Carboxylic acid ester compound, and preparation method therefor and use thereof

Abstract

The present invention relates to an imidazole carboxylate compound as shown in formula I, and a preparation method therefor and a use thereof. The compound can be used for preparing an anesthetic drug, and can reduce the inhibition on corticosteroid synthesis and reduce side effects.

Description

Carboxylic acid ester compounds and preparation methods and uses thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of carboxylic acid ester compounds or pharmaceutically acceptable salts, stereoisomers, solvates, isotope-labeled substances or polymorphs thereof, a preparation method thereof, a pharmaceutical composition containing the same, and uses thereof. Background Art

[0002] Etomidate is a fast-acting intravenous anesthetic based on imidazole. Its mechanism of action is primarily through binding to central nervous system inhibitory GABAA receptors, making them more sensitive to the inhibitory neurotransmitter GABA, thereby producing sedative and anesthetic effects. Etomidate exhibits greater hemodynamic stability than other existing anesthetics and is primarily used clinically for induction anesthesia and outpatient surgical anesthesia. It is characterized by rapid onset, short duration, rapid recovery, and minimal cardiovascular and respiratory side effects.

[0003] However, studies have found that while etomidate exerts its anesthetic effects, it may also inhibit 11β-hydroxylase, a key enzyme in the synthesis of adrenal cortical steroids, thereby reducing the secretion of cortisol and / or corticosterone. Therefore, long-term use of etomidate is potentially fatal.

[0004] Therefore, there is a need to develop an N-substituted imidazole carboxylate compound having sedative, hypnotic and / or anesthetic effects, a preparation method thereof, and a medical use thereof. Such a compound has the advantages of etomidate while reducing the inhibition of corticosteroid synthesis and the side effects of the drug. It can be used not only for anesthesia induction but also for anesthesia maintenance. Summary of the Invention

[0005] The compounds provided herein, or pharmaceutically acceptable salts, stereoisomers, solvates, isotope-labeled substances, or polymorphs thereof, have a variety of excellent properties, such as better anesthetic activity, rapid onset, short duration of action, and short recovery time, while reducing the inhibition of the synthesis of corticosteroids such as cortisol and / or corticosterone. Such compounds can be used as anesthetic drugs, especially intravenous anesthetic drugs, and have good anesthetic effects and safety.

[0006] In one aspect, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein the compound has the structure of Formula I:

[0007] in:

[0008] L is O or S;

[0009] (1) When L is 0:

[0010] R 1 is H or halogen;

[0011] R 2 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0012] R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0013] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0014] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0015] The condition is: when R 1 H, R 2 C 1-6 When X is alkyl, 1、X 2 、X 3 、X 4 and X 5 Different from CH; when R 1 is a halogen, X 1 、X 2 、X 3 、X 4 and X 5 When both are CH, R 5 Not ethyl or isopropyl;

[0016] (2) When L is S:

[0017] R 1 is H or halogen;

[0018] R 2 Selected from H, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0019] R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0020] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0021] R 5Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2.

[0022] On the other hand, the present application also provides a pharmaceutical composition comprising an effective amount of the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, and one or more pharmaceutically acceptable carriers.

[0023] On the other hand, the present application also provides a drug kit comprising the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or the pharmaceutical composition of the present application.

[0024] On the other hand, the present application also provides the use of the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application in the preparation of anesthetic drugs, especially intravenous anesthetic drugs and sedative drugs.

[0025] On the other hand, the present application also provides the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application, for use as a medicine.

[0026] On the other hand, the present application also provides the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application, for use in anesthesia, especially intravenous anesthesia and sedation.

[0027] On the other hand, the present application also provides a method of anesthesia, especially intravenous anesthesia or sedation, comprising administering to a subject an effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition of the present application.

[0028] On the other hand, the present application also provides a method for preparing the compound of the present application.

[0029] Definition and Description

[0030] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0031] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0032] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemicals, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0033] The term "alkyl" herein refers to a saturated linear or branched aliphatic hydrocarbon group of 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. As used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms. The term "C 1-4"Alkyl" refers to a straight or branched chain group having 1 to 4 carbon atoms, which is optionally substituted by one or more (such as 1, 2, 3 or 4) suitable substituents such as halogen. Examples of alkyl groups also include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(C H3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl- 2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

[0034] The term "alkoxy" herein refers to an alkyl group connected to a main carbon chain via an oxygen atom. The "alkyl" group is as defined above. For example, the term "C 1-12 "Alkoxy" refers to "C 1-12In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In yet another embodiment, the alkoxy group contains 1-3 carbon atoms. Such examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexoxy, etc.

[0035] The term "cycloalkyl" herein refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spirocyclic, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as 12 or 3) suitable substituents. For example, the term "C 3-10 "Cycloalkyl" or "3-10 membered cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (including cyclic, bridged or spirocyclic) hydrocarbon ring having 3 to 10 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents, wherein the substituents may be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C(=O)-NH2, carboxyl, -S(=O) t OH, -OS(=O) t -H, -S(=O) t NH2, triazolyl, tetrazolyl, -(CR 3b R 3c ) n -NH2, alkyl, alkyl-S(=O) t -, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido or alkoxyalkyl, etc., t is selected from 1 or 2. For example, C 3-8 Cycloalkyl, C 3-6 Cycloalkyl. R 3b 、R 3c Each is independently selected from H, halogen, O, S, ether, ester, hydroxy, amino, cyano, nitro, alkylamino, alkylthio, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, sulfhydryl, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, C3-10 Cycloalkyl, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-NH-, formamide, alkoxyalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2.

[0036] “C 3-10 "Cycloalkyl" or "3-10 membered cycloalkyl" includes C 3-8 Cycloalkyl (3-8 membered cycloalkyl), C 3-7 Cycloalkyl (3-7 membered cycloalkyl), C 3-6 Cycloalkyl (3-6 membered cycloalkyl). Examples of cycloalkyl further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

[0037] As used herein, the term "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0038] As used herein, the term "halo" refers to substitution with one or more (such as 1, 2 or 3) the same or different halogen atoms.

[0039] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1, 2 or 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkyl" refers to a halogenated alkyl group having 1 to 6 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0040] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted by one or more (such as 1, 2 or 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms, for example, -O-CF3, -O-C2F5, -O-CHF2, -O-CH2F, -O-CH2CF3, -O-CH2Cl or -O-CH2CH2CF3, etc.

[0041] As used herein, the term "alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing at least one carbon-carbon double bond and having 2-15 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) carbon atoms. In one embodiment, the alkenyl group contains about 2 to about 12 carbon atoms. In another embodiment, the alkenyl group contains about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. Alkenyl may be unsubstituted alkenyl or substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl), -NH(cycloalkyl), -OC(=O)-alkyl, -OC(=O)-aryl, -OC(=O)-cycloalkyl, -C(=O)OH, and -C(=O)O-alkyl. The term "C 2-6 "Alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms.

[0042] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, etc.), which is optionally substituted by one or more (e.g., 1, 2 or 3) suitable substituents such as halogen.

[0043] The hydrogen in the groups involved in the present invention may be replaced by isotopes such as protium, deuterium, and tritium.

[0044] The positions of the compounds in the present application that can be substituted can be optionally substituted by one or more suitable substituents, and suitable substituents can be selected from but not limited to oxo (=O), fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, -C(=O)-NH2, carboxyl, -S(=O) t OH, -OS(=O) t -H, -S(=O) t NH2, triazolyl, tetrazolyl, -(CR 3b R 3c ) n -NH2, alkyl, alkyl-S(=O) t-, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, C 3-10 Cycloalkyl, phenyl, alkyl-C(═O)-, alkyl-C(═O)-NH-, formamido or alkoxyalkyl, etc., wherein n and t are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0045] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence in the current context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0046] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.

