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

Abstract

The invention provides a nitrogen-containing heteroaryl compound as well as a preparation method and application thereof. In particular, the present invention relates to a nitrogen-containing heteroaryl compound represented by general formula I, a preparation method 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 pharmaceutical chemistry, and in particular relates to a nitrogen-containing heteroaryl compound, a preparation method and application thereof. Background Art

[0002] Etomidate (CAS No. 33125-97-2), chemical name R-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid ethyl ester, is a non-barbiturate intravenous anesthetic, which is characterized by rapid onset, short duration of action, rapid recovery, and mild inhibitory effects on cardiovascular and respiratory functions. It is mainly used for induction of anesthesia and outpatient surgical anesthesia. Its structure is shown below:

[0003]

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

[0005] Therefore, the development of more new anesthetic drugs with anesthetic activity and better anesthetic properties 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 and application thereof. The nitrogen-containing heteroaryl compound has a strong anesthetic effect, and has good anesthetic properties, a fast onset and a short action time. In addition, the nitrogen-containing heteroaryl compound has substantially no inhibitory effect on the secretion of adrenal cortical hormones (steroid hormones) such as cortisol, corticosterone, etc., and thus has both good anesthetic effect and clinical safety.

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

[0008]

[0009] in,

[0010] R 1 For -L 1 C(O)OT, -L 1 -[C(R aa R bb )]qC(R cc R dd )-C(O)OT、-L 1 -[C(R aa R bb )]qC(R cc R dd )-OT、C 1-6Alkyl, 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;

[0011] L 1 For key, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne;

[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 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 it is connected to form C 3-8 Cycloalkyl;

[0014] 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 it is connected to form C 3-8 Cycloalkyl;

[0015] q is 0 or 1;

[0016] 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;

[0017] R 2 For hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0018] R 3 are independently 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;

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

[0020] M is N or CH;

[0021] 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, provided that when M is N, X and Y are not simultaneously hydrogen;

[0022] Ring A is C 6-14 Aryl, 5-14 membered heteroaryl or C 6-10 Aryl and 3-8 membered heterocyclic group.

[0023] In another aspect, the present invention provides a method for preparing a compound represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that the method comprises the following steps (1):

[0024] (1) the compound represented by formula i-1 undergoes a substitution reaction with the compound represented by formula i-2 to generate the compound represented by formula i-1,

[0025]

[0026] Among them, R 1 , R 2 , p, M, X, Y and ring A are as defined above, R 3a are independently 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;

[0027] And in R 3a C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 When the alkylamino group is present, the method optionally further comprises the following steps (2):

[0028] (2) preparing a compound represented by formula I-2 from a compound represented by formula I-1,

[0029]

[0030] Among them, R 3b Each is independently a hydroxyl group, a thiol group or an amino group.

[0031] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound as described herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0032] In another aspect, the present invention provides the use of the compound shown herein, its stereoisomer or its pharmaceutically acceptable salt or a pharmaceutical composition comprising the same in the preparation of a drug, preferably the drug is GABA A Receptor agonists, preferably the drug is 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. DETAILED DESCRIPTION

[0033] the term

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0035] 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. 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 Alkyl), most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3 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 chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0036] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 8 carbon atoms (i.e., C 1-8 Alkylene), further preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), most preferably an alkylene group having 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. Alkylene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0037] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl 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 The alkenyl group is preferably an alkenyl group having 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. Alkenyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl. When the alkenyl is substituted with a substituent, the substituent is no longer further substituted.

[0038] The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above, having 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 The alkenylene group is preferably an alkenylene group having 2 to 6 carbon atoms (i.e., C 2-6 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. Alkenylene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl. When the alkenylene is substituted with a substituent, the substituent is no longer substituted further.

[0039] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl 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 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl. When the alkynyl is substituted with a substituent, the substituent is no longer substituted further.

[0040] The term "alkynylene" refers to a divalent alkynyl group, wherein alkynyl is as defined above, having 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 The alkynylene group is preferably an alkynylene group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: -C≡C-, -C≡C-CH 2 -、-C≡C-CH 2 -CH 2 -、-C≡C-CH(CH 3 )-, etc. Alkynylidene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl. When the alkynylidene is substituted with a substituent, the substituent is no longer substituted further.

[0041] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic 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 The cycloalkyl group is preferably a cycloalkyl group 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), further 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 The non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl. The non-limiting examples of the polycyclic cycloalkyl include: spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

[0042] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclyl) 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 heterocyclyl), 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 of 0-2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocyclic group), wherein 1-4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic group), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., 3-6 membered heterocyclic group), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., 5-6 membered heterocyclic group), wherein 1-4, 1-3 or 1-2 heteroatoms are 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-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl. 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 and 3-8 membered heterocyclic group, such as C 6-10 The aryl group is a 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, for example, a benzo 5-6 membered nitrogen-containing heterocyclic group or a benzo 5-6 membered oxygen-containing heterocyclic group, for example, an indolinyl group, an isoindolyl group, a dihydrobenzofuranyl group, a dihydroisobenzofuranyl group, a benzodioxolyl group, a benzodioxolyl group or a dihydrobenzodioxinyl group.

