -24.31 Example 5 0.07 Comparative example 1 36.72

[0296] 3.3 Experimental conclusions

[0297] The experimental results exemplarily show that the compounds of the present invention have little or no effect on the secretion of adrenocortical hormones or promote their secretion.

[0298] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention.

Claims

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, R1 is -L1C(O)OT, -L1-[C(R aa R bb )]qC(R cc R dd )-C(O)OT、-L1-[C(R aa R bb )]qC(R cc R dd )-OT、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the above groups are optionally substituted by one or more Ra; L1 is a key, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne; T is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R aa and R bb Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R aa and R bb Together with the carbon to which it is attached, it forms C 3-8 Cycloalkyl; R cc and R dd Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R cc and R dd Together with the carbon to which it is attached, it forms C 3-8 Cycloalkyl; q is 0 or 1; Ra is hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 2-7 Alkoxycarbonyl or C 6-14 Aryl; R2 is hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl; R3 is each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-8 Cycloalkyl; p is 1, 2, 3, 4 or 5; M is N or CH; X and Y are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-8 Cycloalkyl; Ring A is C 6-14 Aryl, 5-14 membered heteroaryl or C 6-10 Aryl and 3-8 membered heterocyclic group.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the above groups are optionally substituted by one or more Ra; R1 is preferably C optionally substituted by one or more Ra 1-6 Alkyl, preferably C 1-6 Alkyl, preferably ethyl; (2) Ra is hydrogen or halogen, preferably hydrogen; (3) R2 is hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, preferably hydrogen; (4) R3 are each independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably hydrogen; (5) p is 1, 2, 3 or 4, preferably 1, 2 or 3, preferably 1 or 2; (6) M is N; (7) X is hydrogen or halogen, preferably hydrogen; (8) Y is hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably halogen, preferably fluorine; (9) Ring A is C 6-14 Aryl, 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or C 6-10 aryl and 1-3 heteroatoms selected from N, O or S 3-8 membered heterocyclic group, preferably C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, or C 6-10 Aryl and 1-3 heteroatoms selected from N, O or S 5-8 membered heterocyclic group, preferably phenyl, naphthyl, benzothiophenyl, benzofuranyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, benzodioxolyl or dihydrobenzodioxinyl, preferably phenyl, naphthyl, Preferred is phenyl or naphthyl, and preferred is phenyl.

3. The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Formula I is further represented by Formula II:

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is the following compound:

5. A pharmaceutical composition comprising a therapeutically effective dose of the compound as claimed in any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

6. Use of the compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a drug, wherein the drug is preferably GABB A Receptor agonists.

7. Use of the compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a drug, wherein the drug is preferably a drug in the field of central nervous system, preferably a drug for inducing and maintaining anesthesia in mammals, promoting sedation and hypnosis in mammals, and treating and / or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions or epilepsy.

8. A compound represented by formula III, its stereoisomer or its salt: in, R4 is -OH or -O-hydroxy protecting group; R1, R2, R3, p, M, X, Y and ring A are as defined in any one of claims 1 to 4; The hydroxy protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, methylsulfonyl, ethylsulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

9. A method for preparing a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: (1) the compound represented by formula iii-1 undergoes a substitution reaction with the compound represented by formula iii-2 to generate the compound represented by formula IIIa, The method optionally further comprises the following steps (2): (2) preparing the compound represented by formula I from the compound represented by formula IIIb, R5 and R5' are the same or different. When R5 and R5' are different, the following step (3) is optionally further included: (3) The compound represented by formula IIIa is subjected to a hydroxyl protecting group removal reaction and a further hydroxyl protecting reaction to obtain a compound represented by formula IIIb, wherein R5 and R5' are each independently an -O-hydroxy protecting group; R1, R2, R3, p, M, X, Y and ring A are as defined in any one of claims 1 to 4; The hydroxy protecting group is preferably trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydropyranyl, formyl, acetyl, propionyl, methylsulfonyl, ethylsulfonyl, benzoyl, p-nitrobenzoyl, p-toluoyl, p-chlorobenzoyl or p-toluenesulfonyl.

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