[0047] If a substituent is described as being "independently selected" from a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0048] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0049] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0050] 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.

[0051] The present invention also includes all pharmaceutically acceptable isotopically labeled substances which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H.3 H, deuterium D, tritium T); carbon isotopes (such as 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0052] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0053] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0054] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0055] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0056] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, may be present in a stoichiometric or non-stoichiometric ratio.

[0057] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0058] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0059] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and when administered to the body or thereon, can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0060] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0061] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0062] This application is in no way limited to the methods and materials described herein. In the event that one or more of the combined literature, patents, and similar materials differ from or contradict this application (including but not limited to defined terms, term applications, described technologies, etc.), the description of this application and the accompanying structural formula shall prevail.

[0063] Compound

[0064] One object of the present application is to provide a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof:

[0065] in:

[0066] L is O or S;

[0067] (1) When L is 0:

[0068] R 1 is H or halogen;

[0069] R 2 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0070] R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0071] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O- and CR 5 ;

[0072] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2;

[0073] The condition is: when R 1 H, R 2 C 1-6 When alkyl, X 1 、X 2 、X 3 、X 4 and X 5 Different from CH; when R 1 is halogen, X 1 、X 2 、X 3 、X 4 and X 5 When both are CH, R 2 Not ethyl or isopropyl;

[0074] (2) When L is S:

[0075] R 1 is H or halogen;

[0076] R 2 Selected from H, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0077] R 3 and R4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0078] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0079] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2.

[0080] In some embodiments, the compounds of the present application have the structure of Formula II:

[0081] Among them, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、X 5 and L are as defined in Formula I.

[0082] In some embodiments, the compounds of the present application have the structure of Formula III-A1 or III-A2:

[0083] in:

[0084] R 1 is H or halogen;

[0085] R 2 Selected from H, C 1-6 Alkyl (e.g. C 1-4 alkyl) and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0086] R 3 and R 4 Each independently selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0087] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0088] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2;

[0089] The condition is: when R 1 H, R 2 C 1-6 When X is alkyl, 1 、X 2 、X 3 、X 4 and X 5 Different from CH; when R 1 is a halogen, X 1 、X 2 、X 3 、X 4 and X5 When both are CH, R 2 Not ethyl or isopropyl.

[0090] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 1 is selected from H, fluorine, chlorine and bromine.

[0091] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 2 Selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2.

[0092] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 2 Selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2-CH(NH2)-C(=O)OCH3 and -CH2CH=CH2.

[0093] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 3 and R 4 Each independently is H or C 1-4 Alkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group.

[0094] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group.

[0095] In some embodiments, in the compound of formula III-A1 or III-A2 of the present application, wherein: R 3 and R 4 Both are H.

[0096] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein: Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl group is substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0097] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein: is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,

[0098] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein: is selected from 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 4-cyanophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,

[0099] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0100] R 1 is selected from H, fluorine, chlorine and bromine;

[0101] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0102] R 3 and R 4 are each independently H or methyl, or R 3 、R 4Together with the attached carbon atom, it forms a cyclopropyl group;

[0103] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0104] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2;

[0105] The condition is: when R 1 H, R 2 C 1-6 When X is alkyl, 1 、X 2 、X 3 、X 4 and X 5 Different from CH; when R 1 is a halogen, X 1 、X 2 、X 3 、X 4 and X 5 When both are CH, R 2 Not ethyl or isopropyl.

[0106] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0107] R 1 is selected from H, fluorine, chlorine and bromine;

[0108] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0109] R 3 and R 4 are each independently H or methyl, or R 3 、R4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0110] Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl group is substituted by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0111] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0112] R 1 For fluorine;

[0113] R 2 is selected from methyl, cyclopropyl, isobutyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0114] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0115] It is phenyl.

[0116] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0117] R 1 is H or halogen;

[0118] R 2 Selected from C 1-6 Alkyl (e.g. C 1-4 alkyl) and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1- 6 alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0119] R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0120] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 , and X 1 、X 2 、X 3 、X 4 and X 5 Not at the same time CH;

[0121] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2.

[0122] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0123] R 1 is selected from H, fluorine, chlorine and bromine;

[0124] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0125] R 3 and R4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0126] is selected from the group consisting of 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,

[0127] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0128] R 1 is H;

[0129] R 2 Selected from C 1-6 Alkyl (e.g. C 1-4 alkyl) and C 3-6 Cycloalkyl, the C 1-6 The alkyl group is replaced by one or more selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Substituted by a cycloalkyl substituent, the C 3-6 Cycloalkyl is optionally substituted by one or more radicals selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0130] R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0131] It is phenyl.

[0132] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0133] R 1 is H;

[0134] R 2 Selected from fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0135] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0136] It is phenyl.

[0137] In some embodiments, the compound of formula III-A1 or III-A2 of the present application, wherein:

[0138] R 1 selected from fluorine, chlorine and bromine;

[0139] R 2 is selected from methyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2;

[0140] R 3 and R 4 are each independently H or methyl, or R 3 、R4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0141] It is phenyl.

[0142] In some embodiments, the compounds of the present application have the structure of Formula III-B1 or III-B2:

[0143] in,

[0144] R 1 is H or halogen;

[0145] R 2 Selected from H, cyano, C 1-6 Alkyl (e.g. C 1-4 alkyl) and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0146] R 3 and R 4 Each independently selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group;

[0147] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0148] R 5 Each is independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2.

[0149] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 1 is selected from H, fluorine, chlorine and bromine.

[0150] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 Selected from cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0151] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 Selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, cyano, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2.

[0152] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 Selected from methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3.

[0153] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 C 1-6Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0154] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 Selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2.

[0155] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 C 1-6 alkyl.

[0156] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 2 Selected from methyl, ethyl and isopropyl.

[0157] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 3 and R 4 Each independently is H or C 1-4 Alkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group.

[0158] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group.

[0159] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: R 3 and R 4 Both are H.

[0160] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0161] R 5 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2.

[0162] In some embodiments, in the compound of formula III-B1 or III-B2 of the present application, wherein: X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0163] R 5 Each is independently selected from H, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0164] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein: Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl, pyridyl and pyrimidinyl groups are each independently optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0165] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein: is phenyl or pyridyl, and the phenyl or pyridyl is optionally substituted by one or more halogens.

[0166] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein: is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,

[0167] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein: is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 4-cyanophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,

[0168] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein:

[0169] R 1 is selected from H, fluorine, chlorine and bromine;

[0170] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3;

[0171] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0172] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N+ -O - and CR 5 ;

[0173] R 5 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2.

[0174] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein:

[0175] R 1 is selected from H, fluorine, chlorine and bromine;

[0176] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3;

[0177] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0178] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ;

[0179] R 5 Each is independently selected from H, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0180] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein:

[0181] R 1 is selected from H, fluorine, chlorine and bromine;

[0182] R 2is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3;

[0183] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0184] Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl, pyridyl and pyrimidinyl groups are each independently optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2.

[0185] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein:

[0186] R 1 is selected from H, fluorine, chlorine and bromine;

[0187] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3;

[0188] R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0189] is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,

[0190] In some embodiments, the compound of formula III-B1 or III-B2 of the present application, wherein:

[0191] R 1 is selected from H, fluorine, chlorine and bromine;

[0192] R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3;

[0193] R 3 and R 4 are each independently selected from H and methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group;

[0194] is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 4-cyanophenyl, 2-cyanophenyl, 2-nitrophenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,

[0195] The present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also within the scope of the present invention.

[0196] In some embodiments, the compound of the present invention is selected from:

[0197] In some embodiments, the compound of the present invention is selected from:

[0198] Pharmaceutical compositions and kits

[0199] Another object of the present application is to provide a pharmaceutical composition comprising an effective amount of the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, and one or more pharmaceutically acceptable carriers.