[0043] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aromatic group) or a fused polycyclic group (i.e., polycyclic aromatic group) 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 The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., C 6-10 The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc.

[0044] The term "heteroaryl" refers to a monocyclic heteroaromatic group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaromatic group (i.e., a 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., a 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3 or 4) of the ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m, n are integers of 0-2) heteroatoms, preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. The heteroaryl group preferably has a heteroaryl group of 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group preferably has a heteroaryl group of 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridone, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group preferably has a 5-6 membered heteroaryl group and a 5-6 membered heteroaryl group, a 5-10 membered heteroaryl group and C 6-10 Aryl or C 6-10 Aryl and 5-10 membered heteroaryl, further 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, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridinyl, pyridothiphenyl, pyridopyrrolyl and the like.

[0045] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein 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 The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C 1-8 Alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (i.e., C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (i.e. C 1-3Alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl. When the alkoxy is substituted with a substituent, the substituent is no longer further substituted.

[0046] The term "alkylamino" refers to -NH-(alkyl), -N-(alkyl) 2 , -NH-(unsubstituted cycloalkyl), -N-(unsubstituted cycloalkyl) 2 , wherein 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 The alkylamino group is preferably an alkylamino group having 1 to 8 carbon atoms (i.e., C 1-8 alkylamino), more preferably an alkylamino having 1 to 6 carbon atoms (i.e., C 1-6 Alkylamino), preferably an alkylamino having 1 to 3 carbon atoms (i.e., C 1-3 The alkylamino group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl. When the alkylamino group is substituted with a substituent, the substituent is no longer further substituted.

[0047] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein 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 The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3The alkylthio group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl. When the alkylthio group is substituted with a substituent, the substituent is no longer further substituted.

[0048] The term "carbonyl" refers to an organic functional group -C(=O)- formed by a double bond between carbon and oxygen atoms.

[0049] The term "alkoxycarbonyl" or "alkoxycarbonyl" refers to an alkoxy-C(=O)- group, i.e., the group is attached to the rest of the compound through a carbonyl group. 2-7 "Alkoxycarbonyl" refers to a C-terminal group attached to the rest of the molecule through a carbonyl bond. 1-6 Alkoxy, wherein the term "C 1-6 The “alkoxy” is as defined above, for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, n-hexyloxycarbonyl and the like.

[0050] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0051] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl 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 and the like, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl and 2,2-difluoroethyl.

[0052] The term "cyano" refers to -CN.

[0053] The term "hydroxy" refers to -OH.

[0054] The term "amino" refers to -NH 2 .

[0055] The term "nitro" refers to -NO 2 .

[0056] The term "thiol" refers to -SH.

[0057] 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".

[0058] 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.

[0059] 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.

[0060] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0061] 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 For example, the expression "C 1 -C 6 ” or “C 1-6" covers the range of 1-6 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 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 "three to ten yuan" should be understood to cover any sub-ranges therein and each point value, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this document should also be understood in a similar manner.

[0062] Different expressions used herein 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” all express the same meaning, that is, X can be any one or more of A, B, C.

[0063] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.

[0064] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only when such combinations form stable compounds. When describing that a substituent does not exist, 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 describing that each carbon atom in a group can be optionally 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.

[0065] If a substituent is described as "optionally substituted by...", the substituent may be unsubstituted or substituted. If an atom or group is described as optionally substituted by one or more of the substituent list, one or more hydrogens on the atom or group may 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 may also mean that the corresponding group is "non-substituted" or "unsubstituted". Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0066] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0067] When any variable (such as R), as well as variables with a tag (such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 When a group (e.g., ) appears more than once in a compound's composition or structure, its definition is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0068] The compounds of the present invention may 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, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which 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 of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity. 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.

[0069] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0070] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0071] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.

[0072] 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 a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0073] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0074] The term "administration" or "administering" refers to a method that enables 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.

[0075] As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms 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 the eradication or improvement of the condition being treated. 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 suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

[0076] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in preventing and / or treating a target disorder, disease or condition. The term "neuropsychiatric disease" refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0077] With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0078] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0079] The term "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C ​​to 25°C.

[0080] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0081] In the context of the present invention, when or whether the words "about" or "approximately" are used, they mean within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% will be explicitly disclosed, where "+ / -" means plus or minus.

