Carboxylate compounds as well as preparation method therefor and use thereof

Abstract

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

Description

Carboxylic acid ester compounds and preparation methods and uses thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202410336386.7 filed on March 22, 2024, priority to Chinese patent application No. 202510172205.6 filed on February 17, 2025, and priority to Chinese patent application No. 202510185841.2 filed on February 19, 2025, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the field of pharmaceutical chemistry, and in particular to carboxylic acid ester compounds or pharmaceutically acceptable salts, stereoisomers, solvates, isotope-labeled substances or polymorphs thereof, preparation methods thereof, pharmaceutical compositions containing the same, and uses thereof. Background Art

[0004] 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.

[0005] 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.

[0006] 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 can be used not only for anesthesia induction but also for anesthesia maintenance. Summary of the Invention

[0007] 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.

[0008] 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 following structure:

[0009] in:

[0010] R 1 is halogen or H;

[0011] (1) When R 1 When it is a halogen:

[0012] 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, 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, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-14 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-NH-C(=O)OC 1-6 Alkyl, -C 1- 6-alkylene-N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl and -C 1-6 Alkylene-NH-C 1-6 substituted by an alkyl substituent;

[0013] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3, the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0014] R 3 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] (2) When R 1 When it is H:

[0016] 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, 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;

[0017] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X5 When both are CH, R 2 Not methyl;

[0018] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, halogen, C 6-10 Aryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-O-, 5-10 membered heteroaryl-C 1-6 Alkylene-NH- and C 6-10 Aryl-C 1-6 Alkylene-NH-.

[0019] On the other hand, the present application also provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of formula I described above in the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, and one or more pharmaceutically acceptable carriers.

[0020] On the other hand, the present application also provides a medicine kit comprising the compound of formula I described above in 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.

[0021] On the other hand, the present application also provides the use of the compound of formula I described above in 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, or the drug kit described above in the present application in the preparation of anesthetic drugs, especially intravenous anesthetic drugs and sedative drugs.

[0022] On the other hand, the present application also provides the compound of formula I described above in 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, or the medicine kit described above in the present application, for use as a medicine.

[0023] On the other hand, the present application also provides a compound of formula I as described above in the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition as described above in the present application, or a drug kit as described above in the present application, for use in anesthesia, especially intravenous anesthesia and sedation.

[0024] On the other hand, the present application also provides a method of anesthesia, especially intravenous anesthesia or sedation, comprising administering to a subject a therapeutically effective amount of a compound of Formula I as described above in the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or the pharmaceutical composition as described above in the present application, or the drug kit as described above in the present application.

[0025] On the other hand, the present application also provides a method for preparing the compound represented by formula I of the present application.

[0026] Definition and Description

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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 1-14 "Alkyl" refers to a straight or branched chain group having 1 to 14 carbon atoms. 1-12 "Alkyl" refers to a straight or branched chain group having 1 to 12 carbon atoms. 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 with one or more (e.g., 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 (n-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.

[0031] As used herein, the term "alkylene" refers to a divalent functional group derived from an alkyl group, wherein alkyl is as defined above.

[0032] 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.

[0033] As used herein, the term "alkyleneoxy" refers to a divalent functional group derived from an alkoxy group, wherein the alkoxy group is as defined above.

[0034] 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 1, 2 or 3) suitable substituents. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (including cyclic, bridged or spirocyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) having 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) ring carbon atoms, 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 (such as C 1- 6 alkyl), alkyl-S(=O) t -(For example, C 1-6 Alkyl-S(=O) t -), haloalkyl (e.g. halo C 1-6 alkyl), hydroxyalkyl, alkoxy (e.g. C 1-6 Alkoxy), alkylamino, alkylthio, haloalkoxy (e.g., halo C 1-6alkoxy), amino, aryl (e.g., phenyl, naphthyl, etc.), heteroaryl, alkenyl, cyano, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, C 3-10 Cycloalkyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido or alkoxyalkyl, etc., n and t are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For example, C 3-8 Cycloalkyl, C 3-6 Cycloalkyl.

[0035] 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, C 3-10 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] Examples of cycloalkyl groups further include, but are in no way 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] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, and "C 6-10"Aryl" refers to an all-carbon aromatic group containing 6-10 (e.g., 6, 7, 8, 9, 10) carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0044] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0045] The term "5-10 membered heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing about 5 to about 10 (e.g., 5, 6, 7, 8, 9, 10) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, 4) ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms. In another embodiment, the heteroaryl or heteroaryl ring is a monocyclic heteroaryl and has 5 or 6 ring atoms. In another embodiment, the heteroaryl or heteroaryl ring is a bicyclic heteroaryl. The heteroaryl group may be optionally substituted with one or more "ring system substituents," which may be the same or different and are as defined herein below. The heteroaryl group is attached through a ring carbon atom, and any nitrogen atom of the heteroaryl group may be optionally oxidized to the corresponding N-oxide. Any carbon atom of the heteroaryl group may be optionally oxidized to a corresponding N-oxide. The term "heteroaryl" also includes heteroaryl groups as defined above fused to heteroaryl, heterocyclyl, or cycloalkyl groups. Non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. In one embodiment, the heteroaryl group is a 5-membered heteroaryl group. In another embodiment, the heteroaryl group is a 6-membered heteroaryl group, for example, a 6-membered nitrogen-containing heteroaryl group.

[0046] The hydrogen in the groups involved in the present invention may be replaced by isotopes such as protium, deuterium, and tritium.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0053] 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.

[0054] 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). The radioactive isotope tritium (i.e., 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.

[0055] 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%).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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)).

[0063] 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.

[0064] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0065] This application is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated 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 herein and the accompanying structural formulas shall prevail. In this application, if a chemical name is inconsistent with a chemical structural formula, the chemical structural formula shall prevail.

[0066] Compound

[0067] One aspect of the present application provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof:

[0068] in:

[0069] R 1 is halogen or H;

[0070] (1) When R 1 When it is a halogen:

[0071] 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, 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, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-14 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-NH-C(=O)OC 1-6 Alkyl, -C 1- 6-alkylene-N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl and -C 1-6 Alkylene-NH-C 1-6 substituted by an alkyl substituent;

[0072] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0073] R 3 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;

[0074] (2) When R 1 When it is H:

[0075] 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, 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;

[0076] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0077] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, halogen, C 6-10 Aryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-O-, 5-10 membered heteroaryl-C 1-6 Alkylene-NH- and C 6-10 Aryl-C 1-6 Alkylene-NH-.

[0078] In some embodiments, the compound of formula I of the present application, wherein:

[0079] R 1 is halogen or H;

[0080] (1) When R 1 When it is a halogen:

[0081] 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6alkyl)2, -C(=O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-14 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-NH-C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl and -C 1-6 Alkylene-NH-C 1-6 substituted by an alkyl substituent;

[0082] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0083] R 3 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;

[0084] (2) When R 1 When it is H:

[0085] 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, C 1-6Alkoxy, 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 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0086] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0087] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, halogen, C 6-10 Aryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-C 1-6 Alkyleneoxy-, 5-10 membered heteroaryl-C 1-6 Alkylene-NH- and C 6-10 Aryl-C 1-6 In some embodiments, the compound of formula I of the present application, wherein:

[0088] (1) When R 1 When it is a halogen:

[0089] 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, 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 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0090] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0091] R 3 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;

[0092] (2) When R 1 When it is H:

[0093] 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, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)2, -C(=O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0094] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0095] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1- 6 haloalkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl and -N(C 1-6 Alkyl)2.

[0096] In some embodiments, the compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, has a structure of Formula II:

[0097] Among them, R 1 、R 2 、X 1 、X 2 、X 3 、X 4 and X 5 As defined in Formula I.

[0098] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein R 1 is H;

[0099] 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, 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 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0100] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein R 1 is H;

[0101] 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, 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 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0102] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein R 1 is H;

[0103] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, -C(=O)-C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0104] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0105] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -C(=O)-OC 1-4Alkyl, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH 3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH 3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2C H3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH (CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl substituents.

[0106] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0107] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C1-4 Haloalkoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH( CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH( CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3) , -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2 , -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2C H3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH (CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl substituents.

[0108] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 H; R 2 Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I, -CH2-C(=O)-OC(CH3)3 and -CH2CHF2.

[0109] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 H; R 2 Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I and -CH2CHF2.

[0110] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 H; R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2-C(=O)-OC(CH3)3 and isobutyl.

[0111] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 H; R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

[0112] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0113] X 1 Selected from CR 3 、N + -O - and N;

[0114] X 2 Selected from CR 3 and N;

[0115] X 3 Selected from CR 3 and N;

[0116] X 4 Selected from CR 3 ;

[0117] X 5 Selected from CR 3 and N;

[0118] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not a methyl group.

[0119] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0120] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6 cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogen, C 6-10 Aryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkyleneoxy- and C 6-10 Aryl-C 1-4 Alkyleneoxy-.

[0121] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0122] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6 cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and C 6-10 Aryl-C 1-4 Alkyleneoxy-.

[0123] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0124] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and phenyl-C 1-4 Alkyleneoxy-.

[0125] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0126] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(C H(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(C H2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH 2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2 CH3)(CH(CH3)CH2CH3), -N(CH2CH(CH3)2)2, F, Cl, Br, I, benzyloxy, phenoxy, -O-CH2CH2-phenyl and -O-CH(CH3)-phenyl.

[0127] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is H;

[0128] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH 3、 -N(CH3)2, F, Br and benzyloxy.

[0129] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R1 is H;

[0130] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -N(CH3)2, F and benzyloxy.

[0131] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0132] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl (e.g. C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl), -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1- 4 alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent.

[0133] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0134] R 2Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl (e.g. C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl), -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent.

[0135] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0136] R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more selected from H, halogen, hydroxyl, amino, cyano, 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 2-4 Alkenyl, C2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent.

[0137] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0138] R 2is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, isobutyl, sec-butyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, sec-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more groups selected from the group consisting of H, F, Cl, Br, I, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, - NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), - N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(C H3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2C -H2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, -CH2OH, -CH2CH2OH,-CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2CH2OH , -CH2CH2CH(OH)CH3, -CH2CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(CH3)CH2OH, -CH2C(CH3)2OH, -CHOHCH(CH 3)2, -CH(CH3)CH2CH2OH, -CH(CH3)CHOHCH3, -C(CH3)(OH)CH2CH3, -C(CH2OH)CH2CH3, -C(CH2OH)(CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2), 10CH3, methoxymethyl, tert-butoxycarbonyl, methoxyethyl, methoxy-n-propyl, methoxyisopropyl, methoxy-n-butyl, methoxyisobutyl, methoxy-tert-butyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, n-butyloxymethyl, isobutyloxymethyl, tert-butyloxymethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, ethoxypropyl, propoxypropyl, -N(CH3)(Boc), -N(CH3)-C(=O)O-isobutyl, -N(CH3)-C(=O)O-n-butyl, -N(CH3)-C(=O)O-isopropyl, -N(CH3)-C(=O)O-n-propyl, -N(CH3)-C(=O)O-ethyl, -N(CH 3) -C(=O)O-methyl, -N(CH2CH3)(Boc), -N(CH2CH2CH3)(Boc), -N(CH(CH3)2)(Boc), -N(n-butyl)(Boc), -N(isobutyl)(Boc), -N(tert-butyl)(Boc), -CH2NH(Boc), -CH2CH2NH(Boc), -CH(CH3)NH(Boc), -n-propyl-NH(Boc), -isopropyl-NH(Boc), -n-butyl-NH(Boc), -isobutyl-NH(Boc), -tert-butyl-NH(Boc), -CH2NH-C(=O)O-isobutyl, -CH2NH-C(=O)O-n-butyl , -CH2NH-C(=O)O-isopropyl, -CH2NH-C(=O)O-n-propyl, -CH2NH-C(=O)O-ethyl, -CH2NH-C(=O)O-methyl, -CH2N(CH3)(Boc), -CH2CH2N(CH3)(Boc), -CH(CH3)N(CH3)(Boc), -n-propyl-N(CH3)(Boc), -isopropyl-N(CH3)(Boc), -n-butyl-N(CH3)(Boc), -isobutyl-N(CH3)(Boc), -tert-butyl-N(CH3)(Boc), -CH2N(CH3)-C(=O)O-isobutyl, -CH2N(CH3)-C(= O) O-n-butyl, -CH2N(CH3)-C(=O)O-isopropyl, -CH2N(CH3)-C(=O)O-n-propyl, -CH2N(CH3)-C(=O)O-ethyl, -CH2N(CH3)-C(=O)O-methyl, -CH2N(CH2CH3)(Boc), -CH2N(CH2CH2CH3)(Boc), -CH2Br, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3, -CBr(CH3)2, -CH2CH2CH2CH2Br, -CH2CH2F, -CHFCH3, -CH2F,-CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CF(CH3)2, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CCl(CH3)2, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH(CH3)NHCH3, -CH(CH3)2NHCH3, -CH(CH3)CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -CH2NHCH(CH3)2, -CF3, -C H2CF3, -CH2CH2CF3, -CH(CF3)CH3, -CH2CH2CH2CF3, -CH(CH3)CH2CF3, -C(CH3)2CF3, -CH2CH(CF3)CH3, -CH(CF3)CH2CH3, -C(CF3)(CH3)2, -CH2I, -CH2CH2I, -CHICH3, -CH2CH2CH2I, -CH2CHICH3, -CHICH2CH3, -CI(CH3)2, -CHF2, -CH2CHF2, -CF2CH3, -CH2CH2CHF2, -CH2CF2CH3, -CF2CH2CH3 and -CH2CF2(CH3) substituents. ,