[0200] Another object of the present application is to provide a drug kit comprising the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance, or polymorph thereof, or the pharmaceutical composition of the present application. Optionally, the drug kit further comprises instructions for use.

[0201] As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0202] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present application include, but are not limited to, sterile liquids. The pharmaceutical composition can be in the form of, for example, a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0203] The pharmaceutical compositions of the present application can act systemically and / or locally. For this purpose, they can be administered by a suitable route, for example by injection or transdermal administration.

[0204] The content or dosage of the compound of the present application in the pharmaceutical composition can be about 0.001 mg to about 5000 mg, suitably 0.01-1000 mg.

[0205] In some embodiments, the present application provides a method for preparing the pharmaceutical composition of the present application, which comprises combining the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph with one or more pharmaceutically acceptable carriers.

[0206] Treatment methods and uses

[0207] The present application also provides the use of the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application in the preparation of anesthetic drugs, especially intravenous anesthetic drugs.

[0208] The present application also provides the use of the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition described above in the present application, in the preparation of sedative drugs.

[0209] The present application also provides the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition described above in the present application, for use as a medicine.

[0210] The present application also provides the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application, for use in anesthesia, especially intravenous anesthesia.

[0211] The present application also provides the compound of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition of the present application, for use in sedation.

[0212] The present application also provides a method of anesthesia, particularly intravenous anesthesia, comprising administering to a subject an effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition of the present application.

[0213] The present application also provides a method of sedation, comprising administering to a subject an effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition of the present application.

[0214] As used herein, the term "effective amount" refers to an amount sufficient to induce or maintain anesthesia or sedation when administered to a subject. The effective amount will vary depending on the subject or the mode of administration and can be determined routinely by those skilled in the art.

[0215] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to the subject's needs and the professional judgment of the person administering or supervising the administration of the compounds of the present invention.

[0216] The amount of the compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In some cases, a dosage level no higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0217] As used herein, "subject" includes humans or non-human animals. Exemplary human subjects include human subjects (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal subjects. "Non-human animals" herein 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.).

[0218] The ones used in this article express The key of the position is the connection key. DETAILED DESCRIPTION

[0219] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's advice.Reagents used or instruments not indicated by manufacturer are all conventional products that can be obtained commercially.

[0220] The structures of the compounds in all examples were determined by NMR ( 1 H-NMR) was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were all by volume.

[0221] The present invention uses the following abbreviations: room temperature (RT, rt); aqueous solution (aq.); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); methanol (MeOH); methyl tert-butyl ether (MTBE); ethanol (EtOH); trifluoroacetic acid (TFA); equivalent (eq); gram / milligram (g / mg); mole / millimole (mol / mmol); liter / milliliter (L / mL); minute (min(s)); hour (h, hr, hrs); nitrogen (N2); nuclear magnetic resonance (NMR); liquid chromatography-mass spectrometry (LC-MS); thin layer chromatography (TLC); preparative liquid chromatography (Pre-HPLC); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); methanol (MeOH); methyl tert-butyl ether (MTBE); tetrahydrofuran (THF); formic acid (FA); di-tert-butyl azodicarboxylate (DBAD).

[0222] Preparation method for preparative high performance liquid chromatography:

[0223] Instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water.

[0224] Aluminum plates (20×20 cm) produced by Merck were used for thin layer chromatography silica gel plates (TLC), and the specifications used for thin layer chromatography separation and purification were GF 254 (1 mm) produced in Yantai.

[0225] The reaction is monitored by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0226] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0227] Column chromatography generally uses 200-300 mesh silica gel as a carrier. Eluent systems include: dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0228] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 35°C);

[0229] The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.

[0230] Intermediate Preparation Example 1: (R)-4-Fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid

[0231] Step 1: Synthesis of (R)-ethyl 4-fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylate

[0232] To (S)-1-phenylethanol (2.00 g, 16.39 mmol) was added tetrahydrofuran (30 mL), ethyl 4-fluoro-1H-imidazole-5-carboxylate (2.09 g, 13.23 mmol), and triphenylphosphine (4.52 g, 17.20 mmol), stirred, and cooled to 0°C. A solution of di-tert-butyl azodicarboxylate (5.32 g, 17.86 mmol) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was allowed to react at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Anhydrous ether (20 mL) was added, and the mixture was stirred at room temperature for 3.5 h. Filtered, the filter cake was discarded, and the filtrate was concentrated under reduced pressure. The crude product was directly used for the next reaction. MS [ESI]: m / z = 263.1, [M+H] + ;

[0233] Step 2: Synthesis of 5-fluoro-3-((1R)-1-phenylethyl)imidazole-4-carboxylic acid

[0234] (R)-ethyl 4-fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (1.98 g, 7.56 mmol), lithium hydroxide (905 mg, 37.80 mmol), tetrahydrofuran (10 mL), methanol (10 mL), and water (4 mL) were added and reacted at room temperature for 6 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 1) to obtain the title compound (1.50 g, 6.41 mmol, 84.78% yield). MS [ESI]: m / z = 235.0, [M+H] + .

[0235] Intermediate Preparation Example 2: (R)-4-Fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid

[0236] Ethyl (R)-4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (1.50 g, 5.35 mmol), lithium hydroxide (640 mg, 26.75 mmol), tetrahydrofuran (10 mL), methanol (10 mL), and water (4 mL) were mixed and reacted at room temperature for 6 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 1 / 1) to give the title compound (1.15 g, 3.00 mmol, 85.29% yield). MS [ESI]: m / z = 253.0, [M+H] + .

[0237] Example 1: Preparation of (((methylthio)carbonyl)oxy)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 93)

[0238] Step 1: Synthesis of O-(chloromethyl)S-methylthiocarbonate (Compound 93-2)

[0239] Chloromethyl chloroformate (500 mg, 3.87 mmol) and tetrahydrofuran (20.0 mL) were mixed, the temperature was lowered to 0°C, and sodium thiomethoxide (543 mg, 7.75 mmol) was added in portions. After the addition, the mixture was stirred at room temperature. LCMS detected that the reaction was complete. The reaction solution was directly used for the next reaction. MS [ESI]: m / z = 141.1, [M+H] + .

[0240] Step 2: Synthesis of (((methylthio)carbonyl)oxy)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 93)

[0241] 1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid (50.0 mg, 0.23 mmol) and DMF (2.0 mL) were mixed and the temperature was lowered to 0°C. Anhydrous potassium carbonate (64 mg, 0.46 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-methylthiocarbonate (39.3 mg, 0.28 mmol) in DMF (0.5 mL). The mixture was warmed to room temperature and reacted for 3 h. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (15 mg, 0.047 mmol, 20.3% yield). MS [ESI]: m / z = 321.2, [M+H] + ;

[0242] 1 H NMR (400MHz, CDCl3) δ7.84 (d, J=36.4Hz, 2H), 7.38–7.28 (m, 3H), 7.20 (d, J=7.9Hz, 2H), 6.30 (q, J= 7.0Hz, 1H), 5.94 (ddd, J = 33.7, 5.7, 1.3Hz, 2H), 2.37 (d, J = 1.4Hz, 3H), 1.87 (dd, J = 7.1, 0.9Hz, 3H).

[0243] Example 2: Preparation of (((ethylthio)carbonyl)oxy)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 94)

[0244] Step 1: Synthesis of O-(chloromethyl) S-ethyl thiocarbonate (Compound 94-2)

[0245] Chloromethyl chloroformate (4.0 g, 31.0 mmol) and diethyl ether (20.0 mL) were mixed, the temperature was lowered to 0°C, and ethanethiol (3.7 g, 62.0 mmol) and pyridine (2.4 g, 30.9 mmol) were added dropwise. After addition, the mixture was stirred at room temperature. LCMS confirmed that the reaction was complete, and the reaction solution was directly used for the next step. MS [ESI]: m / z = 155.2, [M+H] + .