[0082] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0083] Compound

[0084] In one aspect, the present disclosure provides a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0085]

[0086] in,

[0087] R 1 For -L 1 C(O)OT, -L 1 -[C(R aa R bb )]qC(R cc R dd )-C(O)OT、-L 1 -[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;

[0088] L 1 For key, C1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne;

[0089] 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;

[0090] 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;

[0091] 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;

[0092] q is 0 or 1;

[0093] 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;

[0094] R 2 For hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0095] R 3 are independently halogen, hydroxyl, mercapto, cyano, amino, nitro, C 1-6 Haloalkyl, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-8 Cycloalkyl;

[0096] p is 1, 2, 3, 4 or 5;

[0097] M is N or CH;

[0098] 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, provided that when M is N, X and Y are not simultaneously hydrogen;

[0099] Ring A is C 6-14 Aryl, 5-14 membered heteroaryl or C 6-10 Aryl and 3-8 membered heterocyclic group.

[0100] In some embodiments, R 1 For -L 1 C(O)OT, -L 1 -[C(R aa R bb )]qC(R cc R dd )-C(O)OT、-L 1 -[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; R 1 Preferably 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; R 1 Preferably, C is optionally substituted with one or more Ra. 1-6 Alkyl, preferably C 1-6 The alkyl group is preferably an ethyl group.

[0101] In some embodiments, Ra is hydrogen, halogen, hydroxyl, thiol, 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 is preferably hydrogen or halogen, preferably hydrogen.

[0102] In some embodiments, R 2 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl, preferably C 1-3 The alkyl group is preferably a methyl group.

[0103] In some embodiments, R 3 are independently 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, preferably halogen, hydroxyl, C 1-6 Alkyl or C 1-6 The alkoxy group is preferably a hydroxy group.

[0104] 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.

[0105] In some embodiments, M is N or CH, preferably N.

[0106] In some embodiments, X and Y are each independently hydrogen, halogen, hydroxyl, thiol, 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 is preferably halogen or hydrogen, provided that when M is N, X and Y are not simultaneously hydrogen.

[0107] In some embodiments, X is hydrogen and Y is halogen, preferably fluorine.

[0108] In some embodiments, Ring A is C 6-14 Aryl, 5-14 membered heteroaryl or C 6-10 Aryl and 3-8 membered heterocyclic group, preferably 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 The aryl group is a 5-8 membered heterocyclic group having 1-3 heteroatoms selected from N, O or S, preferably a phenyl group, a naphthyl group, a benzothiophenyl group, a benzofuranyl group, an indolyl group, a benzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, a quinazolinyl group, a benzodioxolyl group or a dihydrobenzodioxin group, preferably a phenyl group, a naphthyl group,

[0109] Preferred is phenyl or naphthyl, and preferred is phenyl.

[0110] In some embodiments, Formula I is as shown in Formula II, preferably as shown in Formula III or Formula IV:

[0111]

[0112] In some embodiments, in Formula III, X is hydrogen, and Y is halogen, preferably fluorine.

[0113] In some embodiments, the compound of Formula I is a compound of Formula Ia or Formula Ib or a mixture thereof:

[0114]

[0115] In some embodiments, Formula Ia is as shown in Formula IIa, preferably as shown in Formula IIIa or Formula IVa:

[0116]

[0117] In some embodiments, in Formula IIIa, R 1 C 1-6 Alkyl, R 2 is methyl, R 3 Each independently is hydroxyl or C 1-6 Alkoxy, p is 1 or 2, X is hydrogen, and Y is fluorine.

[0118] In some embodiments, in Formula IIIa, R 1 C 1-6 Alkyl, R 2is methyl, R 3 is hydroxyl, p is 1 or 2, X is hydrogen, and Y is fluorine.

[0119] In some embodiments, the compound of Formula I is selected from the following compounds:

[0120]

[0121]

[0122]

[0123] Preparation method

[0124] The present invention also provides a method for preparing the compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof. The preparation method can be synthesized using commercially available raw materials according to known reaction principles.

[0125] In some embodiments, the preparation method comprises the following steps:

[0126] (1) the compound represented by formula i-1 undergoes a substitution reaction with the compound represented by formula i-2 to generate the compound represented by formula I,

[0127]

[0128] Among them, R 3a are independently 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; R 1 , R 2 , p, M, X, Y and ring A are as defined above.

[0129] In some embodiments, the substitution reaction conditions may be conventional conditions for such reactions in the art.

[0130] In some embodiments, R 3a C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 When the alkylamino group is present, the method optionally further comprises the following steps (2):

[0131] (2) preparing a compound represented by formula I-2 by dealkylation of the compound represented by formula I-1,

[0132]

[0133] Among them, R 3b Each is independently a hydroxyl group, a thiol group or an amino group.