[0139] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0140] R 2is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, isobutyl, sec-butyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, sec-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more groups selected from the group consisting of H, F, Cl, Br, I, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, - NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), - N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(C H3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2C -H2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, -CH2OH, -CH2CH2OH,-CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2CH2OH, -CH2CH2CH(OH)CH3, -CH2CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(CH3)CH2OH, -CH2C(CH3)2OH, -CHOHCH(CH3)2, -CH(CH3)CH2CH2OH, -CH(CH3)CHOHCH3, -C(CH3)(OH)CH2CH3, -C(CH2OH)CH2CH, 3、 -C(CH2OH)(CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10CH3, methoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, methoxy-n-butyl, methoxy-isobutyl, methoxy-tert-butyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, n-butyloxymethyl, isobutyloxymethyl, tert-butyloxymethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, ethoxypropyl, propoxypropyl, -N(CH3)(Boc), -N(CH3)-C(=O)O-isobutyl, -N(CH3)-C(=O)O-n-butyl, -N(CH3)-C(=O)O-isopropyl, -N(CH3)-C(=O)O-n-propyl, -N(CH3)-C(=O)O-ethyl, -N(CH3)-C(=O) O-methyl, -N(CH2CH3)(Boc), -N(CH2CH2CH3)(Boc), -N(CH(CH3)2)(Boc), -N(n-butyl)(Boc), -N(isobutyl)(Boc), -N(tert-butyl)(Boc), -CH2NH(Boc), -CH2CH2NH(Boc), -CH(CH3)NH(Boc), -n-propyl-NH(Boc), -isopropyl-NH(Boc), -n-butyl-NH(Boc), -isobutyl-NH(Boc), -tert-butyl-NH(Boc), -CH2NH-C(=O)O-isobutyl, -CH2NH-C(=O)O-n-butyl, -CH2NH-C (=O)O-isopropyl, -CH2NH-C(=O)O-n-propyl, -CH2NH-C(=O)O-ethyl, -CH2NH-C(=O)O-methyl, -CH2N(CH3)(Boc), -CH2CH2N(CH3)(Boc), -CH(CH3)N(CH3)(Boc), -n-propyl-N(CH3)(Boc), -isopropyl-N(CH3)(Boc), -n-butyl-N(CH3)(Boc), -isobutyl-N(CH3)(Boc), -tert-butyl-N(CH3)(Boc), -CH2N(CH3)-C(=O)O-isobutyl, -CH2N(CH3)-C(=O)O-n-butyl, -CH 2N(CH3)-C(=O)O-isopropyl, -CH2N(CH3)-C(=O)O-n-propyl, -CH2N(CH3)-C(=O)O-ethyl, -CH2N(CH3)-C(=O)O-methyl, -CH2N(CH2CH3)(Boc), -CH2N(CH2CH2CH3)(Boc), -CH2Br, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3, -CBr(CH3)2, -CH2CH2CH2CH2Br, -CH2CH2F, -CHFCH3, -CH2F, -CH2CH2CH2F,-CH2CHFCH3, -CHFCH2CH3, -CF(CH3)2, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CCl(CH3)2, -CH2NHCH3, -CH2CH2NH CH3, -CH2CH2CH2NHCH3, -CH2CH(CH3)NHCH3, -CH(CH3)2NHCH3, -CH(CH3)CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -CH2NHCH(CH3)2, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)CH3, -CH2CH2CH2CF3, -CH(CH3)CH2CF3, -C(CH3)2CF3, -CH2CH(CF3)CH3, -CH(CF3)CH2CH3, -C(CF3)(CH3)2, -CH2I, -CH2CH2I, -CH Substituted with ICH3, -CH2CH2CH2I, -CH2CHICH3, -CHICH2CH3, -CI(CH3)2, -CHF2, -CH2CHF2, -CF2CH3, -CH2CH2CHF2, -CH2CF2CH3, -CF2CH2CH3 and -CH2CF2(CH3). ,

[0141] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0142] R 2Selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2B r, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I, -CH2-C(=O)-OC(CH3)3 and -CH2CHF2.

[0143] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0144] R 2 Selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), - CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2.

[0145] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 selected from the group consisting of F, Cl, Br and I;

[0146] R 2is selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, n-hexyl, -CH2CH2F, -CH2CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2.

[0147] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0148] X 1 Selected from CR 3 、N + -O - and N;

[0149] X 2 Selected from CR 3 and N;

[0150] X 3 Selected from CR 3 and N;

[0151] X 4 CR 3 ;

[0152] X 5 Selected from CR 3 and N;

[0153] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time.

[0154] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0155] R 3Each 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.

[0156] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0157] R 3 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.

[0158] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen;

[0159] R 3each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, -NH-CH3, -NH-CH2-CH3, -NH-( CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2) (CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH 2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH 3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2.

[0160] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein: R 1 is a halogen, such as F, Cl, Br and I;

[0161] R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0162] In some embodiments, in the compounds of Formula I and Formula II of the present application, wherein,

[0163] R 1is H;

[0164] 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, 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 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0165] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0166] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6 cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogen, C 6-10 Aryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkyleneoxy- and C 6-10 Aryl-C1-4 Alkyleneoxy-.

[0167] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0168] R 1 is H;

[0169] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4Haloalkoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NHCH-(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH( CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH( CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3) , -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2 , -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2C H3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl substituents;

[0170] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0171] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6 cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and C 6-10 Aryl-C 1-4 Alkyleneoxy-.

[0172] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0173] R 1 is H;

[0174] R 2 Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I and -CH2CHF2;

[0175] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0176] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, methoxy, ethyl, isopropyl, cyclopropyl, C1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and phenyl-C 1-4 Alkyleneoxy-.

[0177] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0178] R 1 is H;

[0179] R 2 Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I and -CH2CHF2;

[0180] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0181] R 3Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NHCH-(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(C H(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(C H2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH 2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2 CH3)(CH(CH3)CH2CH3), -N(CH2CH(CH3)2)2, F, Cl, Br, I, benzyloxy, phenoxy, -O-CH2CH2-phenyl and -O-CH(CH3)-phenyl.

[0182] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0183] R 1 is H;

[0184] R 2 Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I and -CH2CHF2;

[0185] X 1 Selected from CR 3 、N + -O - and N;

[0186] X 2 Selected from CR 3 and N;

[0187] X 3 Selected from CR 3 and N;

[0188] X 4 Selected from CR 3 ;

[0189] X 5 Selected from CR 3 and N;

[0190] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0191] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH 3、 -N(CH3)2, F, Br and benzyloxy.

[0192] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0193] R 1 is H;

[0194] R 2 selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

[0195] X 1 Selected from CR 3 、N + -O - and N;

[0196] X 2 Selected from CR 3 and N;

[0197] X 3 Selected from CR 3 and N;

[0198] X 4 Selected from CR 3 ;

[0199] X 5 Selected from CR 3 and N;

[0200] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0201] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -N(CH3)2, F, Br and benzyloxy.

[0202] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0203] R 1 is a halogen;

[0204] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl (e.g. C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl), -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC1-4 Alkyl, -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent;

[0205] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0206] R 3 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.

[0207] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0208] R 1 is a halogen;

[0209] R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more selected from H, halogen, hydroxyl, amino, cyano, 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 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C1-4 Alkyl, C 1-12 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent;

[0210] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0211] R 3 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.

[0212] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0213] R 1 is a halogen;

[0214] R 2is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, isobutyl, sec-butyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, sec-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more groups selected from the group consisting of H, F, Cl, Br, I, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, - NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), - N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(C H3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2C -H2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, -CH2OH, -CH2CH2OH,-CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2CH2OH, -CH2CH2CH(OH)CH3, -CH2CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(CH3)CH2OH, -CH2C(CH3)2OH, -CHOHCH(CH3)2, -CH(CH3)CH2CH2OH, -CH(CH3)CHOHCH3, -C(CH3)(OH)CH2CH3, -C(CH2OH)CH2CH, 3、 -C(CH2OH)(CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10CH3, methoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, methoxy-n-butyl, methoxy-isobutyl, methoxy-tert-butyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, n-butyloxymethyl, isobutyloxymethyl, tert-butyloxymethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, ethoxypropyl, propoxypropyl, -N(CH3)(Boc), -N(CH3)-C(=O)O-isobutyl, -N(CH3)-C(=O)O-n-butyl, -N(CH3)-C(=O)O-isopropyl, -N(CH3)-C(=O)O-n-propyl, -N(CH3)-C(=O)O-ethyl, -N(CH3)-C(=O) O-methyl, -N(CH2CH3)(Boc), -N(CH2CH2CH3)(Boc), -N(CH(CH3)2)(Boc), -N(n-butyl)(Boc), -N(isobutyl)(Boc), -N(tert-butyl)(Boc), -CH2NH(Boc), -CH2CH2NH(Boc), -CH(CH3)NH(Boc), -n-propyl-NH(Boc), -isopropyl-NH(Boc), -n-butyl-NH(Boc), -isobutyl-NH(Boc), -tert-butyl-NH(Boc), -CH2NH-C(=O)O-isobutyl, -CH2NH-C(=O)O-n-butyl, -CH2NH-C (=O)O-isopropyl, -CH2NH-C(=O)O-n-propyl, -CH2NH-C(=O)O-ethyl, -CH2NH-C(=O)O-methyl, -CH2N(CH3)(Boc), -CH2CH2N(CH3)(Boc), -CH(CH3)N(CH3)(Boc), -n-propyl-N(CH3)(Boc), -isopropyl-N(CH3)(Boc), -n-butyl-N(CH3)(Boc), -isobutyl-N(CH3)(Boc), -tert-butyl-N(CH3)(Boc), -CH2N(CH3)-C(=O)O-isobutyl, -CH2N(CH3)-C(=O)O-n-butyl, -CH 2N(CH3)-C(=O)O-isopropyl, -CH2N(CH3)-C(=O)O-n-propyl, -CH2N(CH3)-C(=O)O-ethyl, -CH2N(CH3)-C(=O)O-methyl, -CH2N(CH2CH3)(Boc), -CH2N(CH2CH2CH3)(Boc), -CH2Br, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3, -CBr(CH3)2, -CH2CH2CH2CH2Br, -CH2CH2F, -CHFCH3, -CH2F, -CH2CH2CH2F,-CH2CHFCH3, -CHFCH2CH3, -CF(CH3)2, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CCl(CH3)2, -CH2NHCH3, -CH2CH2NHC H3, -CH2CH2CH2NHCH3, -CH2CH(CH3)NHCH3, -CH(CH3)2NHCH3, -CH(CH3)CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -CH2NHCH(CH3)2, -CF3, -CH2CF3, - CH2CH2CF3, -CH(CF3)CH3, -CH2CH2CH2CF3, -CH(CH3)CH2CF3, -C(CH3)2CF3, -CH2CH(CF3)CH3, -CH(CF3)CH2CH3, -C(CF3)(CH3)2, -CH2I, -CH2CH2I, -CHI Substituted with substituents of CH3, -CH2CH2CH2I, -CH2CHICH3, -CHICH2CH3, -CI(CH3)2, -CHF2, -CH2CHF2, -CF2CH3, -CH2CH2CHF2, -CH2CF2CH3, -CF2CH2CH3 and -CH2CF2(CH3);,

[0215] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0216] R 3 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.

[0217] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0218] R 1 is a halogen;

[0219] R 2 Selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), - CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2;

[0220] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0221] R 3 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.

[0222] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0223] R 1 is a halogen;

[0224] R 2Selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), - CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2;

[0225] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0226] R 3each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, -NH-CH3, -NH-CH2-CH3, -NH-( CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2) (CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH 2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH 3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2.

[0227] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0228] R 1 is a halogen;

[0229] R 2Selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), - CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2;

[0230] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0231] R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0232] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0233] R 1 is F;

[0234] R 2is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, n-hexyl, cyclopropyl, -CH2-C(=O)-OC(CH3)3, -CH2CH2F, -CH2CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2;

[0235] X 1 Selected from CR 3 、N + -O - and N;

[0236] X 2 Selected from CR 3 and N;

[0237] X 3 Selected from CR 3 and N;

[0238] X 4 Selected from CR 3 ;

[0239] X 5 Selected from CR 3 and N;

[0240] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0241] R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0242] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0243] R 1 is F;

[0244] R 2 is selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, n-hexyl, -CH2CH2F, -CH2CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2;

[0245] X 1 Selected from CR 3 、N + -O - and N;

[0246] X 2 Selected from CR 3 and N;

[0247] X 3 Selected from CR 3 and N;

[0248] X 4 Selected from CR 3 ;

[0249] X 5 Selected from CR 3 and N;

[0250] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0251] R 3Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0252] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0253] When R 1 When it is H:

[0254] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0255] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0256] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1- 4 haloalkyl, C 1-4 Haloalkoxy, -NH-C 1-4Alkyl and -N(C 1-4 Alkyl)2.