[0246] Step 2: Synthesis of (((ethylthio)carbonyl)oxy)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 94)

[0247] 1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid (415 mg, 1.92 mmol) and DMF (10.0 mL) were mixed and the temperature was lowered to 0°C. Anhydrous potassium carbonate (531 mg, 3.84 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-ethylthiocarbonate (357 mg, 2.32 mmol) in DMF (3 mL). The mixture was warmed to room temperature and reacted for 3 h. The reaction solution was directly purified by Prep-HPLC to obtain the title compound (162 mg, 0.484 mmol, 25.2% yield). MS [ESI]: m / z = 335.1, [M+H] + ;

[0248] 1 H NMR (400MHz, CDCl3) δ7.90 (s, 2H), 7.39–7.30 (m, 3H), 7.21 (d, J = 7.1Hz, 2H), 6.32 (q, J = 6.9Hz, 1H) ,5.94(dd,J=30.8,5.7Hz,2H), 2.90(q,J=7.4Hz,2H), 1.88(d,J=7.0Hz,3H), 1.33(t,J=7.4Hz,3H).

[0249] Example 3: Preparation of (((isopropylthio)carbonyl)oxy)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 95)

[0250] Step 1: Synthesis of O-(chloromethyl)S-isopropylthiocarbonate (Compound 95-2)

[0251] Chloromethyl chloroformate (4.0 g, 31.0 mmol) and diethyl ether (20 mL) were mixed, the temperature was lowered to 0°C, and isopropyl mercaptan (4.6 g, 60.3 mmol) and pyridine (2.4 g, 30.9 mmol) were added dropwise. After addition, the mixture was stirred at room temperature. LCMS detected that the reaction was complete, and the reaction solution was directly used for the next reaction. MS [ESI]: m / z = 169.2, [M+H]+ .

[0252] Step 2: Synthesis of (((isopropylthio)carbonyl)oxy)methyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 95)

[0253] 1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid (497 mg, 2.30 mmol) and DMF (10.0 mL) were mixed and the temperature was lowered to 0°C. Anhydrous potassium carbonate (627 mg, 4.54 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-isopropylthiocarbonate (462 mg, 2.75 mmol) in DMF (5 mL). The mixture was warmed to room temperature and reacted for 3 h. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (216 mg, 0.620 mmol, 26.9% yield). MS [ESI]: m / z = 349.1, [M+H] + ;

[0254] 1 H NMR(400MHz, CDCl3)δ7.84(d,J=35.8Hz,2H),7.38–7.29(m,3H),7.20(d,J=6.9Hz,2H),6.30(q ,J=7.1Hz,1H),6.12-5.81(m,2H),3.62-3.38(m,1H),1.86(t,J=7.5Hz,3H),1.40–1.32(m,6H).

[0255] Example 4: Preparation of (((methylthio)carbonyl)oxy)methyl (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 1)

[0256] (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.46 mmol) and DMF (3.0 mL) were mixed and cooled to 0°C. Anhydrous potassium carbonate (128 mg, 0.92 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-methylthiocarbonate (77.0 mg, 0.56 mmol) in DMF (1 mL). The mixture was allowed to warm to room temperature and allowed to react for 3 h. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (45 mg, 0.14 mmol, 30.5% yield). MS [ESI]: m / z = 321.2, [M+H] + ;

[0257] 1H NMR (400MHz, CDCl3) δ7.90–7.78(m,2H),7.38–7.27(m,3H),7.22–7.17(m,2H),6.30 (q, J=7.1Hz, 1H), 5.94 (dd, J=33.7, 5.7Hz, 2H), 2.37 (s, 3H), 1.87 (d, J=7.1Hz, 3H).

[0258] Example 5: Preparation of (((ethylthio)carbonyl)oxy)methyl (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 2)

[0259] (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (415 mg, 1.92 mmol) and DMF (10 mL) were mixed and the temperature was lowered to 0°C. Anhydrous potassium carbonate (531 mg, 3.84 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-ethylthiocarbonate (357 mg, 2.32 mmol) in DMF (3 mL). The mixture was allowed to warm to room temperature and reacted for 3 h. The reaction solution was purified by Pre-HPLC to obtain the title compound (162 mg, 0.484 mmol, 25.2% yield). MS [ESI]: m / z = 335.1, [M+H] + ;

[0260] 1 H NMR(400MHz, CDCl3) δ7.86(d,J=38.0Hz,2H),7.38–7.27(m,3H),7.20(d,J=6.9Hz,2H),6.31(q,J=6.9Hz ,1H),5.94(dd,J=31.7,5.7Hz,2H),2.90(q,J=7.4Hz,2H),1.87(d,J=7.1Hz,3H),1.32(t,J=7.4Hz,3H).

[0261] Example 6: Preparation of (((isopropylthio)carbonyl)oxy)methyl (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 3)

[0262] (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid (497 mg, 2.30 mmol) and DMF (10.0 mL) were mixed and the temperature was lowered to 0°C. Anhydrous potassium carbonate (627 mg, 4.54 mmol) was added, followed by dropwise addition of a solution of O-(chloromethyl) S-isopropylthiocarbonate (462 mg, 2.75 mmol) in DMF (5.0 mL). The mixture was warmed to room temperature and reacted for 3 h. The reaction solution was directly purified by Pre-HPLC to obtain the title compound (216 mg, 0.62 mmol, 26.9% yield). MS [ESI]: m / z = 349.3, [M+H] + ;

[0263] 1 H NMR (400MHz, CDCl3) δ7.88(s,1H),7.79(s,1H),7.38–7.27(m,3H),7.20(dd,J=5.3,3.3Hz,2H),6.30(q,J=7.1Hz ,1H),5.92(dd,J=31.3,5.7Hz,2H),3.64-3.43(m,1H),2.01(s,1H),1.87(d,J=7.1Hz,3H),1.36(d,J=6.9Hz,6H).

[0264] Example 7: Preparation of ((((2-ethoxy-2-oxoethyl)thio)carbonyl)oxy)methyl (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 5)

[0265] (((2-Ethoxy-2-oxoethyl)thio)carbonyl)oxy)methyl 1H-imidazole-5-carboxylate (616.32 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL) were mixed and cooled to -20°C. (S)-1-(Phenyl)ethanol (262 mg, 2.14 mmol) was then added. After stirring for 10 minutes, a solution of di-tert-butyl azodicarboxylate (739.14 mg, 3.21 mmol) in diethyl ether (5 mL) was added dropwise. The atmosphere was purged with nitrogen and the mixture was stirred for 6 hours. After completion of the reaction, the mixture was returned to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / MTBE = 35 / 65) to obtain the title compound (470 mg, 1.35 mmol, 56.07% yield). MS [ESI]: m / z = 393.4, [M+H] + ;

[0266] 1H NMR (400MHz, CDCl3) δ7.87(d,J=0.8Hz,1H),7.77(s,1H),7.38-7.27(m,3H),7.21-7.17(m,2H),6.28(q,J=7.1Hz ,1H),5.94(dd,J=32.5,5.7Hz,2H),4.27-4.16(m,2H),3.69(s,2H),1.87(d,J=7.1Hz,3H),1.28(t,J=7.1Hz,3H).