[0134] In some embodiments, the dealkylation reaction conditions may be conventional conditions for such reactions in the art.

[0135] In some embodiments, Formula I is as shown in Formula I-1 or Formula I-2.

[0136] In some embodiments, the compound of formula I-1 is a compound of formula Ia-1 or formula Ib-1 or a mixture thereof:

[0137]

[0138] In some embodiments, the compound of formula I-2 is a compound of formula Ia-2 or formula Ib-2 or a mixture thereof:

[0139]

[0140] In some embodiments, Formula Ia is as shown in Formula Ia-1 or Formula Ia-2.

[0141] In some embodiments, the racemate of the compound represented by Formula I-1 can be resolved by enantiomers to prepare the compound represented by Formula Ia-1 or Formula Ib-1. Similarly, the racemate of the compound represented by Formula I-2 can be resolved by enantiomers to prepare the compound represented by Formula Ia-2 or Formula Ib-2. In some embodiments, the resolution can be performed using conventional methods and / or conditions in the art.

[0142] Pharmaceutical composition

[0143] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

[0144] In some embodiments of the present invention, the pharmaceutical composition can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers. The carrier refers to a conventional carrier in the pharmaceutical field, for example: a diluent such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinyl pyrrolidone, etc.; a filler such as starch, etc.; a disintegrant such as calcium carbonate, sodium bicarbonate; a lubricant such as calcium stearate or magnesium stearate, etc. In addition, other adjuvants such as sweeteners, aromatics or colorants can also be added to the composition.

[0145] In some embodiments of the present invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir.

[0146] application

[0147] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs. In some embodiments, the drug is GABA A In some embodiments, the drug is 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.

[0148] The present invention also relates to a method 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, which comprises administering to a subject a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or a pharmaceutical composition thereof.

[0149] Beneficial Effects

[0150] The present invention relates to a novel type of nitrogen-containing heteroaryl compound, further to etomidate derivatives, which have good sedative and anesthetic effects. In some embodiments, such nitrogen-containing heteroaryl compounds have strong anesthetic efficacy. In some embodiments, such nitrogen-containing heteroaryl compounds have good anesthetic properties, that is, they have fast onset, short anesthesia time, and rapid recovery. In some embodiments, such nitrogen-containing heteroaryl compounds have higher safety, for example, lower toxicity. In some embodiments, such nitrogen-containing heteroaryl compounds have lower or substantially no inhibitory effect on 11β-hydroxylase, and thus have less or substantially no effect on the secretion of adrenal cortical hormones (such as cortisol and / or corticosterone).

[0151] Example

[0152] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially. If not otherwise specified, the ratios or percentages used herein are by weight.

[0153] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0154] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Advanced 400 NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CDMSO-d6), and 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0155] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 liquid mass spectrometer.

[0156] Agilent 1260 liquid chromatograph was used for HPLC measurement.

[0157] The thin layer chromatography silica gel plate used was Qingdao Ocean Silica Gel Plate, the specification used by TLC was 0.2mm-0.25mm, and the specification used by the thin layer chromatography separation and purification product was 0.2mm-0.25mm.

[0158] General synthetic route of the compounds of the present invention:

[0159]

[0160] Among them, R 1 , R 2 , p, M, X, Y and ring A are as defined above; R 3a are independently 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.

[0161] Specifically, 4-amino-5-imidazole / pyrrolecarboxamide derivative hydrochloride reacts with alcohol under the action of methanesulfonic acid to obtain 4-amino-1H-imidazole / pyrrole-5-carboxylate derivative, which is diazotized and then subjected to substitution reaction to obtain the corresponding imidazole / pyrrolecarboxylate derivative, which is then subjected to Mitsunobu reaction with the substituted alcohol to obtain the substituted imidazole / pyrrolecarboxylate derivative. 3a C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 When the alkylamine group is present, it is further dealkylated under the action of boron tribromide to convert R 3a Convert to R 3b , where R 3b Each is independently a hydroxyl group, a thiol group or an amino group.

[0162] Example 1 Ethyl 4-fluoro-1-[1-(2-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate (1)

[0163]

[0164] 1.1 Preparation of ethyl 4-amino-1H-imidazole-5-carboxylate

[0165] Add 600 ml of anhydrous ethanol, methanesulfonic acid (621 g, 6.46 mol), and 4-amino-5-imidazolecarboxamide hydrochloride (150 g, 0.92 mol) to a 2L glass reaction bottle in sequence, and react at 80°C for 80 hours. After the reaction is completed, the ethanol is removed by concentration under reduced pressure, and the pH is adjusted to 8-9 with a saturated sodium bicarbonate aqueous solution. The mixture is extracted 3 times (3×200 mL) with a mixed solvent of tetrahydrofuran and ethyl acetate (volume ratio 2:1), and the organic phase is washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 72.4 g of a gray solid with a yield of 50.58%.