[0257] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0258] When R 1 When it is H:

[0259] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4Haloalkoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH( CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH( CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3) , -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2 , -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2C H3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl substituents;

[0260] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0261] R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1- 4 haloalkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2.

[0262] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0263] When R 1 When it is H:

[0264] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl and isobutyl;

[0265] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0266] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl and -N(C 1-4 Alkyl)2.

[0267] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0268] When R 1 When it is H:

[0269] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl and isobutyl;

[0270] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0271] R 3each independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2 CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), - N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)( CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(C H3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2.

[0272] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0273] When R 1 When it is H:

[0274] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl and isobutyl;

[0275] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0276] R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0277] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0278] When R 1 When it is H:

[0279] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl and isobutyl;

[0280] X 1 Selected from CR 3 、N + -O - and N;

[0281] X 2 Selected from CR 3 and N;

[0282] X 3 Selected from CR 3 and N;

[0283] X 4 Selected from CR 3 ;

[0284] X 5 Selected from CR 3 and N;

[0285] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl;

[0286] R 3Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0287] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0288] When R 1 When it is a halogen:

[0289] R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0290] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0291] R 3 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.

[0292] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0293] When R 1 When it is a halogen:

[0294] R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more selected from H, halogen, hydroxyl, amino, cyano, 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 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent;

[0295] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0296] R 3 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.

[0297] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0298] When R 1 When it is a halogen:

[0299] R 2is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, -NH-CH3, - NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH 2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N( CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH( CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)( substituted with a substituent selected from the group consisting of CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH(CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl;

[0300] X1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0301] R 3 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.

[0302] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0303] When R 1 When it is a halogen:

[0304] R 2 selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl and isobutyl;

[0305] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0306] R 3 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.

[0307] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0308] When R 1 When it is a halogen:

[0309] R 2 selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl and isobutyl;

[0310] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0311] R 3each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, -NH-CH3, -NH-CH2-CH3, -NH-( CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2) (CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH 2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH 3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2.

[0312] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0313] When R 1 When it is a halogen:

[0314] R 2 is selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, -CH2-C(=O)-OC(CH3)3 and isobutyl;

[0315] X 1 、X 2 、X 3 、X 4 and X 5Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0316] R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0317] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0318] When R 1 When it is a halogen:

[0319] R 2 selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl and isobutyl;

[0320] X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0321] R 3 Each is independently selected from H, F, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0322] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0323] When R 1 When it is F:

[0324] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isopropyl and isobutyl;

[0325] X 1 Selected from CR 3 、N+ -O - and N;

[0326] X 2 Selected from CR 3 and N;

[0327] X 3 Selected from CR 3 and N;

[0328] X 4 Selected from CR 3 ;

[0329] X 5 Selected from CR 3 and N;

[0330] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0331] R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0332] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0333] When R 1 When it is F:

[0334] R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, isopropyl and isobutyl;

[0335] X 1 Selected from CR 3 、N + -O - and N;

[0336] X 2 Selected from CR 3 and N;

[0337] X 3 Selected from CR 3 and N;

[0338] X 4 Selected from CR 3 ;

[0339] X 5 Selected from CR 3 and N;

[0340] The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time;

[0341] R 3 Each is independently selected from H, F, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2.

[0342] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0343] is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, 2-fluorophenyl, 3-fluorophenyl, 3-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-benzyloxy, 2-methylphenyl, 2-ethylphenyl, 2-cyclopropylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,

[0344] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0345] is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-benzyloxy, 2-methylphenyl, 2-ethylphenyl, 2-cyclopropylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,

[0346] In some embodiments, the compounds of Formula I and Formula II of the present application, wherein:

[0347] is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, 2-fluorophenyl, 3-fluorophenyl, 3-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,

[0348] In some embodiments, the compound of the present invention is selected from:

[0349] In some embodiments, the compound of the present invention is selected from:

[0350] In some embodiments, the pharmaceutically acceptable salt of the compound of the present invention is a hydrochloride salt, such as the hydrochloride salt of Compound 53 and the hydrochloride salt of Compound 215.

[0351] The compounds of the present application may be substituted with suitable substituents at any substitutable position.

[0352] The present application covers 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.

[0353] Preparation method of compound

[0354] The present application provides a method for preparing a compound of formula I, which comprises reacting a compound of formula I-1 with a compound of formula I-2 to obtain a compound of formula I.

[0355] Among them, X 1 、X 2 、X 3 、X 4 、X 5 、R 1 and R2 As defined above.

[0356] In some embodiments, the suitable reaction is performed in the presence of Ph3P and DBAD or DEAD.

[0357] In some embodiments, the suitable reaction temperature is -30°C to 70°C.

[0358] In some embodiments, the molar ratio of the compound of formula I-1 to the compound of formula I-2 is (1-15):1, for example, the molar ratio of the compound of formula I-1 to the compound of formula I-2 is (1-10):1, for example, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, for example, 1.5:1, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1.

[0359] Pharmaceutical compositions and kits

[0360] Another object of the present application is to provide a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound represented by Formula I described above in the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph, and one or more pharmaceutically acceptable carriers.

[0361] Another object of the present application is to provide a medicine kit comprising the compound of formula I described in the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or the pharmaceutical composition of the present application, and optionally, the medicine kit further comprises instructions for use.

[0362] 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.

[0363] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition described herein include, but are not limited to, sterile liquids. The pharmaceutical composition can be in the form of, for example, a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.

[0364] Pharmaceutical composition described herein can act systemically and / or locally.For this purpose, they can be administered by the approach that is suitable for, for example, administration is by parenteral route, for example, by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal route administration, preferably, described administration is for administration by intravenous route.

[0365] The compound described herein may be present in a pharmaceutical composition in an amount of about 0.001 mg to about 5000 mg, preferably 0.01-1000 mg.

[0366] In some embodiments, the present application provides a method for preparing the pharmaceutical composition described above in the present application, which comprises combining the present application or its pharmaceutically acceptable salts, stereoisomers, solvates, isotope labels or polymorphs with one or more pharmaceutically acceptable carriers.

[0367] Treatment methods and uses

[0368] The present application also provides the use of the compound represented by Formula I described above in 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 anesthetic drugs, especially intravenous anesthetic drugs.

[0369] The present application also provides the use of the compound represented by Formula I described above in 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.

[0370] The present application also provides the compound represented by Formula I described above in 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, or the medicine kit described above in the present application, for use as a medicine.

[0371] The present application also provides a compound represented by Formula I as described above in the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition as described above in the present application, or a drug kit as described above in the present application, for use in anesthesia, particularly intravenous anesthesia.

[0372] The present application also provides a compound represented by Formula I as described above in the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or a pharmaceutical composition as described above in the present application, or a drug kit as described above in the present application, for use in sedation.

[0373] The present application also provides a method of anesthesia, particularly intravenous anesthesia, comprising administering to a subject an effective amount of the compound of formula I as described above in the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or the pharmaceutical composition as described above in the present application, or the drug kit as described above in the present application.

[0374] The present application also provides a method of sedation, comprising administering to a subject an effective amount of the compound represented by Formula I as described above in the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled substance or polymorph thereof, or the pharmaceutical composition as described above in the present application, or the drug kit as described above in the present application.

[0375] As used herein, the term "effective amount" refers to an amount sufficient to induce or maintain anesthesia or sedation when administered to a mammal. 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.

[0376] 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.

[0377] 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.

[0378] 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.). DETAILED DESCRIPTION

[0379] 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.

[0380] The structures of the compounds in all examples were determined by NMR ( 1H-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.

[0381] 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); benzyl chloroformate (CbzCl); benzyloxycarbonyl (Cbz); methoxymethyl (MOM); diethyl azodicarboxylate (DEAD); triethylamine (TEA); N,N-dimethylformamide (DMF); tert-butyloxycarbonyl (Boc); m-chloroperbenzoic acid (m-CPBA); diethyl ether (Et2O); palladium on carbon (Pd / C); acetonitrile (ACN, or MeCN); sodium cyanoborohydride (NaBH3CN); triphenylphosphine (PPh3); dimethyl sulfoxide (DMSO).

[0382] Preparation method for preparative high performance liquid chromatography:

[0383] 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.

[0384] 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.

[0385] 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.

[0386] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0387] 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.

[0388] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 35°C);

[0389] The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.

[0390] Example 1: Preparation of (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 17)

[0391] To a dry three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 1H-imidazole-5-carboxylate (113 mg, 0.81 mmol), and tetrahydrofuran (3 mL) were added, and the atmosphere was replaced with nitrogen three times. The temperature was lowered to -10°C, and a solution of (S)-1-(pyridin-2-yl)ethanol (100 mg, 0.81 mmol) in tetrahydrofuran and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in tetrahydrofuran were added sequentially. The mixture was allowed to react at -30°C for 4 hours. LCMS confirmed the complete reaction of the starting material. The reaction was quenched with water and extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to afford the title compound (106 mg, 0.43 mmol, 53.3% yield). MS [ESI]: m / z = 263.2, [M+NH3] + ;

[0392] 1H NMR (400MHz, CDCl3) δ8.58(dd,J=4.8,0.8Hz,1H),8.03(s,1H),7.77(s,1H),7.63(td,J=7.7,1.8Hz,1H),7.20(ddd,J=7.6,4.8,1. 0Hz, 1H), 7.13 (d, J = 7.8Hz, 1H), 6.46 (q, J = 7.1Hz, 1H), 4.27 (qq, J = 10.8, 7.1Hz, 2H), 1.91 (d, J = 7.2Hz, 3H), 1.31 (t, J = 7.1Hz, 3H).

[0393] Example 2: Preparation of (R)-ethyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 47)

[0394] To a 100 mL round-bottom flask, ethyl 4-fluoro-1H-imidazole-5-carboxylate (500 mg, 3.16 mmol), triphenylphosphine (1.66 g, 6.32 mmol), and tetrahydrofuran (10 mL) were added and cooled to -20°C. (S)-1-(pyridin-2-yl)ethanol (389 mg, 3.16 mmol) was then added and stirred for 10 minutes. A solution of di-tert-butyl azodicarboxylate (1.46 g, 6.32 mmol) in tetrahydrofuran (5 mL) was then added dropwise. The atmosphere was purged with nitrogen three times and stirred for 6 hours. The reaction was complete by LCMS. The mixture was returned to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / MTBE = 2 / 1) to afford the title compound (380 mg, 1.44 mmol). MS [ESI]: m / z = 264.2, [M+H] + ;

[0395] 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.0Hz,1H),8.07(d,J=1.6Hz,1H),7.79(td,J=7.6,1.6Hz,1H),7.3 5-7.16(m,2H),6.19(q,J=7.2Hz,1H),4.23–4.05(m,2H),1.83(d,J=7.2Hz,3H),1.16(t,J=7.2Hz,3H).

[0396] Example 3: Preparation of 1-[1-(4-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 57-rac)

[0397] Step 1: Synthesis of 4-acetylphenyl benzyl carbonate (Compound 57-rac-2)

[0398] To a 100 mL reaction flask, add p-hydroxyacetophenone (2.0 g, 14.69 mmol), benzyl chloroformate (3.76 g, 22.03 mmol), DMF (20 mL), and triethylamine (4.46 g, 44.07 mmol). The mixture was allowed to react overnight at room temperature. LC-MS confirmed the reaction was complete. Purified water (15 mL) was added to the reaction solution, which was extracted three times with ethyl acetate (20 mL x 3). After extraction, the mixture was concentrated under reduced pressure to obtain the title compound (3.97 g, 14.69 mmol, equivalent yield). MS: m / z = 271.2, [M+H] + .

[0399] Step 2: Synthesis of benzyl (4-(1-hydroxyethyl)phenyl) carbonate (compound 57-rac-3)

[0400] To the product of step 1 (3.97 g, 14.69 mmol), anhydrous methanol (30 mL) was added and the temperature was lowered to 0°C. Sodium borohydride (850 mg, 22.47 mmol) was slowly added and the reaction was allowed to react at room temperature for 3 h. TLC confirmed the reaction was complete. The pH was adjusted to 5 with 2N hydrochloric acid. The reaction solution was concentrated under reduced pressure to dryness, ethyl acetate (20 mL) was added, stirred for 10 min, and filtered. The filter cake was discarded and the filtrate was concentrated under reduced pressure to obtain the title compound (4 g, 14.69 mmol, equivalent yield). MS: m / z = 255.2, [M-17] + .

[0401] Step 3: Synthesis of ethyl 1-(1-(4-((benzyloxy)carbonyl)oxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 57-rac-4)

[0402] To the product of step 2 (4g, 14.69mmol), tetrahydrofuran (15mL), ethyl imidazole-4-carboxylate (1.58mg, 11.27mmol), and triphenylphosphine (3.85g, 14.68mmol) were added and stirred and cooled to 0°C. A solution of di-tert-butyl azodicarboxylate (3.51g, 15.24mmol) in tetrahydrofuran (15mL) was added dropwise and reacted at room temperature overnight. LC-MS detection showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Anhydrous ether (20mL) was added and stirred at room temperature for 3.5h. Filter, discard the filter cake, and concentrate the filtrate under reduced pressure. The crude product was directly reacted in the next step. MS: m / z=395.2, [M+H] + .