[0267] Example 8: Preparation of ((isopropylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 28)

[0268] 5-Fluoro-3-((1R)-1-(2-fluorophenyl)ethyl)imidazole-4-carboxylic acid (50 mg, 198.24 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to obtain the title compound (45 mg, 117.07 μmol, 59.05% yield). MS [ESI]: m / z = 385.1, [M+H] + ;

[0269] 1 H NMR (400MHz, CDCl3) δ7.43(s,1H),7.32(ddd,J=15.2,5.3,1.7Hz,1H),7.13(dd,J=13.5,6.0Hz,1H),7.10-7.02(m,2H),6.40(q,J=7 .0Hz, 1H), 5.97 (d, J = 5.7Hz, 1H), 5.88 (d, J = 5.7Hz, 1H), 3.55 (dt, J = 13.7, 6.9Hz, 1H), 1.87 (d, J = 7.1Hz, 3H), 1.35 (d, J = 6.9Hz, 6H).

[0270] Example 9: Preparation of ((isopropylthio)carbonyl)oxy)methyl (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 96)

[0271] 3-((1R)-1-(3-Aminophenyl)ethyl)-5-fluoro-imidazole-4-carboxylic acid (100 mg, 401.22 μmol) was dissolved in DMF (3 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to obtain the title compound (56 mg, 146.82 μmol, yield 74.06%). MS [ESI]: m / z = 382.2, [M+H] + ;

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=1.7Hz,1H),6.96(t,J=7.8Hz,1H),6.44(dd,J=8.0,1.4Hz,1H),6.31(dd,J=10.7,4.8Hz,2H),5 .98-5.90(m,2H),5.86(d,J=6.2Hz,1H),5.10(s,2H),3.48(dt,J=13.7,6.8Hz,1H),1.76(d,J=7.2Hz,3H),1.30(d,J=6.9Hz,6H).

[0273] Example 10: Preparation of ((isopropylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 97)

[0274] 5-Fluoro-3-((1R)-1-(3-nitrophenyl)ethyl)imidazole-4-carboxylic acid (80 mg, 286.51 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to give the title compound (46 mg, 111.81 μmol, 56.40% yield). MS [ESI]: m / z = 412.2, [M+H] + ;

[0275] 1H NMR (400MHz, CDCl3) δ8.18(ddd,J=8.1,2.2,1.1Hz,1H),8.06(t,J=2.0Hz,1H),7.55(t,J=7.9Hz,2H),7.48(d,J=7.8Hz,1H),6.30(q,J =7.2Hz, 1H), 5.93 (d, J = 5.7Hz, 1H), 5.86 (d, J = 5.7Hz, 1H), 3.54 (dt, J = 13.8, 6.9Hz, 1H), 1.92 (d, J = 7.2Hz, 3H), 1.35 (d, J = 6.9Hz, 6H).

[0276] Example 11: Preparation of ((isopropylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 41)

[0277] 5-Fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (300 mg, 1.28 mmol) was dissolved in DMF (5 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to obtain the title compound (56 mg, 152.42 μmol, 76.89% yield). MS [ESI]: m / z = 368.1, [M+H] + ;

[0278] 1 H NMR(400MHz, CDCl3)δ8.59(dd,J=5.8,1.6Hz,1H),7.89-7.66(m,2H),7.37-7.11(m,2H),6.34(q,J=7.1Hz ,1H),5.93(dd,J=25.4,5.7Hz,2H),3.61-3.49(m,1H),1.91(d,J=7.1Hz,3H),1.35(dd,J=6.9,0.9Hz,6H).

[0279] Example 12: Preparation of ((isopropylthio)carbonyl)oxy)methyl 4-fluoro-1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 98)

[0280] 5-Fluoro-3-(1-(3-hydroxyphenyl)ethyl)imidazole-4-carboxylic acid (100 mg, 399.64 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to obtain the title compound (15 mg, 39.23 μmol, 19.79% yield). MS [ESI]: m / z = 383.1, [M+H] + ;

[0281] 1 H NMR (400MHz, CDCl3) δ7.41(s,1H),7.22(t,J=7.9Hz,1H),6.79(dd,J=6.8,4.0Hz,2H),6.62(s,1H),6.15(q,J=7.0 Hz, 1H), 5.93 (dd, J = 24.4, 5.7Hz, 2H), 3.55 (dt, J = 13.8, 6.9Hz, 1H), 1.82 (d, J = 7.1Hz, 3H), 1.35 (d, J = 6.9Hz, 6H).

[0282] Example 13: Preparation of ((isopropylthio)carbonyl)oxy)methyl (R)-1-(1-(4-cyanophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 31)

[0283] 3-((1R)-1-(4-Cyanophenyl)ethyl)-5-fluoro-imidazole-4-carboxylic acid (380 mg, 1.47 mmol) was dissolved in DMF (5 mL) and cooled to 0°C. Potassium carbonate (54.80 mg, 396.48 μmol) was added and stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to obtain the title compound (12 mg, 30.66 μmol, yield 15.46%). MS [ESI]: m / z = 392.1, [M+H] + ;

[0284] 1H NMR (400MHz, CDCl3) δ7.67-7.63(m,2H),7.54(d,J=1.4Hz,1H),7.24(d,J=8.2Hz,2H),6.22(q,J=7.2Hz,1H ), 5.88 (dd, J = 24.3, 5.7Hz, 2H), 3.53 (dq, J = 13.8, 6.9Hz, 1H), 1.88 (d, J = 7.2Hz, 3H), 1.35 (d, J = 6.9Hz, 6H).

[0285] Example 14: Preparation of ((isopropylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 25)

[0286] 5-Fluoro-3-((1R)-1-phenylethyl)imidazole-4-carboxylic acid (199.66 mg, 852.44 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (235.62 mg, 1.70 mmol) was added. Stirring was continued for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (172.51 mg, 1.02 mmol) was added dropwise in an ice bath. The reaction was allowed to proceed at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to afford the title compound (180 mg, 491.26 μmol, 57.63% yield). MS [ESI]: m / z = 367.1, [M+H] + ;

[0287] 1 H NMR (400MHz, CDCl3) δ7.40-7.31(m,4H),7.23-7.19(m,2H),6.21(q,J=7.0Hz,1H),5.93(dd,J =28.0, 5.7Hz, 2H), 3.55 (dt, J = 13.7, 6.9Hz, 1H), 1.85 (d, J = 7.1Hz, 3H), 1.36 (d, J = 6.9Hz, 6H).

[0288] Example 15: Preparation of ((isopropylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 99)

[0289] 5-Fluoro-3-((1R)-1-(3-fluorophenyl)ethyl)imidazole-4-carboxylic acid (100 mg, 396.48 μmol) was dissolved in DMF (1 mL), cooled to 0°C, and potassium carbonate (54.80 mg, 396.48 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-isopropylthiocarbonate (40.12 mg, 237.89 μmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to give the title compound (20 mg, 52.03 μmol, yield 26.25%). MS [ESI]: m / z = 385.4, [M+H] + ;

[0290] 1 H NMR (400MHz, CDCl3) δ7.41(s,1H),7.32(td,J=8.0,5.9Hz,1H),7.03-6.95(m,2H),6.91-6.86(m,1H),6.27(q,J=7. 1Hz, 1H), 5.35 (dd, J = 34.5, 12.2Hz, 2H), 3.13 (dq, J = 13.5, 6.8Hz, 1H), 1.84 (d, J = 7.1Hz, 3H), 1.31 (t, J = 6.0Hz, 6H).

[0291] Example 16: Preparation of ((methylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 100)

[0292] 5-Fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (325 mg, 1.38 mmol) was dissolved in DMF (8 mL), cooled to 0°C, and potassium carbonate (381.92 mg, 2.76 mmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-methylthiocarbonate (194.25 mg, 1.38 mmol) was added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-HPLC and lyophilized to give the title compound (50 mg, 147.34 μmol, 10.66% yield). MS [ESI]: m / z = 340.1, [M+H] + ;

[0293] 1H NMR (400MHz, CDCl3) δ8.61-8.58(m,1H),7.73(ddd,J=9.4,8.9,1.6Hz,2H),7.27(t,J=3.9Hz,1H),7 .25(s,1H),6.34(q,J=7.1Hz,1H),5.95(dd,J=28.0,5.7Hz,2H),2.36(s,3H),1.92(d,J=7.1Hz,3H).