[0166] 1.2 Preparation of ethyl 4-fluoro-1H-imidazole-5-carboxylate

[0167] Add 4-amino-1H-imidazole-5-carboxylic acid ethyl ester (10g, 64.45mmol) and 50% fluoroboric acid 250mL to a 500mL multi-mouth bottle, stir magnetically, cool to -5~0℃, and slowly drop sodium nitrite (9g, 130mmol) and 150g water prepared sodium nitrite aqueous solution. After addition, react for 30 minutes, filter after the reaction, irradiate the filtrate with ultraviolet light, and react for 15 hours. After the reaction, adjust the pH of the reaction solution to 8~9 with sodium bicarbonate aqueous solution, then extract with ethyl acetate 3 times, wash the organic phase with 2% dilute hydrochloric acid 2 times (2×50mL), 8% sodium bicarbonate once (50ml), saturated sodium chloride aqueous solution once (50ml), spin dry the organic phase, and slurry the product with ethyl acetate and n-heptane (volume ratio 1:6) mixed solvent for 1 hour, filter and dry to obtain 4.67g of light yellow solid, with a yield of 45.83%.

[0168] 1.3 Preparation of ethyl 4-fluoro-1-[1-(2-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0169] 4-Fluoro-1H-imidazole-5-carboxylic acid ethyl ester (4g, 25mmol), triphenylphosphine (8.6g, 33mmol), tetrahydrofuran (80mL) were placed in a 250mL three-necked flask, and diisopropyl azodicarboxylate (6.7g, 33mmol) was slowly added under ice bath conditions. After the addition was completed, a tetrahydrofuran solution of 1-(2-methoxyphenyl)ethanol (4.2g, 28mmol) was slowly added. After the addition was completed, the mixture was transferred to room temperature and reacted for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and then silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) was performed to obtain 2.6g of an oily substance with a yield of 32.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ7.91(s,1H),7.33–7.24(m,1H),7.03(d,J=8.2Hz,1H),6.91(t,J=7.5Hz,1H),6.73(d,J=7.6Hz,1H),6.31(q,J=7.1H z,1H),4.15(qd,J=7.2,3.7Hz,2H),3.81(s,3H),1.75(d,J=7.1Hz,3H),1.21–1.12(m,3H).MS(ESI,m / z):293.1(M+H)+.

[0170] Example 2 Ethyl 4-fluoro-1-[1-(4-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate (2)

[0171]

[0172] 2.1 Preparation of ethyl 4-fluoro-1-[1-(4-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0173] According to the method of 1.3 in Example 1, 4-methoxyphenylethanol was reacted with 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 2.5 g of an oily product with a yield of 32.56%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.07(s,1H),7.17(d,J=8.2Hz,2H),6.94–6.87(m,2H),6.11(q,J=7.2Hz,1H),4.20(tt,J=8.2,6.3 Hz,2H),3.73(s,3H),1.80(d,J=7.1Hz,3H),1.22(td,J=7.1,1.4Hz,3H).MS(ESI,m / z):293.1(M+H)+.

[0174] Example 3 Preparation of 1-[1-(3,4-dimethoxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester (3)

[0175]

[0176] 3.1 Preparation of ethyl 1-[1-(3,4-dimethoxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylate

[0177] According to the method of 1.3 in Example 1, 3,4-dimethoxyphenylethanol was reacted with 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 2.2 g of an oily product with a yield of 31.47%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(s,1H),6.95–6.87(m,2H),6.72(dd,J=8.4,2.0Hz,1H),6.11(q,J=7.2Hz,1H),4.22(qd,J=7.2,3. 0Hz,2H),3.73(d,J=4.4Hz,6H),1.82(d,J=7.2Hz,3H),1.23(t,J=7.1Hz,3H).MS(ESI,m / z):319.2(M+H)+.

[0178] Example 4 Preparation of ethyl 4-fluoro-1-[1-(3-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate (4)

[0179]

[0180] 4.1 Preparation of ethyl 4-fluoro-1-[1-(3-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0181] According to the method of 1.3 in Example 1, 3-methoxyphenylethanol was reacted with 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 2.4 g of an oily product with a yield of 30.97%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(s,1H),7.25(t,J=7.9Hz,1H),6.85(dd,J=8.3,2.3Hz,1H),6.80–6.70(m,2H),6.14(q,J=7.2Hz,1H),4.1 9(p,J=6.8Hz,2H),3.73(s,3H),1.83(d,J=7.3Hz,3H),1.20(td,J=7.1,1.4Hz,3H).MS(ESI,m / z):293.1(M+H)+.