[0403] Step 4: Synthesis of ethyl 1-[1-(4-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylate (Compound 57-rac): To the product from Step 3 (5.79 g, 14.69 mmol), anhydrous methanol (30 mL) and 10% Pd / C (400 mg) were added, and the mixture was allowed to react overnight under a hydrogen balloon. LC-MS confirmed the reaction was complete, and the filtrate was filtered and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to afford the title compound (400 mg, 1.54 mmol). MS [ESI]: m / z = 261.2, [M+H] + ;

[0404] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=67.9Hz,2H),7.08(d,J=8.5Hz,2H),6.80(d,J=8.5Hz,2H ), 6.29 (q, J = 6.9Hz, 1H), 4.37–4.24 (m, 2H), 1.80 (d, J = 7.0Hz, 3H), 1.35 (t, J = 7.1Hz, 3H).

[0405] Example 4: Preparation of 1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 1-rac)

[0406] Step 1: Synthesis of 3-(1-hydroxyethyl)phenol (Compound 1-rac-2)

[0407] To a 100 mL reaction flask, add 3-hydroxyacetophenone (2.0 g, 14.69 mmol) and anhydrous methanol (30 mL). Stir and cool to 0°C. Slowly add sodium borohydride (830 mg, 22.03 mmol) and react at room temperature for 3 h. The reaction is complete by TLC. Adjust the pH to 5 with 2N hydrochloric acid and concentrate under reduced pressure at 45°C. Add ethyl acetate (20 mL), stir for 10 min, and filter. Discard the filter cake and concentrate the filtrate under reduced pressure to obtain the title compound (2.0 g, 14.69 mmol). MS: m / z = 121.2, [M-17]. + .

[0408] Step 2: Synthesis of 1-[1-(3-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 1-rac)

[0409] To the product of step 1 (2.0 g, 14.69 mmol), tetrahydrofuran (20 mL), ethyl imidazole-4-carboxylate (1.75 mg, 12.49 mmol), and triphenylphosphine (4.26 g, 16.24 mmol) were added, stirred, and cooled to 0°C. A solution of di-tert-butyl azodicarboxylate (3.88 g, 16.85 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was allowed to react at room temperature overnight. LC-MS analysis confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to obtain the title compound (433 mg, 1.66 mmol). MS [ESI]: m / z = 261.1, [M+H] + ;

[0410] 1 H NMR(400MHz, CDCl3) δ7.78(d,J=43.2Hz,2H),7.21(t,J=7.9Hz,1H),6.80(dd,J=10.5,4.5Hz,2H),6 .42(s,1H),6.28(q,J=7.1Hz,1H),4.32–4.18(m,2H),1.82(d,J=7.1Hz,3H),1.30(t,J=7.1Hz,3H).

[0411] Example 5: Preparation of 1-[1-(2-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 2-rac)

[0412] Step 1: Synthesis of 1-(2-(methoxymethoxy)phenyl)ethan-1-ol (compound 2-rac-2)

[0413] To a 100 mL reaction flask, 1-[2-(methoxymethoxy)phenyl]ethan-1-one (1.5 g, 8.32 mmol) and anhydrous methanol (15 mL) were added. The mixture was stirred and cooled to 0°C. Sodium borohydride (470 mg, 12.48 mmol) was slowly added and allowed to react at room temperature for 2 h. The reaction was complete by TLC. The pH was adjusted to 5 with 2N hydrochloric acid. The reaction solution was concentrated under reduced pressure to dryness, ethyl acetate (15 mL) was added, stirred for 10 min, and filtered. The filter cake was discarded, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.52 g, 8.32 mmol, equivalent yield). MS: m / z = 121.2, [M-17]. + .

[0414] Step 2: Synthesis of ethyl 1-(1-(2-(methoxymethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (compound 2-rac-3)

[0415] To the product of step 1 (1.52 g, 8.32 mmol), tetrahydrofuran (10 mL), ethyl imidazole-4-carboxylate (940 mg, 6.71 mmol), and triphenylphosphine (2.3 g, 8.77 mmol) were added, stirred, and cooled to 0°C. A solution of di-tert-butyl azodicarboxylate (2.09 g, 9.08 mmol) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was allowed to react at room temperature overnight. LC-MS analysis confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure, and the crude product was directly reacted in the next step. MS [ESI]: m / z = 305.1, [M+H] + .

[0416] Step 3: Synthesis of 1-[1-(2-hydroxyphenyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 2-rac)

[0417] To the product from step 2, ethyl acetate (40 mL), purified water (10 mL), and concentrated hydrochloric acid (5 mL) were added and the mixture was allowed to react at 30°C for 9 h. LC-MS confirmed the reaction was complete. The pH was adjusted to 7 with 40% aqueous sodium hydroxide solution. The layers were separated and the aqueous phase was discarded. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crude product was isolated by preparative HPLC to afford the title compound (163 mg, 0.63 mmol, 9.39% yield over two steps). MS [ESI]: m / z = 261.2, [M+H] + ;

[0418] 1 H NMR(400MHz, CDCl3)δ7.79(d,J=36.4Hz,2H),7.18–7.10(m,2H),6.90–6.84(m,2H),6 .48(q,J=7.0Hz,1H),4.34–4.24(m,2H),1.88(d,J=7.1Hz,3H),1.32(t,J=7.1Hz,3H).

[0419] Example 6: Preparation of ethyl 1-[1-(4-aminophenyl)ethyl]-1H-imidazole-5-carboxylate (Compound 58-rac)

[0420] To a 50 mL reaction flask, add ethyl imidazole-4-carboxylate (930 mg, 6.63 mmol), triphenylphosphine (2.26 g, 8.62 mmol), and tetrahydrofuran (8 mL). Stir and cool to 0°C. Add a solution of 1-(4-aminophenyl)-1-ethanol (1.0 g, 7.29 mmol) in tetrahydrofuran (8 mL). Add dropwise a solution of di-tert-butyl azodicarboxylate (2.06 g, 8.95 mmol) in tetrahydrofuran (8 mL). Allow to react at room temperature overnight. LC-MS analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to yield the title compound (268 mg, 1.03 mmol). MS [ESI]: m / z = 260.1, [M+H] + ;

[0421] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=27.7Hz,2H),6.96(d,J=8.4Hz,2H),6.63(d,J=8.4Hz,2H),5.23( q, J=6.9Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 3.67 (s, 2H), 1.80 (d, J=7.0Hz, 3H), 1.34 (t, J=7.1Hz, 3H).

[0422] Example 7: Preparation of ethyl 1-[1-(3-aminophenyl)ethyl]-1H-imidazole-5-carboxylate (Compound 3-rac)

[0423] To a 50 mL reaction flask, add ethyl imidazole-4-carboxylate (930 mg, 6.63 mmol), triphenylphosphine (2.26 g, 8.62 mmol), and tetrahydrofuran (8 mL). Stir and cool to 0°C. Add a solution of 1-(3-aminophenyl)-1-ethanol (1.0 g, 7.29 mmol) in tetrahydrofuran (8 mL). Add dropwise a solution of di-tert-butyl azodicarboxylate (2.06 g, 8.95 mmol) in tetrahydrofuran (8 mL). Allow to react at room temperature overnight. LC-MS analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to yield the title compound (180 mg, 0.69 mmol). MS [ESI]: m / z = 260.2, [M+H] + ;

[0424] 1H NMR (400MHz, CDCl3) δ7.74(d,J=15.3Hz,2H),7.10(t,J=7.8Hz,1H),6.61–6.54(m,2H),6.43(t,J=1.8Hz, 1H), 6.25 (q, J = 7.1Hz, 1H), 4.33–4.18 (m, 2H), 3.58 (s, 2H), 1.80 (d, J = 7.1Hz, 3H), 1.31 (t, J = 7.1Hz, 3H).

[0425] Example 8: Preparation of ethyl 1-[1-(2-aminophenyl)ethyl]-1H-imidazole-5-carboxylate (Compound 4-rac)

[0426] To a 50 mL reaction flask, add ethyl imidazole-4-carboxylate (930 mg, 6.63 mmol), triphenylphosphine (2.26 g, 8.62 mmol), and tetrahydrofuran (8 mL). Stir and cool to 0°C. Add a solution of 1-(2-aminophenyl)-1-ethanol (1.0 g, 7.29 mmol) in tetrahydrofuran (8 mL). Add dropwise a solution of di-tert-butyl azodicarboxylate (2.06 g, 8.95 mmol) in tetrahydrofuran (8 mL). Allow to react at room temperature overnight. LC-MS analysis confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was isolated by Pre-HPLC to yield the title compound (782 mg, 3.02 mmol). MS [ESI]: m / z = 260.2, [M+H] + ;

[0427] 1 H NMR (400MHz, CDCl3) δ7.77–7.55(m,2H),7.19(dd,J=7.8,1.2Hz,1H),7.14(td,J=7.7,1.4Hz,1H),6.80(td,J=7.6,1.0Hz ,1H),6.68(dd,J=8.0,1.1Hz,1H),6.37(q,J=6.9Hz,1H),4.39–4.23(m,2H),1.79(d,J=6.9Hz,3H),1.36(t,J=7.1Hz,3H).

[0428] Example 9: Preparation of ethyl 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 8-rac)

[0429] To a 100 mL round-bottom flask were added ethyl 1H-imidazole-5-carboxylate (500 mg, 3.57 mmol), triphenylphosphine (1.87 g, 7.14 mmol), and tetrahydrofuran (10 mL), and the mixture was cooled to -20°C. Subsequently, (1-(2-nitrophenyl)ethane-1-ol (500 mg, 3.57 mmol) was added, and after stirring for 10 minutes, a solution of di-tert-butyl azodicarboxylate (1.64 g, 7.14 mmol) in tetrahydrofuran (5 mL) was added dropwise. The atmosphere was purged with nitrogen three times, and the mixture was stirred for 6 hours. LCMS analysis confirmed the reaction was complete, and the mixture was returned to room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / MTBE = 2 / 1) to obtain the title compound (426 mg, 1.47 mmol). MS [ESI]: m / z = 290.2, [M+H] + ;

[0430] 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.99-7.96(m,1H),7.89(s,1H),7.69-7.49( m,3H),5.16-5.08(m,1H),4.24-4.06(m,2H),1.89(d,J=7.2Hz,3H),1.18(t,3H).

[0431] Example 10: Preparation of ethyl 1-(1-(2-ethylphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 59-rac)

[0432] To a 100 mL round-bottom flask were added ethyl 1H-imidazole-5-carboxylate (500 mg, 3.57 mmol), triphenylphosphine (1.87 g, 7.14 mmol), and tetrahydrofuran (10 mL), and the mixture was cooled to -20°C. Subsequently, (1-(2-ethylphenyl)ethane-1-ol (535 mg, 3.57 mmol) was added, and after stirring for 10 min, a solution of di-tert-butyl azodicarboxylate (1.64 g, 7.14 mmol) in tetrahydrofuran (5 mL) was added dropwise. The atmosphere was purged with nitrogen three times, and the mixture was stirred for 6 h. LCMS analysis indicated that the reaction was complete, and the mixture was allowed to return to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / MTBE = 2 / 1) to obtain the title compound (388 mg, 1.42 mmol). MS [ESI]: m / z = 273.2, [M+H] + ;

[0433] 1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.89(s,1H),7.20-7.17(m,4H),5.16-5.08(m, 1H), 4.23–4.05 (m, 2H), 2.61-2.58 (m, 2H), 1.89 (d, J = 7.2Hz, 3H), 1.30-1.18 (m, 6H).

[0434] Example 11: Preparation of ethyl 1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 60-rac)

[0435] To a 100 mL round-bottom flask, ethyl 1H-imidazole-5-carboxylate (500 mg, 3.57 mmol), triphenylphosphine (1.57 g, 7.14 mmol), and tetrahydrofuran (10 mL) were added and cooled to -20°C. 1-(2-cyclopropylphenyl)ethane-1-ol (578 mg, 3.57 mmol) was then added and stirred for 10 min. A solution of di-tert-butyl azodicarboxylate (1.64 g, 7.14 mmol) in tetrahydrofuran (5 mL) was then added dropwise. The atmosphere was purged with nitrogen three times and stirred for 6 h. The reaction was complete by LCMS. The mixture was returned to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / MTBE = 2 / 1) to afford the title compound (493 mg, 1.74 mmol). MS [ESI]: m / z = 285.2, [M+H] + ;

[0436] 1 H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.70(s,1H),7.22–7.12(m,2H),7.04(dd,J= 7.2,1.1Hz,1H),6.90–6.84(m,1H),6.67(q,J=7.0Hz,1H),4.26–4.10(m,2H),1.98 (qd,J=8.4,5.5Hz,1H),1.81(d,J=7.0Hz,3H),1.19(t,J=7.1Hz,3H),0.96–0.88(m ,1H),0.82–0.73(m,1H),0.69(td,J=9.8,5.5Hz,1H),0.55(dt,J=9.3,4.7Hz,1H).