[0294] Example 17: Preparation of ((methylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 101)

[0295] 5-Fluoro-3-((1R)-1-(p-Tolyl)ethyl)imidazole-4-carboxylic acid (100 mg, 402.82 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (111.34 mg, 805.63 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-methylthiocarbonate (67.96 mg, 483.38 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-TLC and pre-HPLC and lyophilized to afford the title compound (50 mg, 141.89 μmol, 35.23% yield). MS [ESI]: m / z = 353.1, [M+H] + ;

[0296] 1 H NMR (400MHz, CDCl3) δ7.34 (d, J=1.4Hz, 1H), 7.14 (dd, J=22.5, 8.1Hz, 4H), 6.17 (q, J=7. 0Hz, 1H), 5.96 (dd, J = 29.2, 5.7Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.82 (d, J = 7.1Hz, 3H).

[0297] Example 18: Preparation of ((methylthio)carbonyl)oxy)methyl (R)-4-fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 23)

[0298] 5-Fluoro-3-((1R)-1-phenylethyl)imidazole-4-carboxylic acid (102 mg, 435.48 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (120.37 mg, 870.95 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-methylthiocarbonate (73.47 mg, 522.57 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-TLC and pre-HPLC, and lyophilized to afford the title compound (80 mg, 236.44 μmol, 54.29% yield). MS [ESI]: m / z = 339.1, [M+H] + ;

[0299] 1 H NMR (400MHz, CDCl3) δ7.40-7.29(m,4H),7.24-7.18(m,2H),6.21(q,J=7.1Hz,1H),5.95(dd,J=30.5,5.7Hz,2H),2.37(s,3H),1.85(d,J=7.1Hz,3H).

[0300] Example 19: Preparation of ((methylthio)carbonyl)oxy)methyl (R)-1-(1-(4-cyanophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 102)

[0301] 3-((1R)-1-(4-Cyanophenyl)ethyl)-5-fluoro-imidazole-4-carboxylic acid (110 mg, 424.32 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (117.29 mg, 848.65 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-methylthiocarbonate (71.59 mg, 509.19 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-TLC and pre-HPLC and lyophilized to afford the title compound (66 mg, 181.64 μmol, 42.81% yield). MS [ESI]: m / z = 364.0, [M+H] + ;

[0302] 1H NMR (400MHz, CDCl3) δ7.67-7.63(m,2H),7.54(d,J=1.3Hz,1H),7.24(d,J=8.4Hz,2H),6.22(q, J=7.2Hz,1H),5.93(d,J=5.7Hz,1H),5.85(d,J=5.7Hz,1H),2.36(s,3H),1.88(d,J=7.2Hz,3H).

[0303] Example 20: Preparation of ((isopropylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 34)

[0304] 5-Fluoro-3-((1R)-1-(p-Tolyl)ethyl)imidazole-4-carboxylic acid (100 mg, 402.82 μmol) was dissolved in DMF (2 mL), cooled to 0°C, and potassium carbonate (111.34 mg, 805.63 μmol) was added. The mixture was stirred for 30 min. O-(chloromethyl) S-methylthiocarbonate (81.52 mg, 483.38 μmol) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the crude product was purified by pre-TLC and pre-HPLC and lyophilized to afford the title compound (35 mg, 92.00 μmol, 22.84% yield). MS [ESI]: m / z = 381.1, [M+H] + ;

[0305] 1 H NMR (400MHz, CDCl3) δ7.33 (d, J=1.6Hz, 1H), 7.14 (dd, J=21.5, 8.1Hz, 4H), 6.16 (q, J=7.0Hz, 1H), 5.94 (dd,J=26.6,5.7Hz,2H),3.63-3.29(m,1H),2.34(s,3H),1.82(d,J=7.1Hz,3H),1.36(d,J=6.9Hz,6H).

[0306] Example 21: Preparation of (R)-((isopropoxycarbonyl)oxy)methyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 88)

[0307] 5-Fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (100 mg, 0.42 mmol), chloromethyl isopropyl carbonate (194.60 mg, 1.28 mmol), potassium carbonate (293.79 mg, 2.13 mmol), and N,N-dimethylformamide (0.5 mL) were reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the crude product was separated by Pre-HPLC to obtain the title compound (26.16 mg, 0.074 mmol, yield 17.51%). MS [ESI]: m / z = 352.2, [M+H] + ;

[0308] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.3Hz,1H),8.16(d,J=1.6Hz,1H),7.79(td,J=7.7,1.7Hz,1H),7.33-7.24(m,2H),6.15(q ,J=7.2Hz,1H),5.80(d,J=6.2Hz,1H),5.76(d,J=6.1Hz,1H),4.85-4.74(m,1H),1.84(d,J=7.2Hz,3H),1.22(d,J=6.2Hz,6H).

[0309] Example 22: Preparation of ((isopropoxycarbonyl)oxy)methyl (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 46)

[0310] Reference Example 23 was synthesized by replacing 1-((1R)-1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid with (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.43 mmol) to obtain the title compound (135 mg, 0.39 mmol, yield 91.23%). MS [ESI]: m / z = 351.3, [M+H] + ;

[0311] 1H NMR(400MHz, DMSO-d6)δ8.35(s,1H),7.80(d,J=0.7Hz,1H),7.38-7.31(m,1H),7.23-7.13(m,2H),6.92(td,J=7.8,1.5Hz, 1H), 6.37 (q, J = 7.1Hz, 1H), 5.78 (dd, J = 19.4, 6.2Hz, 2H), 4.83-4.75 (m, 1H), 1.84 (d, J = 7.2Hz, 3H), 1.22 (d, J = 6.2Hz, 6H).

[0312] Example 23: Preparation of ((isopropoxycarbonyl)oxy)methyl (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 57)

[0313] 1-((1R)-1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.46 mmol) and potassium carbonate (318 mg, 2.30 mmol) were dissolved in DMF (2 mL), and chloromethyl isopropyl carbonate (586 mg, 3.84 mmol) was added and stirred for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified by preparative column chromatography (H2O / MeCN = 45 / 55) to give the title compound (175 mg, 0.53 mmol, 87.48% yield). MS [ESI]: m / z = 334.2, [M+H] + ;

[0314] 1 H NMR (400MHz, DMSO-d6) δ8.51-8.48(m,1H),8.33(s,1H),7.80-7.75(m,2H),7.29(ddd,J=7.5,4.8,0.8Hz,1H),7.20(d,J=7.9 Hz, 1H), 6.24 (q, J = 7.1Hz, 1H), 5.85-5.75 (m, 2H), 4.79 (dq, J = 12.5, 6.2Hz, 1H), 1.85 (d, J = 7.2Hz, 3H), 1.22 (d, J = 6.2Hz, 6H).

[0315] Example 24: Preparation of ((isobutoxycarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 106)

[0316] Synthesize Reference Example 21, using chloromethyl isobutyl carbonate (213 mg, 1.28 mmol) instead of chloromethyl isopropyl carbonate to obtain the title compound (111 mg, 0.30 mmol, yield 71.23%), MS [ESI]: m / z = 365.1, [M+H] + ;

[0317] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=4.4Hz,1H),8.19(d,J=1.4Hz,1H),7.82(td,J=7.7,1.7Hz,1H),7.34-7.23(m,2H),6 .19(q,J=7.1Hz,1H),5.82(dd,J=18.8,6.2Hz,2H),3.95(d,J=6.5Hz,2H),1.87(d,J=7.2Hz,3H),0.89(d,J=6.7Hz,6H).