[0182] Example 5 Preparation of ethyl 4-fluoro-1-[1-(2-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate (5)

[0183]

[0184] 5.1 Preparation of ethyl 4-fluoro-1-[1-(2-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0185] 4-Fluoro-1-[1-(2-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (1 g, 3.4 mmol) and 20 mL of dichloromethane were placed in a 100 mL single-necked flask in sequence, stirred under an ice bath, and boron tribromide (5.14 g, 20.4 mmol) was slowly added dropwise. The reaction was carried out under ice bath conditions for 4 h. After the reaction was completed, 10 ml of ice water was added to quench the reaction, and the mixture was washed with water twice (2×20 ml), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and then chromatographed on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain 0.44 g of the product with a yield of 46%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.76(s,1H),7.82(s,1H),7.11(t,J=7.6Hz,1H),6.85–6.68(m,3H),6.28(q,J=7.0Hz,1H),4.16 (qd,J=7.6,3.9Hz,2H),1.75(d,J=7.0Hz,3H),1.19(t,J=7.1Hz,3H).MS(ESI,m / z):279.1(M+H)+.

[0186] Example 6 Preparation of ethyl 4-fluoro-1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate (6)

[0187]

[0188] 6.1 Preparation of ethyl 4-fluoro-1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0189] According to the method of 5.1 in Example 5, 4-fluoro-1-[1-(3-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester was reacted with boron tribromide to obtain 0.39 g of a colorless oil with a yield of 41.27%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.46(s,1H),8.11(s,1H),7.13(t,J=7.8Hz,1H),6.66(d,J=8.1Hz,1H),6.61(d,J=7.7Hz,1H),6.51(s,1H),6.07(q ,J=7.2Hz,1H),4.19(p,J=6.9Hz,2H),1.79(d,J=7.2Hz,3H),1.20(td,J=7.1,1.4Hz,3H).MS(ESI,m / z):279.1(M+H)+.

[0190] 6.2 Ethyl 4-fluoro-1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate can be decomposed by conventional methods to obtain the substance with the following structural formula R-ethyl 4-fluoro-1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate.

[0191]

[0192] Example 7 Preparation of ethyl 4-fluoro-1-[1-(4-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate (7)

[0193]

[0194] 7.1 Preparation of ethyl 4-fluoro-1-[1-(4-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate

[0195] According to the method of 5.1 in Example 5, 4-fluoro-1-[1-(4-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester was reacted with boron tribromide to obtain 0.47 g of colorless oil. The yield was 49.75%. 1 H NMR (400 MHz, DMSO-d 6)δ9.48(d,J=1.4Hz,1H),8.00(s,1H),7.06(d,J=8.1Hz,2H),6.75–6.68(m,2H),6.07(q,J=7.2Hz,1H),4 .21(qd,J=7.1,3.3Hz,2H),1.77(d,J=7.1Hz,3H),1.22(td,J=7.1,1.5Hz,3H).MS(ESI,m / z):279.1(M+H) + .

[0196] Example 8 Preparation of 1-[1-(3,4-dihydroxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester (8)

[0197]

[0198] 8.1 Preparation of ethyl 1-[1-(3,4-dihydroxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylate

[0199] According to the method of 5.1 in Example 5, 4-fluoro-1-[1-(3,4-dimethoxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester was reacted with boron tribromide to obtain 0.31 g of a colorless oil with a yield of 33.95%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.95(d,J=10.9Hz,2H),7.99(s,1H),6.68(d,J=8.1Hz,1H),6.56(s,1H),6.51(d,J=8.3Hz,1H),6.00(q,J= 7.1Hz,1H),4.21(qd,J=7.4,3.8Hz,2H),1.75(d,J=7.2Hz,3H),1.25–1.21(m,3H).MS(ESI,m / z):295.1(M+H) + .

[0200] 8.2 Ethyl 1-[1-(3,4-dihydroxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylate can be decomposed by conventional methods to obtain the following structural formula substance R-1-[1-(3,4-dihydroxyphenyl)ethyl]-4-fluoro-1H-imidazole-5-carboxylate.

[0201]

[0202] Example 9 Preparation of 1-[1-(4-fluorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (9)

[0203]

[0204] 9.1 Preparation of 1-[1-(4-fluorophenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester

[0205] According to the method of 1.3 in Example 1, 1-(4-fluorophenyl)ethane-1-ol was used instead of 2-methoxyphenylethanol, and 1H-pyrrole-2-carboxylic acid ethyl ester was used instead of 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 0.52 g of an oily product with a yield of 27.96%. 1 H NMR (400 MHz, DMSO-d 6 )δ7.50–7.36(m,2H),7.30(td,J=8.9,2.0Hz,2H),6.75–6.68(m,2H),6.36–6.30(m,1H),6.11(q,J=7.2Hz,1H ),4.26(qd,J=7.1,3.3Hz,2H),1.68(d,J=7.1Hz,3H),1.19(td,J=7.1,1.5Hz,3H).MS(ESI,m / z):262.1(M+H) + .