[0437] Example 12: Preparation of ethyl 1-(1-(2-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 61-rac)

[0438] To a dry three-necked flask, triphenylphosphine (1.22 g, 4.64 mmol), ethyl 1H-imidazole-5-carboxylate (500 mg, 3.57 mmol), and tetrahydrofuran (10 mL) were added, and the atmosphere was purged with N2 three times. The temperature was lowered to -10°C, and a solution of 1-(2-(trifluoromethyl)phenyl)ethan-1-ol (746 mg, 3.92 mmol) in tetrahydrofuran and a solution of diethyl azodicarboxylate (1.11 g, 4.82 mmol) in tetrahydrofuran were added sequentially. The mixture was allowed to warm to room temperature and react for 2 h. LCMS confirmed the complete reaction of the starting material. The reaction was quenched with water and extracted three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to afford the title compound (700 mg, 2.24 mmol). MS [ESI]: m / z = 313.1, [M+H] + ;

[0439] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=0.5Hz,1H),7.72(d,J=7.7Hz,1H),7.62(s,1H),7.57(t,J=7.6Hz,1H),7.45(t,J=7.6H z,1H),7.27–7.21(m,1H),6.68(q,J=6.9Hz,1H),4.33–4.20(m,2H),1.89(d,J=6.9Hz,3H),1.29(dd,J=8.9,5.3Hz,3H).

[0440] Example 13: Preparation of ethyl 1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 12-rac)

[0441] To a dry three-necked flask, triphenylphosphine (2.43 g, 9.28 mmol), ethyl 1H-imidazole-5-carboxylate (1.0 g, 7.14 mmol), and tetrahydrofuran (20 mL) were added, and the atmosphere was replaced with N2 three times. The temperature was lowered to -10°C, and a solution of 1-(4-(trifluoromethyl)phenyl)ethane-1-ol (1.49 g, 7.85 mmol) in tetrahydrofuran (5 mL) and a solution of diethyl azodicarboxylate (2.22 g, 9.63 mmol) in tetrahydrofuran (5 mL) were added in sequence. The mixture was allowed to warm to room temperature and react for 2 h. LCMS confirmed the complete reaction of the starting material. The reaction was quenched with water and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (1.2 g, 3.85 mmol) was isolated by silica gel column chromatography (EA / PE = 1 / 1). MS [ESI]: m / z = 313.1 [M+H] + ;

[0442] 1 H NMR(400MHz, CDCl3)δ7.84(d,J=33.6Hz,2H),7.59(d,J=8.2Hz,2H),7.27–7.22(m,2H),6.40 (q, J=7.2Hz, 1H), 4.24 (qq, J=10.8, 7.1Hz, 2H), 1.89 (d, J=7.2Hz, 3H), 1.30 (t, J=7.1Hz, 3H).

[0443] Example 14: Preparation of ethyl 1-[1-(oxypyridin-2-yl)ethyl]-1H-imidazole-5-carboxylate (Compound 20-rac)

[0444] Step 1: Synthesis of 1-[1-(pyridin-2-yl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 17-rac)

[0445] To a 50 mL reaction flask, ethyl imidazole-4-carboxylate (517 mg, 3.69 mmol), triphenylphosphine (1.38 g, 5.28 mmol), and tetrahydrofuran (5 mL) were added, stirred, and cooled to 0°C. A solution of 1-(pyridin-2-yl)ethanol (500 mg, 4.06 mmol) in tetrahydrofuran (5 mL) was added, and a solution of di-tert-butyl azodicarboxylate (1.26 g, 4.48 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was allowed to react at room temperature overnight. LC-MS analysis indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, and diethyl ether (15 mL) was added to the product from step 1. The mixture was stirred at room temperature for 2.5 h, filtered, and the filtrate was concentrated. The crude product was separated by silica gel column chromatography (EA / PE = 1 / 1) to obtain the title compound (350 mg, 1.43 mmol). MS [ESI]: m / z = 246.2, [M+H] + ;

[0446] 1 H NMR (400MHz, CDCl3) δ8.56(dd,J=4.7,0.7Hz,1H),7.98(s,1H),7.75(s,1H),7.61(td,J=7.7,1.8Hz,1H),7.20-7.14( m,1H),7.11(d,J=7.8Hz,1H),6.44(q,J=7.1Hz,1H),4.32-4.17(m,2H),1.89(d,J=7.2Hz,3H),1.29(t,J=7.1Hz,3H).

[0447] Step 2: Synthesis of 1-[1-(oxypyridin-2-yl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 20-rac)

[0448] To a 25 mL reaction flask, add the product from step 1 (60 mg, 0.244 mmol) and dichloromethane (5 mL). The temperature was lowered to 0°C, and m-CPBA (211 mg, 1.22 mmol) was added. The mixture was allowed to react at room temperature for 2 h. LC-MS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was isolated by Pre-HPLC to obtain the title compound (35 mg, 0.134 mmol). MS [ESI]: m / z = 262.2, [M+H] + ;

[0449] 1 H NMR (400MHz, CDCl3) δ8.29–8.23(m,1H),7.89(d,J=52.2Hz,2H),7.24–7.14(m,2H),6.65(dd d,J=10.9,9.8,4.6Hz,2H),4.26–4.10(m,2H),1.98(d,J=7.1Hz,3H),1.23(t,J=7.1Hz,3H).

[0450] Example 15: Preparation of 1-[1-(pyridin-3-yl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 18-rac)

[0451] To a 50 mL reaction flask, add ethyl imidazole-4-carboxylate (517 mg, 3.69 mmol), triphenylphosphine (1.38 g, 5.28 mmol), and tetrahydrofuran (5 mL). Stir and cool to 0°C. Add a solution of 3-(1-hydroxyethyl)pyridine (500 mg, 4.06 mmol) in tetrahydrofuran (5 mL), and dropwise add a solution of di-tert-butyl azodicarboxylate (1.26 g, 4.48 mmol) in tetrahydrofuran (5 mL). Allow to react at room temperature overnight. LC-MS analysis confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure, and diethyl ether (15 mL) was added. The mixture was stirred at room temperature for 1 h, then filtered and the filtrate concentrated. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to afford the title compound (670 mg, 2.73 mmol). MS [ESI]: m / z = 246.2, [M+H] + ;

[0452] 1H NMR (400MHz, CDCl3) δ8.56 (dd, J=4.7, 0.7Hz, 1H), 7.86 (d, J=94.3Hz, 2H), 7.61 (td, J=7.7, 1.8Hz, 1H), 7.17 (ddd, J=7.5, 4.8, 0.9 Hz,1H),7.11(d,J=7.8Hz,1H),6.44(q,J=7.1Hz,1H),4.25(qq,J=10.8,7.1Hz,2H),1.89(d,J=7.2Hz,3H),1.29(t,J=7.1Hz,3H).

[0453] Example 16: Preparation of 1-[1-(pyridin-4-yl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester (Compound 19-rac)

[0454] To a 50 mL reaction flask, add ethyl imidazole-4-carboxylate (517 mg, 3.69 mmol), triphenylphosphine (1.38 g, 5.28 mmol), and tetrahydrofuran (5 mL). Stir and cool to 0°C. Add a solution of 1-(4-pyridyl)ethanol (500 mg, 4.06 mmol) in tetrahydrofuran (5 mL), and dropwise add a solution of di-tert-butyl azodicarboxylate (1.26 g, 4.48 mmol) in tetrahydrofuran (5 mL). Allow to react at room temperature overnight. LC-MS analysis confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure, and diethyl ether (15 mL) was added. The mixture was stirred at room temperature for 1 h, then filtered and the filtrate concentrated. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to afford the title compound (520 mg, 2.12 mmol). MS [ESI]: m / z = 246.2, [M+H] + ;

[0455] 1 H NMR (400MHz, CDCl3) δ8.54 (dd, J=4.6, 1.5Hz, 2H), 7.81 (d, J=13.9Hz, 2H), 7.01–6.93 (m, 2H), 6.31 (q, J=7.2Hz, 1H), 4.20 (qq, J=10.8, 7.1Hz, 2H), 1.87 (d, J=7.3Hz, 3H), 1.27 (dd, J=9.7, 4.6Hz, 3H).

[0456] Example 17: Preparation of (R)-1-(1-(p-Tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 9)

[0457] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 1H-imidazole-5-carboxylate (113 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C for 4 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 5) to afford the title compound (130 mg, 0.50 mmol). MS [ESI]: m / z = 259.3, [M+H] + ;

[0458] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.67(s,1H),7.09(dd,J=20.5,8.1Hz,4H),6.21(q,J =7.2Hz, 1H), 4.22-4.13 (m, 2H), 2.24 (s, 3H), 1.81 (d, J = 7.2Hz, 3H), 1.21 (t, J = 7.1Hz, 3H).

[0459] Example 18: Preparation of ethyl 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 21-rac)

[0460] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 1H-imidazole-5-carboxylate (113 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of 1-(pyrimidin-2-yl)ethanol (100 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The mixture was allowed to react at -30°C for 4 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (MeOH / DCM = 1 / 20) to obtain the title compound (110 mg, 0.45 mmol). MS [ESI]: m / z = 247.3, [M+H] + ;

[0461] 1H NMR(400MHz, DMSO-d6)δ8.75(d,J=4.9Hz,2H),8.20(s,1H),7.69(s,1H),7.40(t,J=4.9Hz, 1H), 6.28 (q, J = 7.2Hz, 1H), 4.13-4.04 (m, 2H), 1.90 (d, J = 7.3Hz, 3H), 1.14 (t, J = 7.1Hz, 3H).

[0462] Example 19: Preparation of ethyl 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 62-rac)

[0463] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 1H-imidazole-5-carboxylate (113 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of 1-(2-methoxyphenyl)ethanol (123 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C for 4 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to obtain the title compound (156 mg, 0.57 mmol). MS [ESI]: m / z = 275.4, [M+H] + ;

[0464] 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.67(s,1H),7.33-7.21(m,1H),7.01(d,J=8.2Hz,1H),6.88(t,J=7.5Hz,1H),6.6 9(d,J=7.5Hz,1H),6.40(q,J=7.1Hz,1H),4.2-4.07(m,2H),3.79(s,3H),1.76(d,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H).

[0465] Example 20: Preparation of (R)-1-(1-(4-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 11)

[0466] Referring to the procedure of Example 17, (S)-1-(4-methoxyphenyl)ethanol (123 mg, 0.81 mmol) was substituted for (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) to obtain the title compound (90.4 mg, 0.33 mmol). MS [ESI]: m / z = 275.2, [M+H] + ;

[0467] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.65(s,1H),7.15(d,J=8.7Hz,2H),6.88(d,J=8.7Hz,2H),6. 20(q,J=7.2Hz,1H),4.28-4.08(m,2H),3.71(s,3H),1.80(d,J=7.2Hz,3H),1.22(t,J=7.1Hz,3H).

[0468] Example 21: Preparation of (R)-1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 4)

[0469] Step 1: Synthesis of (R)-1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester

[0470] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 1H-imidazole-5-carboxylate (113 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(2-nitrophenyl)ethanol (135.2 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The mixture was allowed to react at -30°C for 4 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 5) to obtain the title compound (159 mg, 0.55 mmol). MS [ESI]: m / z = 290.3, [M+H] + ;

[0471] Step 2: Synthesis of (R)-1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 4)

[0472] To a single-necked flask, add (R)-ethyl 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (159 mg, 0.55 mmol), methanol (3 mL), and palladium on carbon (50 mg). After H2 substitution, stir at room temperature overnight. After completion of the reaction, filter the reaction mixture through Celite and concentrate. The crude product is separated by Pre-HPLC to obtain the title compound (98.42 mg, 0.38 mmol). MS [ESI]: m / z = 260.4, [M+H] + ;

[0473] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.69(s,1H),6.98-6.94(m,1H),6.65(d,J=7.6Hz,1H),6.60-6.55(m,1H),6.5 2-6.48(m,1H),6.18(q,J=6.9Hz,1H),5.03(s,2H),4.23-4.13(m,2H),1.71(d,J=6.8Hz,3H),1.21(t,J=7.2Hz,3H).

[0474] Example 22: Preparation of (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 22)

[0475] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), methyl 1H-imidazole-5-carboxylate (102 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C for 4 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 2) to obtain the title compound (134 mg, 0.58 mmol). MS [ESI]: m / z = 232.3, [M+H] + ;

[0476] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.6Hz,1H),8.25(s,1H),7.77(td,J=7.7,1.7Hz,1H),7.69(s,1H),7.2 8(dd,J=7.2,5.1Hz,1H),7.16(d,J=7.8Hz,1H),6.29(q,J=7.2Hz,1H),3.70(s,3H),1.84(d,J=7.2Hz,3H).

[0477] Example 23: Preparation of (R)-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 63)

[0478] Ethyl 1H-imidazole-5-carboxylate (499.95 mg, 3.57 mmol) and triphenylphosphine (1.87 g, 7.13 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (20 mL). The atmosphere was replaced with N2. (1S)-1-(2-fluorophenyl)ethanol (500 mg, 3.57 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (1.64 g, 7.13 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction mixture. The mixture was stirred at -30°C. After completion of the reaction, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (685 mg, 2.61 mmol). MS [ESI]: m / z = 263.1, [M+H] + ;

[0479] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.6Hz,2H),7.31(td,J=8.0,5.9Hz,1H),6.97(ddd,J=8.5,8.1,4.8Hz,2H),6.8 6(dt,J=9.7,2.0Hz,1H), 6.37(q,J=7.1Hz,1H), 4.33-4.20(m,2H), 1.87(d,J=7.2Hz,3H), 1.32(t,J=7.1Hz,3H).