[0318] Example 25: Preparation of ((ethylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 107)

[0319] Synthesis of Reference Example 26: 5-fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (13 mg, 0.056 mmol) was substituted for 5-fluoro-3-((1R)-1-phenylethyl)imidazole-4-carboxylic acid to give the title compound 107 (10 mg, 0.028 mmol, 50.41% yield). MS [ESI]: m / z = 354.0, [M+H] + ;

[0320] 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=4.2Hz,1H),8.19(d,J=1.6Hz,1H),7.82(td,J=7.7,1.8Hz,1H),7.36-7.28(m,2H),6 .18(q,J=7.2Hz,1H), 5.90(dd,J=19.6,6.2Hz,2H), 2.89(q,J=7.3Hz,2H), 1.87(d,J=7.2Hz,3H), 1.25(t,J=7.3Hz,3H).

[0321] Example 26: Preparation of ((ethylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-phenylethyl)-1H-imidazole-5-carboxylate (Compound 24)

[0322] 5-Fluoro-3-((1R)-1-phenylethyl)imidazole-4-carboxylic acid (100 mg, 0.427 mmol), O-(chloromethyl) S-ethyl thiocarbonate (98 mg, 0.640 mmol), potassium carbonate (88 mg, 0.640 mmol), and anhydrous DMF (4 mL) were mixed and reacted at room temperature for 4 h. After completion of the reaction, purified water (15 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL) and concentrated under reduced pressure. The crude product was purified by Pre-HPLC (acetonitrile / water = 45 / 55) to obtain the title compound (5 mg, 0.014 mmol, 32.78% yield). MS [ESI]: m / z = 353.1, [M+H] + ;

[0323] 1 H NMR(400MHz, DMSO-d6)δ8.23(d,J=1.7Hz,1H),7.38-7.31(m,2H),7.31-7.25(m,1H),7.23-7.17(m,2H),6.09(q, J=7.2Hz, 1H), 5.89 (dd, J=21.3, 6.2Hz, 2H), 2.87 (q, J=7.3Hz, 2H), 1.83 (d, J=7.2Hz, 3H), 1.23 (t, J=7.3Hz, 3H).

[0324] Example 27: Preparation of ((ethylthiocarbonyl)oxy)methyl (R)-4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 108)

[0325] 5-Fluoro-3-((1R)-1-(2-fluorophenyl)ethyl)imidazole-4-carboxylic acid (100 mg, 0.4 mmol), O-(chloromethyl) S-ethyl thiocarbonate (92 mg, 0.594 mmol), potassium carbonate (82 mg, 0.594 mmol), and anhydrous DMF (4 mL) were mixed and reacted at room temperature for 4 h. After completion of the reaction, purified water (15 mL) was added to the reaction solution, which was extracted with ethyl acetate (20 mL) and concentrated under reduced pressure. The crude product was purified by Pre-HPLC (acetonitrile / water = 45 / 55) to obtain the title compound (4 mg, 0.014 mmol, 25.25% yield). MS [ESI]: m / z = 371.0, [M+H] + ;

[0326] 1H NMR(400MHz, DMSO-d6)δ8.22(d,J=1.5Hz,1H),7.44-7.34(m,1H),7.28-7.16(m,2H),6.98(td,J=7.8,1.4Hz,1H),6.3 0(q,J=7.1Hz,1H),5.89(dd,J=22.3,6.2Hz,2H),2.88(q,J=7.3Hz,2H),1.85(d,J=7.2Hz,3H),1.25(t,J=7.3Hz,3H).

[0327] Example 28: Preparation of (R)-((isopropyloxycarbonyl)oxy)methyl 4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 77)

[0328] Synthesis Reference Example 23: 5-fluoro-3-((1R)-1-(2-fluorophenyl)ethyl)imidazole-4-carboxylic acid (48 mg, 0.19 mmol) was substituted for 5-fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid to give the title compound (38 mg, 0.10 mmol, yield 52.04%). MS [ESI]: m / z = 369.3, [M+H] + ;

[0329] 1 H NMR(400MHz, DMSO-d6)δ8.18(d,J=1.6Hz,1H),7.39-7.32(m,1H),7.25-7.14(m,2H),6.95(tt,J=13.5,6.7Hz,1H),6 .28(q,J=7.1Hz,1H),5.77(dd,J=20.8,6.2Hz,2H),4.83-4.73(m,1H),1.82(d,J=7.1Hz,3H),1.21(d,J=6.2Hz,6H).

[0330] Example 29: Preparation of (R)-((methoxycarbonyl)oxy)methyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 109)

[0331] Synthesize Reference Example 30 by replacing chloromethyl ethyl carbonate with chloromethyl methyl carbonate (159 mg, 1.28 mmol) to obtain the title compound (17 mg, 0.05 mmol, yield 15.46%), MS [ESI]: m / z = 324.3, [M+H] + ;

[0332] 1 H NMR (400MHz, CDCl3) δ8.62(d,J=4.0Hz,1H),7.78(d,J=1.6Hz,1H),7.71(td,J=7.7,1.8Hz,1H),7.29- 7.25(m,2H),6.36(q,J=7.1Hz,1H),5.95(dd,J=29.1,5.7Hz,2H),3.89(s,3H),1.93(d,J=7.1Hz,3H).

[0333] Example 30: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 110)

[0334] 5-Fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (100 mg, 0.42 mmol), chloromethyl ethyl carbonate (117.81 mg, 0.85 mmol), potassium carbonate (176.27 mg, 1.28 mmol), and N,N-dimethylformamide (0.5 mL) were mixed and reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the crude product was separated by Pre-HPLC to obtain the title compound (38.66 mg, 0.11 mmol, yield 26.96%). MS [ESI]: m / z = 338.1, [M+H] + ;

[0335] 1 H NMR (400MHz, DMSO-d6) δ8.53-8.46(m,1H),8.16(d,J=1.7Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.33-7.25(m,2H),6.15(q,J= 7.2Hz, 1H), 5.81 (d, J = 6.2Hz, 1H), 5.76 (d, J = 5.7Hz, 1H), 4.15 (q, J = 7.1Hz, 2H), 1.84 (d, J = 7.2Hz, 3H), 1.20 (t, J = 7.1Hz, 3H).

[0336] Experimental Example 1: LORR ED of Compounds in Mice or Rats 50 and LD 50 test

[0337] Accurately weigh the appropriate amount of test compound and add DMSO to a final volume of 5%. Once the compound is fully dissolved, add HS-15 to a final volume of 5%. Shake thoroughly, then add physiological saline to a final volume of 90%. Sonicate in an ultrasound machine for several minutes to create a homogeneous, clear solution. For mice, a fixed dosing concentration is used, and the dosing volume can be varied based on actual conditions.

[0338] Sequential method to measure LORR ED in mice 50 LD 50 Values ​​and rat LORR ED 50 Healthy and qualified ICR mice or SD rats (half male and half female) were selected for experimental administration. The drug was injected into the tail vein at a constant speed within 10 seconds. Five doses were explored for each compound, with 10 rats in each group. The efficacy and survival curves were fitted according to the number of anesthetized or dead animals, and the LORR ED was calculated. 50 or LD 50 The calculation formula of TI is: TI = LD 50 / ED 50 .

[0339] Experimental results: Compounds induce LORR in mice 50 LD 50 , TI index and LORR ED in rats 50 The test results are shown in Tables 1-3 below.

[0340] Table 1. Mouse LORR ED of Compounds 50 Test results (n=10)

[0341] Table 2. Mouse LORR ED of Compounds 50 LD 50 and TI index test results (n=10)

[0342] Table 3. Rat LORR ED of Compounds 50 Test results (n=10)

[0343] It can be seen that the compound of the present invention can exert an anesthetic effect on both mice and rats and has better safety.