[0206] Example 10 Preparation of 1-[1-(p-Tolyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (10)

[0207]

[0208] 10.1 Preparation of 1-[1-(p-Tolyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester

[0209] According to the method of 1.3 in Example 1, 1-(p-tolyl)ethane-1-ol was used instead of 2-methoxyphenylethanol, and 1H-pyrrole-2-carboxylic acid ethyl ester was used instead of 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 0.61 g of an oily product with a yield of 32.28%. 1 H NMR (400 MHz, DMSO-d 6 )δ7.52–7.39(m,2H),7.31(td,J=8.9,2.0Hz,2H),6.75–6.70(m,2H),6.38–6.32(m,1H),6.13(q,J=7.2Hz,1H),4.21(qd ,J=7.1,3.3Hz,2H),2.37(s,J=0.9Hz,3H),1.65(d,J=7.1Hz,3H),1.23(td,J=7.1,1.5Hz,3H).MS(ESI,m / z):258.1(M+H) + .

[0210] Example 11 Preparation of 1-[1-(4-hydroxyphenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester (11)

[0211]

[0212] 11.1 Preparation of 1-[1-(4-methoxyphenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester

[0213] According to the method of 1.3 in Example 1, 4-methoxyphenethanol was used instead of 2-methoxyphenethanol, and 1H-pyrrole-2-carboxylic acid ethyl ester was used instead of 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 0.67 g of an oily product with a yield of 31.02%.

[0214] 11.2 Preparation of 1-[1-(4-hydroxyphenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester

[0215] According to the method of 5.1 in Example 5, 1-[1-(4-methoxyphenyl)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester was used to replace 4-fluoro-1-[1-(2-methoxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester to obtain 0.29 g of colorless oil with a yield of 45.31%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.48(d,J=1.4Hz,1H),7.11–7.05(m,2H),7.06(d,J=8.1Hz,2H),6.75–6.68(m,2H),6.36–6.30(m,1H),6.07(q,J=7 .2Hz,1H),4.21(qd,J=7.1,3.3Hz,2H),1.77(d,J=7.1Hz,3H),1.22(td,J=7.1,1.5Hz,3H).MS(ESI,m / z):260.1(M+H) + .

[0216] Biological test evaluation

[0217] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0218] The compound of comparative example 1 of the present application is etomidate; the structure of the compound of comparative example 2 is shown below, and it is prepared by referring to the method of Example 9 of patent application PCT / CN2016 / 101696.

[0219]

[0220] The structure of the compound in Comparative Example 3 is shown below, and the compound was prepared by referring to the method of Example 4 of patent application CN117003699A.

[0221]

[0222] Test Example 1: Mouse Hypnosis Test

[0223] 1.1 Experimental methods

[0224] 1.1.1 Experimental animals

[0225] ICR mice, SPF grade, weight 20-40 g, animal source: Sibeifu (Beijing) Biotechnology Co., Ltd., animal use license: SYXK (Su) 2019-0053.

[0226] 1.1.2 Test compounds

[0227] The compound of Comparative Example 1 was tested using an emulsion injection, namely etomidate injection, which is commercially available (2 mg / ml) from Jiangsu Enhua Pharmaceutical Co., Ltd.

[0228] The compounds of Example 2 and Comparative Examples 3 were prepared into emulsions with a compound concentration of 2 mg / ml using 20% ​​blank fat emulsion (Sichuan Kelun Pharmaceutical Co., Ltd.) for experiments.

[0229] 1.1.3 Test environment:

[0230] 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℃, relative humidity 40%-70%, illumination adjusted according to test requirements, and keep quiet during the test.

[0231] 1.1.4 Test steps:

[0232] The drug was administered through the tail vein of mice, and the disappearance of righting reflex was observed to determine whether the compound had an anesthetic effect. The sequential method was used to conduct a preliminary test on the anesthetic effect of the test compound on mice.

[0233] (1) The mice were administered drugs via the tail vein. First, 10 mL / kg of the drug was administered at a constant rate of 10 seconds. After administration, the mice were observed to see whether their righting reflex disappeared.

[0234] (2) Criteria for judging the disappearance of righting reflex: Observe the state of the animal. When the animal enters a quiet state, gently place the mouse with its back facing down in the cage. If the mouse can regain its feet within 30 seconds, it is judged that the righting reflex exists. After the mouse regains a quiet state, repeat the above operation until the righting reflex disappears.