[0480] Example 24: Preparation of methyl 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 64-rac)

[0481] Step 1: Synthesis of 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid

[0482] Compound 21-rac (500 mg, 2.03 mmol), tetrahydrofuran (5 mL), methanol (5 mL), and water (2 mL) were added to a single-necked flask. Lithium hydroxide hydrate (426 mg, 10.15 mmol) was then added and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction mixture was separated by Pre-HPLC to obtain the title compound (379 mg, 1.74 mmol). MS [ESI]: m / z = 219.1, [M+H] + ;

[0483] Step 2: Synthesis of methyl 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylate

[0484] Compound 64-2 (100 mg, 0.46 mmol) and methanol (5 mL) were added to a single-necked flask. The temperature was lowered to 0°C, and thionyl chloride (274 mg, 2.30 mmol) was added. The mixture was heated to 75°C and allowed to react overnight. After completion of the reaction, the reaction solution was separated by silica gel column chromatography (MeOH / DCM = 1 / 20) to obtain the title compound (69 mg, 0.30 mmol). MS [ESI]: m / z = 233.3, [M+H] + ;

[0485] 1 H NMR(400MHz,DMSO-d6)δ8.76(d,J=4.9Hz,2H),8.30(s,1H),7.74(s,1H),7.4 0 (t, J = 4.9 Hz, 1H), 6.30 (q, J = 7.2 Hz, 1H), 3.64 (s, 3H), 1.90 (d, J = 7.3 Hz, 3H).

[0486] Example 25: Preparation of methyl 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 65-rac)

[0487] Step 1: Synthesis of 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid

[0488] Referring to the operating procedures of the first step of Example 24, the title compound (383 mg, 1.55 mmol) was obtained by replacing compound 21-rac with (1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (500 mg, 1.82 mmol). MS [ESI]: m / z = 247.1, [M+H] + ;

[0489] Step 2: Synthesis of methyl 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate

[0490] Referring to the procedure of step 2 of Example 24, 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid (383 mg, 1.55 mmol) was substituted for 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid to obtain the title compound (252 mg, 0.97 mmol). MS [ESI]: m / z = 261.4, [M+H] + ;

[0491] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.68(s,1H),7.26(t,J=7.4Hz,1H),7.01(d,J=8.2Hz,1H),6.89(t,J= 7.5Hz, 1H), 6.72 (d, J = 7.4Hz, 1H), 6.41 (q, J = 7.0Hz, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 1.76 (d, J = 7.1Hz, 3H).

[0492] Example 26: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 66)

[0493] Referring to the procedure of Example 18, (S)-1-(2-fluorophenyl)ethanol (113 mg, 0.81 mmol) was substituted for 1-(pyrimidin-2-yl)ethanol to obtain the title compound (122 mg, 0.47 mmol). MS [ESI]: m / z = 263.2, [M+H] + ;

[0494] 1 H NMR (400MHz, DMSO-d6) δ8.26 (s, 1H), 7.70 (s, 1H), 7.33 (dd, J = 13.5, 6.1Hz, 1H), 7.25-7.11 (m, 2H), 6.86 (t, J=7.3Hz, 1H), 6.41 (q, J=7.1Hz, 1H), 4.21-4.08 (m, 2H), 1.83 (d, J=7.2Hz, 3H), 1.18 (t, J=7.1Hz, 3H).

[0495] Example 27: Preparation of methyl 1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 67)

[0496] To a round-bottom flask, methyl 1H-imidazole-5-carboxylate (269.64 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL) were added and cooled to -20°C. (S)-1-((4-trifluoromethyl)phenyl)ethanol (406 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. After nitrogen substitution, the mixture was stirred and allowed to cool to room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / MTBE = 35 / 65) to obtain the title compound (327 mg, 1.11 mmol). MS [ESI]: m / z = 299.1, [M+H] + ;

[0497] 1 H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 7.85-7.63 (m, 3H), 7.35 (d, J = 8.1Hz, 2H), 6.29 (q, J = 7.2Hz, 1H), 3.69 (s, 3H), 1.87 (d, J = 7.2Hz, 3H).

[0498] Example 28: Preparation of Isopropyl 1-(1-(4-(Trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 69)

[0499] Anhydrous isopropanol (2 mL) was added to a round-bottom flask, followed by sodium hydride (56.98 mg, 1.42 mmol) under ice-cooling. After stirring for 5 minutes, a solution of compound 67 (141 mg, 474.80 μmol) in anhydrous isopropanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (51 mg, 0.156 mmol). MS [ESI]: m / z = 327.1, [M+H] + ;

[0500] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.70(d,J=8.9Hz,3H),7.33(d,J=8.2Hz,2H),6. 28(q,J=7.1Hz,1H), 4.97(m,1H), 1.87(d,J=7.2Hz,3H), 1.16(dd,J=6.2,2.0Hz,6H).

[0501] Example 29: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 5)

[0502] Ethyl 1H-imidazole-5-carboxylate (500 mg, 3.57 mmol) and triphenylphosphine (1.87 g, 7.15 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (20 mL). The atmosphere was replaced with N2 and 4-[(1S)-1-hydroxyethyl]benzonitrile (526 mg, 3.57 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (1.65 g, 7.15 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction solution. After the reaction was complete, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (421 mg, 1.56 mmol). MS [ESI]: m / z = 270.2, [M+H] + ;

[0503] 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 1H), 7.86-7.79 (m, 2H), 7.71 (s, 1H), 7.29 (d, J = 8.3Hz, 2H), 6.26 ( q, J=7.2Hz, 1H), 4.14 (qdd, J=14.2, 9.0, 5.4Hz, 2H), 1.85 (d, J=7.2Hz, 3H), 1.18 (t, J=7.1Hz, 3H).

[0504] Example 30: Preparation of (R)-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 70)

[0505] Methyl 1H-imidazole-5-carboxylate (399.52 mg, 3.17 mmol) and triphenylphosphine (1.66 g, 6.34 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (20 mL). The atmosphere was replaced with N2 and (1S)-1-(2-fluorophenyl)ethanol (444 mg, 3.17 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (1.46 g, 6.34 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (398 mg, 1.60 mmol). MS [ESI]: m / z = 249.2, [M+H] + ;

[0506] 1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.71(s,1H),7.37(td,J=8.0,6.2Hz,1H),7.15-7.01 (m, 2H), 6.97 (d, J = 7.8Hz, 1H), 6.24 (q, J = 7.2Hz, 1H), 3.72 (s, 3H), 1.84 (d, J = 7.2Hz, 3H).

[0507] Example 31: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 71)

[0508] Methyl 1H-imidazole-5-carboxylate (400.22 mg, 3.17 mmol) and triphenylphosphine (1.66 g, 6.35 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (20 mL). The atmosphere was replaced with nitrogen. 4-[(1S)-1-hydroxyethyl]benzonitrile (467 mg, 3.17 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (1.44 g, 6.26 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction mixture. After completion of the reaction at -30°C with stirring, the mixture was concentrated at low temperature. The crude product was purified by preparative HPLC and lyophilized to obtain the title compound (458 mg, 1.79 mmol). MS [ESI]: m / z = 256.1, [M+H] + ;

[0509] 1 H NMR(400MHz,DMSO-d6)δ8.39(d,J=0.6Hz,1H),7.83-7.79(m,2H),7.73(d,J=0.9Hz,1 H), 7.31 (d, J = 8.3Hz, 2H), 6.26 (q, J = 7.2Hz, 1H), 3.69 (s, 3H), 1.85 (t, J = 6.5Hz, 3H).

[0510] Example 32: Preparation of (R)-butyl 1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 72)

[0511] Anhydrous butanol (2 mL) was added to a single-necked flask. Sodium hydride (57 mg, 1.42 mmol) was added under ice-cooling. After stirring for 5 minutes, a solution of compound 7 (157 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (53 mg, 0.17 mmol). MS [ESI]: m / z = 318.5, [M+H] + ;

[0512] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.16-8.10(m,1H),7.98(s,1H),7.72(s,1H),7.69-7.56(m,2H),6.32(q,J=7 .2Hz,1H),4.17-4.04(m,2H),1.90(d,J=7.2Hz,3H),1.59-1.49(m,2H),1.30-1.21(m,2H),0.84(t,J=7.4Hz,3H).

[0513] Example 33: Preparation of (R)-butyl 1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 73)

[0514] Compound 72 (50 mg, 0.16 mmol), methanol (3 mL), and palladium on carbon (50 mg) were added to a single-necked flask. After H2 substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered through a pad of celite and concentrated. The crude product was separated by Pre-HPLC to obtain the title compound (37 mg, 0.13 mmol). MS [ESI]: m / z = 288.4, [M+H] + ;

[0515] 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.66(s,1H),6.94(t,J=7.7Hz,1H),6.49-6.36(m,1H),6.32-6.27(m,2H),6.09(q,J=7.1Hz,1 H), 5.08 (s, 2H), 4.15 (qt, J = 10.8, 6.6Hz, 2H), 1.76 (d, J = 7.2Hz, 3H), 1.64-1.53 ​​(m, 2H), 1.38-1.27 (m, 2H), 0.89 (t, J = 7.4Hz, 3H).

[0516] Example 34: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 3)

[0517] Referring to the operating procedures of Example 33, compound 7 (50 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (37 mg, 0.14 mmol). MS [ESI]: m / z = 260.4, [M+H] + ;

[0518] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.67(s,1H),6.95(t,J=7.8Hz,1H),6.44(d,J=8.5Hz,1H),6.32-6.31( m, 2H), 6.10 (q, J = 7.1Hz, 1H), 5.08 (s, 2H), 4.29-4.11 (m, 2H), 1.76 (d, J = 7.2Hz, 3H), 1.23 (t, J = 7.1Hz, 3H).

[0519] Example 35: Preparation of (R)-butyl 1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 74)

[0520] Anhydrous butanol (2 mL) was added to a single-necked flask, followed by sodium hydride (57 mg, 1.42 mmol) under ice-cooling. After stirring for 5 minutes, a solution of compound 66 (123 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to afford the title compound (52 mg, 0.54 mmol). MS [ESI]: m / z = 291.4, [M+H] + ;

[0521] 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.70(s,1H),7.36-7.25(m,1H),7.23-7.11(m,2H),6.90-6.80(m,1H),6.42(q, J=7.1Hz,1H),4.17-4.02(m,2H),1.83(d,J=7.2Hz,3H),1.57-1.49(m,2H),1.32-1.22(m,2H),0.84(t,J=7.4Hz,3H).

[0522] Example 36: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 75)

[0523] Referring to the operating procedures of Example 35, butanol was replaced by propanol (2 mL) to obtain the title compound (56 mg, 0.20 mmol). MS [ESI]: m / z = 277.4, [M+H] + ;

[0524] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.71(s,1H),7.33(dd,J=13.4,6.3Hz,1H),7.24-7.11(m,2H),6.87(t,J=7.4Hz ,1H),6.41(q,J=7.1Hz,1H),4.14-3.98(m,2H),1.83(d,J=7.2Hz,3H),1.58(h,J=7.1Hz,2H),0.84(t,J=7.4Hz,3H).

[0525] Example 37: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 76)

[0526] Referring to the operating procedures of Example 35, methanol (2 mL) was used to replace butanol to obtain the title compound (47 mg, 0.19 mmol). MS [ESI]: m / z = 249.3, [M+H] + ;

[0527] 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.72(s,1H),7.33(dd,J=13.5,6.5Hz,1H),7.26-7.1 0(m,2H),6.89(t,J=7.6Hz,1H),6.42(q,J=7.1Hz,1H),3.69(s,3H),1.83(d,J=7.2Hz,3H).

[0528] Example 38: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 77)

[0529] Referring to the operating procedures of Example 35, butanol was replaced by isopropanol (2 mL) to obtain the title compound (53 mg, 0.19 mmol). MS [ESI]: m / z = 277.3, [M+H] + ;

[0530] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.68(s,1H),7.33(dd,J=13.5,6.5Hz,1H),7.22-7.12(m,2H),6.82(t,J=7.6 Hz, 1H), 6.39 (q, J = 7.1Hz, 1H), 4.97 (dt, J = 12.5, 6.2Hz, 1H), 1.83 (d, J = 7.2Hz, 3H), 1.15 (dd, J = 12.6, 6.2Hz, 6H).

[0531] Example 39: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 78)

[0532] Referring to the operating procedures of Example 35, butanol was replaced by isobutanol (2 mL) to obtain the title compound (53 mg, 0.18 mmol). MS [ESI]: m / z = 291.4, [M+H] + ;

[0533] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.73(s,1H),7.32(dd,J=13.2,6.5Hz,1H),7.24-7.09(m,2H),6.88(t,J=7.5Hz,1H ), 6.42 (q, J=6.9Hz, 1H), 3.90 (qd, J=10.6, 6.8Hz, 2H), 1.94-1.85 (m, 1H), 1.83 (d, J=7.1Hz, 3H), 0.84 (d, J=6.0Hz, 6H).