[0344] Experimental Example 2: Determination of the anesthetic latency, duration, and recovery period of the compound in mice and rats

[0345] ICR mice or SD rats were divided into groups according to each test compound, with 10 mice in each group (half male and half female). The ED of mice or rats was obtained according to Experimental Example 1. 50 , using 3×ED 50The test drug was injected into the tail vein at a constant speed, and the injection was completed in 10 seconds. The anesthesia maintenance time (duration) and walking time (recovery period) were recorded.

[0346] The results of the anesthesia duration and recovery period of the compounds on mice and rats are shown in Tables 4-5 below.

[0347] Table 4. Results of the compound's effect on the duration of anesthesia and recovery period in mice (mg / kg, grouping method, n=10)

[0348] Table 5. Results of the determination of the duration of anesthesia of rats by the compounds (mg / kg, grouping method n=10)

[0349] The compound of the present invention can rapidly exert anesthetic effects in mice and rats, for example, the anesthetic effect takes effect within 1 second, and both exhibit shorter anesthesia duration and recovery time.

[0350] Experimental Example 3: Inhibitory effect of compounds on corticosterone secretion in rats

[0351] The degree of inhibition of rat corticosterone secretion by the compounds of the present invention was evaluated according to the method reported in the literature Carboetomidate: A Pyrrole Analog of Etomidate Designed Not to Suppress Adrenocortical Function, Joseph F. Cotton, et al., Anesthesiology 2010, Vol. 112(3): 637-644.

[0352] SD rats were selected and a negative control group and a test compound group were set up, with 10 rats in each group. 0.2 mg / kg dexamethasone (concentration of 0.04 mg / mL, administration volume of 5 mL / kg) was injected into the tail vein. 0.2 mg / kg dexamethasone was administered again 2 hours later, and blood was collected from the carotid artery to determine the basal value of serum corticosterone (corticosterone C 0min The test compound group was given the test compound (the compound of the present invention) according to the dosage in the table below, and the negative control group was not given any drug. Immediately thereafter, 25 μg / kg of ACTH1-24 (concentration of 5 μg / mL, administration volume of 5 mL / kg) was injected into the tail vein. Blood was collected from the carotid artery 15 minutes and 30 minutes later to measure the corticosterone concentration (corticosterone C 15min 、C 30min ).

[0353] The results of the test on the inhibition of rat corticosterone secretion by the compounds are shown in Table 6 below.

[0354] Table 6. Inhibition of the compounds on corticosterone secretion in rats

[0355] As can be seen from Table 6, the compounds of the present invention have no inhibitory effect on the secretion of corticosterone in rats, indicating that they have no significant inhibitory effect on the function of the adrenal cortex.

[0356] In summary, the compounds of the present invention not only have superior pharmacodynamics (i.e., the compounds of the present invention have better anesthetic activity, rapid onset, short duration and recovery time; have a better anesthetic index and good anesthetic stability), but also almost do not inhibit the secretion of cortisol and / or corticosterone, thus having both good anesthetic effect and safety, and the subjects have better blood pressure, heart rate, blood oxygen saturation and respiratory rate; the compounds of the present invention have no obvious inhibition on CYP enzymes, and the risk of drug interactions is lower; there is no risk of cardiac toxicity; the compounds of the present invention can be rapidly metabolized while taking effect quickly.

[0357] The above-described embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled form or polymorph thereof, wherein the compound has the structure of Formula I: in: L is O or S; 1) When L is S: R 1 is H or halogen; R 2 Selected from H, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 Each independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; 2) When L is 0: R 1 is H or halogen; R 2 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 Each independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N-(C 1-6 Alkyl)2; The condition is: when R 1 H, R 2 C 1-6 When X is alkyl, 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; when R 1 is halogen, X 1 、X 2 、X 3 、X 4 and X 5 When both are CH, R 2 Not ethyl or isopropyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: The compound has the structure of Formula II: Among them, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、X 5 and L as defined in claim 1.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: The compound has the structure of formula III-B1 or III-B2: in: R 1 is H or halogen; R 2 Selected from H, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 Each independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2.

4. The compound according to claim 3 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: One or more of the following conditions are met: i)R 1 is selected from H, fluorine, chlorine and bromine; ii) R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, cyano, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2; iii) R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3; iv) R 3 and R 4 Each independently is H or C 1-4 Alkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; v)R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; vi) R 3 and R 4 All are H; vii)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 each independently selected from H, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2; viii) Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl, pyridyl and pyrimidinyl groups are each independently optionally substituted with one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2; ix) is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 5. The compound according to any one of claims 3 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: One or more of the following conditions are met: 1) R 1 is selected from H, fluorine, chlorine and bromine; R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3; R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2; 2) R 1 is selected from H, fluorine, chlorine and bromine; R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, fluoroethyl, cyano and -CH2C(=O)OCH2CH3; R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 6. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance, or polymorph thereof, wherein: The compound has the structure of formula III-A1 or III-A2: in: R 1 is H or halogen; R 2 Selected from H, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N-(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-4 Alkyl and C 1-4 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 ; R 5 Each independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2; The condition is: when R 1 H, R 2 C 1-6 When X is alkyl, 1 、X 2 、X 3 、X 4 and X 5 Different from CH; when R 1 is halogen, X 1 、X 2 、X 3 、X 4 and X 5 When both are CH, R 2 Not ethyl or isopropyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: One or more of the following conditions are met: i)R 1 is selected from H, fluorine, chlorine and bromine; ii) R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2; iii) R 3 and R 4 Each independently is H or C 1-4 Alkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; iv) R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; v)R 3 and R 4 All are H; we) Selected from phenyl, pyridinyl, pyrimidinyl and The phenyl group is substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, -NH-CH3 and -N-(CH3)2; vii) is selected from the group consisting of phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 8. The compound according to any one of claims 6 to 7, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: One or more of the following conditions are met: 1) R 1 is H or halogen; R 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with one or more radicals selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 5 , and X 1 、X 2 、X 3 、X 4 and X 5 Not at the same time CH; R 5 Each independently selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N-(C 1-4 Alkyl)2; 2) R 1 is selected from H, fluorine, chlorine and bromine; R 2 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2; R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; is selected from the group consisting of 2-fluorophenyl, 2-hydroxyphenyl, 2-aminophenyl, 2-cyanophenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-fluorophenyl, 3-hydroxyphenyl, 3-aminophenyl, 3-cyanophenyl, 3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3) R 1 is H; R 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 1-6 The alkyl group is replaced by one or more selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Substituted by a cycloalkyl substituent, the C 3-6 Cycloalkyl is optionally substituted by one or more radicals selected from halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N-(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; R 3 and R 4 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 3 、R 4 Together with the attached carbon atom, it forms a 3-6 membered cycloalkyl group; is phenyl; 4) R 1 is H; R 2 Selected from fluoroethyl, hydroxymethyl, hydroxyethyl, -CH2CH2-N(CH3)2, -CH2CH2-NO2, -CH2CH2-OCH3, -CH2C(=O)OCH2CH3, -CH2CH(NH2)C(=O)OCH3 and -CH2CH=CH2; R 3 and R 4 are each independently H or methyl, or R 3 、R 4 Together with the attached carbon atom, it forms a cyclopropyl group; It is phenyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, wherein: The compound is selected from: Preferably, the compound is selected from:

10. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, and one or more pharmaceutically acceptable carriers.

11. Use of the compound according to any one of claims 1 to 9 or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, or the pharmaceutical composition according to claim 10, in the preparation of anesthetic drugs (especially intravenous anesthetic drugs) and sedative drugs.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled product or polymorph thereof, or a pharmaceutical composition according to claim 10, for use in anesthesia (particularly for intravenous anesthesia) and sedation.

13. A method of anesthesia (especially intravenous anesthesia) or sedation, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition according to claim 10.

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