[0235] (3) The dosage was adjusted up and down according to the dosage volume / dose ratio of 1:0.8. That is, when the compound did not exert an anesthetic effect at a dosage volume of 10 mL / kg, the next mouse was given a higher dose, injected with a dosage volume of 12.5 mL / kg; when the compound showed an anesthetic effect at a dosage volume of 10 mL / kg, the next mouse was given a lower dose, injected with a dosage volume of 8 mL / kg; and so on, until the ED could be calculated using AOT425 Statpgm software. 50 until.

[0236] 1.2 Experimental Results

[0237] The experimental results are shown in the following table.

[0238] Compound No. <![CDATA[ED 50 (mg / kg)]]> Comparative Example 1 2.5 Comparative Example 2 2.0 Example 6 5.9 Embodiment 11 5.6

[0239] 1.3 Experimental Results

[0240] The experimental results exemplarily show that the compound of the present invention has a strong anesthetic effect.

[0241] Test Example 2: Determination of the latency and duration of anesthesia in mice

[0242] 2.1 Experimental methods

[0243] The experimental mice described in Test Example 1 were divided into groups, with 10 mice in each group, and the drug was administered through the tail vein of the mice. The test compound was prepared similarly to that in Test Example 1, and the dosage was 2*ED 50 Record the time when the righting reflex of the mouse disappears and continue to observe. If the animal wakes up and lands on all fours, it is considered awake, record the corresponding time and continue to observe. If the animal can walk independently, record the corresponding time.

[0244] Latency = time from righting reflex disappearance to drug administration start time

[0245] Duration = awakening time – righting reflex disappearance time

[0246] Walking time = autonomous walking time – awakening time

[0247] 2.2 Experimental Results

[0248] The experimental results are shown in the following table.

[0249]

[0250] 2.3 Experimental Conclusion

[0251] The experimental results exemplarily show that the compounds of the present invention have a shorter latent period, indicating that the anesthesia takes effect quickly; have a shorter duration, indicating that the anesthetic effect lasts for a short time; and have a shorter walking time, indicating that the patient can recover quickly after anesthesia.

[0252] Test Example 3: Experiment on the effect of NCI-H295R cells secreting cortisol

[0253] 3.1 Experimental methods

[0254] NCI-H295R cells were cultured to the logarithmic growth phase, and a cell suspension was prepared and inoculated into a 24-well plate for overnight culture. The test compound was prepared (the test compound was dissolved in DMSO (the blank control group was only an equal amount of solvent DMSO), and then diluted in the cell culture medium to a final concentration of 1 μM), incubated with the cells, and then placed in an incubator at 37°C and 5% CO. 2 The culture was continued for 48 h under the same conditions; the culture supernatant was collected and centrifuged at 1000 rpm for 5 min. After the supernatant was taken, the cortisol level was detected using a cortisol detection kit (R&D, catalog number: KGE008B), and the inhibition rate of the test compound on the secretion of cortisol by NCI-H295R cells was calculated.

[0255] 3.2 Experimental Results

[0256] The experimental results are shown in the following table.

[0257] Compound No. Inhibition rate (%) Example 6 0.42 Example 8 27.15 Embodiment 11 36.73 Comparative Example 1 80.54 Comparative Example 2 36.72 Comparative Example 3 75.45

[0258] 3.3 Experimental Conclusion

[0259] The experimental results exemplarily show that the compounds of the present invention have little or no effect on the secretion of adrenal cortex hormones.

[0260] Although the present invention has been described in detail above, it will be appreciated by those skilled in the art that various modifications and changes may 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 it is connected to form 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 it is connected to form 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 independently 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, provided that when M is N, X and Y are not simultaneously hydrogen; 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 C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably methyl; (4) R3 are each independently halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, preferably hydroxy; (5) p is 1, 2, 3 or 4, preferably 1, 2 or 3, preferably 1 or 2; (6) The compound of formula I is a compound of formula Ia or formula Ib or a mixture thereof: (7) X and Y are each independently hydrogen or halogen, provided that when M is N, X and Y are not both hydrogen; preferably, X is hydrogen and Y is halogen, preferably fluorine; (8) 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 a pharmaceutically acceptable salt thereof, characterized in that: Formula I is as shown in Formula II, preferably as shown in Formula III or Formula IV:

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

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 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 i-1 undergoes a substitution reaction with the compound represented by formula i-2 to generate the compound represented by formula i-1, wherein R1, R2, p, M, X, Y and ring A are as defined in any one of claims 1 to 4, R 3a are independently 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; And in R 3a C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 When the alkylamino group is present, the method optionally further comprises the following steps (2): (2) preparing a compound represented by formula I-2 from a compound represented by formula I-1, Among them, R 3b Each is independently a hydroxyl group, a thiol group or an amino group.

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