[0534] Example 40: Preparation of (R)-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 79)

[0535] Referring to the operating procedures of Example 28, isopropanol was replaced with isobutanol to obtain the title compound (53 mg, 0.156 mmol). MS [ESI]: m / z = 341.2, [M+H] + ;

[0536] 1H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.74(d,J=0.6Hz,1H),7.69(d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),6. 28(q,J=7.2Hz,1H), 3.90(qd,J=10.6,6.6Hz,2H), 3.34(s,1H), 1.87(d,J=7.3Hz,3H), 0.83(d,J=6.7Hz,6H).

[0537] Example 41: Preparation of 1-(1-(2-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 80-rac)

[0538] To a round-bottom flask, add isobutyl 1H-imidazole-5-carboxylate (359.52 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL) and cool to -20°C. Then, add (S)-1-(2-hydroxy)phenylethanol (295 mg, 2.14 mmol) and stir for 10 minutes. Then, add dropwise a solution of di-tert-butyl azodicarboxylate (739.14 mg, 3.21 mmol) in diethyl ether (5 mL). Replace the atmosphere with nitrogen and maintain the mixture with stirring. After completion of the reaction, return the mixture to room temperature and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / MTBE = 35 / 65) to obtain the title compound (323 mg, 1.12 mmol). MS [ESI]: m / z = 289.2, [M+H] + ;

[0539] 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),7.99(s,1H),7.68(s,1H),7.14-7.00(m,1H),6.80(d,J=7.9Hz,1H),6.77-6.67(m,2H),6.37(q, J=7.0Hz, 1H), 3.93 (ddd, J=24.1, 10.6, 6.6Hz, 2H), 1.91 (dp, J=13.3, 6.7Hz, 1H), 1.76 (d, J=7.1Hz, 3H), 0.88 (dd, J=6.7, 4.3Hz, 6H).

[0540] Example 42: Preparation of (R)-butyl 1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 81)

[0541] Referring to the operating procedures of Example 28, the title compound (47 mg, 0.156 mmol) was obtained by replacing isopropanol with n-butanol. MS [ESI]: m / z = 341.1, [M+H] + ;

[0542] 1 H NMR(400MHz, DMSO-d6)δ8.38(s,1H),7.70(dd,J=12.2,4.4Hz,3H),7.32(d,J=8.1Hz,2H),6.28(q,J=7.1Hz,1H), 4.10(qt,J=10.9,6.5Hz,2H),1.87(d,J=7.2Hz,3H),1.62-1.42(m,2H),1.32-1.15(m,2H),0.82(t,J=7.4Hz,3H).

[0543] Example 43: Preparation of (R)-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 82)

[0544] Referring to the operating procedures of Example 28, the title compound (51 mg, 0.156 mmol) was obtained by replacing isopropanol with n-propanol. MS [ESI]: m / z = 327.2, [M+H] + ;

[0545] 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.76(d,J=0.6Hz,1H),7.72(d,J=8.2Hz,2H),7.36(d,J=8.2Hz,2H),6.32( q, J=7.1Hz, 1H), 4.09 (qt, J=10.7, 6.6Hz, 2H), 1.90 (d, J=7.2Hz, 3H), 1.66-1.51 (m, 2H), 0.85 (t, J=7.4Hz, 3H).

[0546] Example 44: Preparation of butyl 1-(1-(2-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 83-rac)

[0547] Anhydrous n-butanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 80-rac (136 mg, 474.80 μmol) in anhydrous n-butanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After completion of the reaction, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (45 mg, 0.156 mmol). MS [ESI]: m / z = 289.1, [M+H] + ;

[0548] 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.00(s,1H),7.66(s,1H),7.21-7.03(m,1H),6.80(d,J=7.7Hz,1H),6.71(dt,J=7.6,7.0Hz, 2H), 6.36 (q, J = 7.0Hz, 1H), 4.23-3.97 (m, 2H), 1.75 (d, J = 7.1Hz, 3H), 1.64-1.49 (m, 2H), 1.42-1.23 (m, 2H), 0.87 (t, J = 7.4Hz, 3H).

[0549] Example 45: Preparation of methyl 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 84-rac)

[0550] Methyl 1H-imidazole-5-carboxylate (37.72 mg, 299.11 μmol) and triphenylphosphine (189.84 mg, 723.78 μmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and 1-(2-nitrophenyl)ethanol (50 mg, 361.89 μmol) was added at 0°C. Di-tert-butyl azodicarboxylate (164.29 mg, 713.50 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the solution was concentrated at low temperature. The crude product was purified by pre-HPLC and lyophilized to obtain the title compound (15.0 mg, 54.49 μmol). MS [ESI]: m / z = 276.1, [M+H] + ;

[0551] 1H NMR(400MHz, DMSO-d6)δ8.53(s,1H),8.00(dd,J=8.2,1.3Hz,1H),7.71-7.64(m,2H),7.55-7.48 (m, 1H), 7.07 (dd, J = 7.9, 1.2Hz, 1H), 6.44 (q, J = 7.0Hz, 1H), 3.59 (s, 3H), 1.97 (d, J = 7.1Hz, 3H).

[0552] Example 46: Preparation of (R)-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 7)

[0553] Referring to the procedure of Example 18, (S)-1-(3-nitrophenyl)ethanol (113 mg, 0.81 mmol) was substituted for 1-(pyrimidin-2-yl)ethanol to obtain the title compound (135 mg, 0.47 mmol). MS [ESI]: m / z = 290.4, [M+H] + ;

[0554] 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=0.6Hz,1H),8.17-8.10(m,1H),7.99(t,J=1.9Hz,1H),7.72(d,J=0.9Hz,1 H),7.68-7.60(m,2H),6.33(q,J=7.2Hz,1H),4.22-4.09m,2H),1.90(d,J=7.2Hz,3H),1.19(t,J=7.1Hz,3H).

[0555] Example 47: Preparation of butyl 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 85-rac)

[0556] Anhydrous butanol (2 mL) was added to a single-necked flask. Sodium hydride (57 mg, 1.42 mmol) was added under ice-cooling. After stirring for 5 minutes, a solution of compound 21-rac (116 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (51 mg, 0.18 mmol). MS [ESI]: m / z = 275.4, [M+H] + ;

[0557] 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=4.9Hz,2H),8.20(s,1H),7.68(s,1H),7.40(t,J=6.8Hz,1H),6.26(q,J=8.2 Hz,1H),4.14-3.96(m,2H),1.90(d,J=6.5Hz,3H),1.54-1.47(m,2H),1.29-1.23(m,2H),0.85(t,J=7.2Hz,3H).

[0558] Example 48: Preparation of 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 86-rac)

[0559] Referring to the operating procedures of Example 47, butanol was replaced by propanol (2 mL) to obtain the title compound (48 mg, 0.19 mmol). MS [ESI]: m / z = 261.3, [M+H] + ;

[0560] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=4.8Hz,2H),8.20(s,1H),7.69(s,1H),7.39(t,J=4.8Hz,1H),6.27 (q,J=7.2Hz,1H),4.07-3.94(m,2H),1.90(d,J=7.3Hz,3H),1.58-1.46(m,2H),0.83(t,J=7.4Hz,3H).

[0561] Example 49: Preparation of 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 87-rac)

[0562] Referring to the operating procedures of Example 47, butanol was replaced by isopropanol (2 mL) to obtain the title compound (49 mg, 0.19 mmol). MS [ESI]: m / z = 261.3, [M+H] + ;

[0563] 1H NMR (400MHz, DMSO-d6) δ8.76(d,J=4.9Hz,2H),8.17(s,1H),7.65(s,1H),7.40(t,J=4.9Hz,1H),6.24(q,J=7 .2Hz, 1H), 4.91 (dt, J = 12.4, 6.2Hz, 1H), 1.90 (d, J = 7.3Hz, 3H), 1.13 (d, J = 6.2Hz, 3H), 1.09 (d, J = 6.2Hz, 3H).

[0564] Example 50: Preparation of 1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 88-rac)

[0565] Referring to the operating procedures of Example 47, butanol was replaced by isobutanol (2 mL) to obtain the title compound (51 mg, 0.19 mmol). MS [ESI]: m / z = 261.3, [M+H] + ;

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=4.9Hz,2H),8.20(s,1H),7.70(s,1H),7.39(t,J=4.9Hz,1H),6.28( q,J=7.3Hz,1H),3.90-3.81(m,2H),1.90(d,J=7.3Hz,3H),1.88-1.81(m,1H),0.85(dd,J=1.2Hz,6H).

[0567] Example 51: Preparation of (R)-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 89)

[0568] Referring to the operating procedures of Example 32, methanol (2 mL) was used to replace butanol to obtain the title compound (48 mg, 0.17 mmol). MS [ESI]: m / z = 276.4, [M+H] + ;

[0569] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.13(dt,J=6.8,2.3Hz,1H),7.99(s,1H),7.73( s,1H),7.68-7.60(m,2H),6.33(q,J=7.2Hz,1H),3.70(s,3H),1.90(d,J=7.2Hz,3H).

[0570] Example 52: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 90)

[0571] Referring to the operating procedures of Example 33, compound 89 (47 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (33 mg, 0.14 mmol). MS [ESI]: m / z = 260.4, [M+H] + ;

[0572] 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.68(s,1H),6.95(t,J=8.0Hz,1H),6.44(d,J=8.3Hz,1H ), 6.34-6.31 (m, 2H), 6.10 (q, J = 7.1Hz, 1H), 5.07 (s, 2H), 3.73 (s, 3H), 1.76 (d, J = 7.2Hz, 3H).

[0573] Example 53: Preparation of (R)-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 91)

[0574] Referring to the operating procedures of Example 32, butanol was replaced by isobutanol (2 mL) to obtain the title compound (52 mg, 0.16 mmol). MS [ESI]: m / z = 318.4, [M+H] + ;

[0575] 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.16-8.09(m,1H),7.99(s,1H),7.74(s,1H),7.68-7.53(m,2H),6.33( q, J=7.1Hz, 1H), 3.90 (qd, J=10.6, 6.6Hz, 2H), 1.91 (d, J=7.2Hz, 3H), 1.88-1.84 (m, 1H), 0.86-0.81 (m, 6H).

[0576] Example 54: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 92)

[0577] Referring to the operating procedures of Example 33, compound 91 (54 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (40 mg, 0.14 mmol). MS [ESI]: m / z = 288.4, [M+H] + ;

[0578] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.69(s,1H),6.95(t,J=7.7Hz,1H),6.44(d,J=8.4Hz,1H),6.34-6.27(m,2H),6. 10(q,J=7.1Hz,1H),5.07(s,2H),4.00-3.89(m,2H),1.98-1.86(m,1H),1.77(d,J=7.2Hz,3H),0.90(d,J=6.7Hz,6H).

[0579] Example 55: Preparation of (R)-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 93)

[0580] Referring to the operating procedures of Example 32, butanol was replaced by propanol (2 mL) to obtain the title compound (51 mg, 0.17 mmol). MS [ESI]: m / z = 304.3, [M+H] + ;

[0581] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.13-8.10(m,1H),8.00(s,1H),7.73(s,1H),7.67-7.60(m,2H),6. 34(q,J=7.1Hz,1H),4.12-4.00(m,2H),1.91(d,J=7.2Hz,3H),1.61-1.52(m,2H),0.82(t,J=7.4Hz,3H).

[0582] Example 56: Preparation of (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 23)

[0583] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), 1H-imidazole-5-carboxylic acid propyl ester (125 mg, 0.81 mmol), and diethyl ether (3 mL) were added, and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in that order. After completion of the reaction at -30°C, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 2) to afford the title compound (142 mg, 0.55 mmol). MS [ESI]: m / z = 260.3, [M+H] + ;

[0584] 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.4Hz,1H),8.23(s,1H),7.77(td,J=7.7,1.5Hz,1H),7.68(s,1H),7.28(dd,J=7.1,5.0Hz,1H) ,7.13(d,J=7.9Hz,1H),6.28(q,J=7.2Hz,1H),4.15-4.00(m,2H),1.85(d,J=7.2Hz,3H),1.65-1.53(m,2H),0.86(t,J=7.4Hz,3H).

[0585] Example 57: Preparation of (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 24)

[0586] To a three-necked flask, add triphenylphosphine (425 mg, 1.62 mmol), isopropyl 1H-imidazole-5-carboxylate (125 mg, 0.81 mmol), and diethyl ether (3 mL). The atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added sequentially. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 2) to afford the title compound (145 mg, 0.56 mmol). MS [ESI]: m / z = 260.2, [M+H] + ;

[0587] 1H NMR (400MHz, DMSO-d6) δ8.51(d,J=4.4Hz,1H),8.21(s,1H),7.79-7.75m,1H),7.64(s,1H),7.30-7.27(m,1H ),7.11(d,J=8.0Hz,1H),6.28-6.23(m,1H),5.01-4.95(m,1H),1.85(d,J=7.2Hz,3H),1.16(d,J=6.4Hz,6H).

[0588] Example 58: Preparation of (R)-butyl 1-(1-(p-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 94)

[0589] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), 1H-imidazole-5-carboxylic acid butyl ester (136 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to obtain the title compound (137 mg, 0.48 mmol). MS [ESI]: m / z = 287.2, [M+H] + ;

[0590] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.66(s,1H),7.09(dd,J=24.4,8.1Hz,4H),6.19(q,J=7.2Hz,1H),4.17- 4.08(m,2H),2.24(s,3H),1.81(d,J=7.2Hz,3H),1.57-1.51(m,2H),1.33-1.27(m,2H),0.86(t,J=7.4Hz,3H).

[0591] Example 59: Preparation of (R)-1-(1-(p-Tolyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 95)

[0592] Referring to the operating procedures of Example 57, (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) was substituted for (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) to obtain the title compound (166.0 mg, 0.61 mmol). MS [ESI]: m / z = 273.2, [M+H] + ;

[0593] 1 H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.63(s,1H),7.12(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),6. 19(q,J=7.2Hz,1H),5.04-4.97(m,1H),2.24(s,3H),1.80(d,J=7.2Hz,3H),1.20(d,J=6.4Hz,6H).

[0594] Example 60: Preparation of (R)-1-(1-(p-Tolyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 96)

[0595] To a three-necked flask, add triphenylphosphine (425 mg, 1.62 mmol), isobutyl 1H-imidazole-5-carboxylate (136 mg, 0.81 mmol), and diethyl ether (3 mL). The atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added sequentially. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to afford the title compound (141 mg, 0.49 mmol). MS [ESI]: m / z = 287.2, [M+H] + ;

[0596] 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.68(s,1H),7.12(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),6.20(q,J=7 .2Hz,1H),3.96-3.88(m,2H),2.24(s,3H),1.95-1.87(m,1H),1.81(d,J=7.2Hz,3H),0.88(d,J=6.8Hz,6H).

[0597] Example 61: Preparation of butyl 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 97-rac)

[0598] Referring to the procedure of Example 58, (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) was replaced with 1-(2-nitrophenyl)ethanol (135 mg, 0.81 mmol) to obtain the title compound (181.0 mg, 0.57 mmol). MS [ESI]: m / z = 318.2, [M+H] + ;

[0599] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.02(d,J=7.6Hz,1H),7.71-7.68(m,2H),7.56-7.52(m,1H),7.07(d,J=7.6Hz,1H),6. 48(q,J=7.2Hz,1H),4.05-4.02(m,2H),1.99(d,J=7.2Hz,3H),1.49-1.44(m,2H),1.25-1.15(m,2H),0.81(t,J=7.6Hz,3H).

[0600] Example 62: Preparation of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 98-rac)

[0601] Step 1: Synthesis of 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 112-rac-1)

[0602] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), 1H-imidazole-5-carboxylic acid propyl ester (125 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of 1-(2-nitrophenyl)ethanol (135 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to obtain the title compound (167 mg, 0.55 mmol). MS [ESI]: m / z = 304.3, [M+H] + ;

[0603] 1H NMR (400MHz, DMSO-d6) δ8.51(s,1H),8.01-7.99(m,1H),7.70-7.65(m,2H),7.54-7.49(m,1H),7.05(d,J=7.8Hz ,1H),6.45(q,J=7.2Hz,1H),4.07-3.88(m,2H),1.97(d,J=6.4Hz,3H),1.54-1.49(m,2H),0.79(t,J=7.4Hz,3H).

[0604] Step 2: Synthesis of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 98-rac)

[0605] To a single-necked flask, 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (167 mg, 0.55 mmol), methanol (3 mL), and palladium on carbon (50 mg) were added. After H2 substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered through a pad of celite and concentrated. The crude product was separated by Pre-HPLC to obtain the title compound (106.93 mg, 0.39 mmol). MS [ESI]: m / z = 274.2, [M+H] + ;

[0606] 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.71(s,1H),6.97(t,J=7.2Hz,1H),6.65(dd,J=13.8,7.8Hz,2H),6.51(t,J=7.1Hz,1 H), 6.20 (q, J = 7.2Hz, 1H), 5.01 (s, 2H), 4.14-4.07 (m, 2H), 1.72 (d, J = 6.4Hz, 3H), 1.64-1.61 (m, 2H), 0.86 (t, J = 7.2Hz, 3H).

[0607] Example 63: Preparation of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 99-rac)

[0608] Step 1: Synthesis of 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 110-rac)

[0609] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), isopropyl 1H-imidazole-5-carboxylate (125 mg, 0.81 mmol), and diethyl ether (3 mL) were added and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of 1-(2-nitrophenyl)ethanol (135 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added in sequence. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to afford the title compound (170 mg, 0.56 mmol). MS [ESI]: m / z = 304.3, [M+H] + ;

[0610] 1 H NMR(400MHz, DMSO-d6)δ8.48(s,1H),8.00(dd,J=8.2,1.2Hz,1H),7.69-7.65(m,1H),7.63(d,J=0.8Hz,1H),7.54-7.50(m,1H ),7.03(dd,J=7.8,1.2Hz,1H),6.48(q,J=7.2Hz,1H),4.89-4.83(m,1H),1.96(d,J=7.2Hz,3H),1.10(dd,J=30.2,6.2Hz,6H).

[0611] Step 2: Synthesis of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 99-rac)

[0612] To a single-necked flask, add isopropyl 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (170 mg, 0.56 mmol), methanol (3 mL), and palladium on carbon (50 mg). After H2 substitution, stir at room temperature overnight. After completion of the reaction, filter the reaction mixture through a pad of celite and concentrate. The crude product is separated by Pre-HPLC to obtain the title compound (109.6 mg, 0.40 mmol). MS [ESI]: m / z = 274.2, [M+H] + ;

[0613] 1H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.71(s,1H),6.97(t,J=7.2Hz,1H),6.65(dd,J=13.8,7.8Hz,2H),6.51(t,J=7.1Hz,1 H), 6.20 (q, J = 7.2Hz, 1H), 5.01 (s, 2H), 4.14-4.07 (m, 2H), 1.72 (d, J = 6.4Hz, 3H), 1.64-1.61 (m, 2H), 0.86 (t, J = 7.2Hz, 3H).

[0614] Example 64: Preparation of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 100-rac)

[0615] Step 1: Synthesis of 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 218-rac)

[0616] To a three-necked flask, add triphenylphosphine (425 mg, 1.62 mmol), isobutyl 1H-imidazole-5-carboxylate (136 mg, 0.81 mmol), and diethyl ether (3 mL). The atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of 1-(2-nitrophenyl)ethanol (135 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added sequentially. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to afford the title compound (197 mg, 0.62 mmol). MS [ESI]: m / z = 318.2, [M+H] + ;

[0617] 1 H NMR (400MHz, DMSO-d6) δ8.51(s,1H),7.99(dd,J=8.2,1.2Hz,1H),7.72-7.64(m,2H),7.54-7.49(m,1H),7.05(dd,J=8.0,1 .2Hz, 1H), 6.45 (q, J = 7.2Hz, 1H), 3.85-3.76 (m, 2H), 1.98 (d, J = 6.2Hz, 3H), 1.85-1.78 (m, 1H), 0.80 (dd, J = 6.8, 2.8Hz, 6H).

[0618] Step 2: Synthesis of 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 100-rac)

[0619] To a single-necked flask, 1-(1-(2-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (197 mg, 0.62 mmol), methanol (3 mL), and palladium on carbon (50 mg) were added. After H2 replacement, the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was filtered through a pad of celite and concentrated. The crude product was separated by Pre-HPLC to obtain the title compound (124.0 mg, 0.43 mmol). MS [ESI]: m / z = 288.2, [M+H] + ;

[0620] 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.71(s,1H),6.99-6.95(m,1H),6.69-6.61(m,2H),6.53-6.49(m,1H),6.16(q, J=6.8Hz,1H),5.00(s,2H),4.01-3.94(m,2H),1.97-1.91(m,1H),1.71(d,J=6.8Hz,3H),0.88(dd,J=6.8,3.6Hz,6H).

[0621] Example 65: Preparation of 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 101-rac)

[0622] To a round-bottom flask, add isopropyl 1H-imidazole-5-carboxylate (360 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL) and cool to -20°C. Then, add (S)-1-(2-methoxy)phenylethanol (325 mg, 2.14 mmol) and stir for 10 minutes. Then, add a solution of di-tert-butyl azodicarboxylate (739.14 mg, 3.21 mmol) in diethyl ether (5 mL) dropwise. After nitrogen substitution and continued stirring, return the mixture to room temperature and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / MTBE = 35 / 65) to obtain the title compound (322 mg, 1.12 mmol). MS [ESI]: m / z = 289.1, [M+H] + ;

[0623] 1H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.64(s,1H),7.30-7.21(m,1H),7.01(d,J=8.0Hz,1H),6.87(t,J=7.5Hz,1H),6.63(dd,J=7.6 ,1.3Hz,1H),6.37(q,J=7.1Hz,1H),4.97(m,1H),3.79(s,3H),1.76(d,J=7.1Hz,3H),1.18(d,J=6.3Hz,3H),1.11(d,J=6.2Hz,3H).

[0624] Example 66: Preparation of Isopropyl 1-(1-(4-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 102)

[0625] To a round-bottom flask, add isopropyl 1H-imidazole-5-carboxylate (360 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL). The mixture was cooled to -20°C. (S)-1-(4-methoxy)phenylethanol (325 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. After nitrogen substitution, the mixture was stirred and allowed to cool. 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 (383 mg, 1.33 mmol). MS [ESI]: m / z = 289.2, [M+H] + ;

[0626] 1 H NMR (400MHz, DMSO-d6) δ8.22 (s, 1H), 7.61 (d, J = 0.6Hz, 1H), 7.18-7.09 (m, 2H), 6.92-6.81 (m, 2H), 6 .18(q,J=7.2Hz,1H),5.13-4.94(m,1H),3.71(s,3H),1.80(d,J=7.2Hz,3H),1.22(d,J=6.3Hz,6H).

[0627] Example 67: Preparation of 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 103-rac)

[0628] Anhydrous n-propanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring for 5 minutes, a solution of compound 101-rac (136 mg, 474.80 μmol) in anhydrous n-butanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (45 mg, 0.156 mmol). MS [ESI]: m / z = 289.2, [M+H] + ;

[0629] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.72(d,J=0.6Hz,1H),7.39-7.18(m,1H),7.04(d,J=8.0Hz,1H),6.92(t,J=7.3Hz,1H),6.73(dd,J= 7.6, 1.2Hz, 1H), 6.44 (q, J = 7.1Hz, 1H), 4.17-4.01 (m, 2H), 3.82 (s, 3H), 1.80 (d, J = 7.1Hz, 3H), 1.69-1.52 (m, 2H), 0.89 (t, J = 7.4Hz, 3H).

[0630] Example 68: Preparation of (R)-1-(1-(4-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 104)

[0631] Anhydrous n-propanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 102 (136 mg, 474.80 μmol) in anhydrous n-propanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (45 mg, 0.156 mmol). MS [ESI]: m / z = 289.3, [M+H] + ;

[0632] 1H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.67(s,1H),7.16(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.20(q,J=7 .1Hz,1H),4.23-4.00(m,2H),3.71(s,3H),1.81(d,J=7.2Hz,3H),1.70-1.55(m,2H),0.88(t,J=7.4Hz,3H).

[0633] Example 69: Preparation of methyl 1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 105-rac)

[0634] Methyl 1H-imidazole-5-carboxylate (45.64 mg, 361.89 μmol) and triphenylphosphine (189.84 mg, 723.78 μmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and 3-(1-hydroxyethyl)phenol (50 mg, 361.89 μmol) was added at 0°C. Di-tert-butyl azodicarboxylate (164.29 mg, 713.50 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the solution was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (41 mg, 166.49 μmol). MS [ESI]: m / z = 247.1, [M+H] + ;

[0635] 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.30(d,J=0.7Hz,1H),7.69(d,J=0.9Hz,1H),7.11(t,J=7.9Hz,1H ), 6.65-6.58 (m, 2H), 6.49 (t, J = 2.0Hz, 1H), 6.15 (q, J = 7.2Hz, 1H), 3.72 (s, 3H), 1.79 (t, J = 6.3Hz, 3H).

[0636] Example 70: Preparation of ethyl 1-(1-(4-(benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 106-rac)

[0637] Ethyl 1H-imidazole-5-carboxylate (153.47 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (504.32 mg, 2.19 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (70 mg, 199.77 μmol). MS [ESI]: m / z = 351.1, [M+H] + ;

[0638] 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J = 30.5Hz, 2H), 7.46-7.25 (m, 6H), 7.05-7.02 (m, 1H), 6.97-6.90 (m, 2H), 5. 55(q,J=7.1Hz,1H),5.08(s,2H),4.20(q,J=7.1Hz,2H),1.82(t,J=6.9Hz,3H),1.25(dd,J=8.9,5.3Hz,3H).

[0639] Example 71: Preparation of methyl 1-(1-(4-(benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 107-rac)

[0640] Methyl 1H-imidazole-5-carboxylate (138.11 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (100.86 mg, 438.05 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (125 mg, 371.60 μmol). MS [ESI]: m / z = 337.1, [M+H] + ;

[0641] 1H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 7.69 (d, J = 0.8Hz, 1H), 7.44-7.32 (m, 5H), 7.24 (t, J = 7.9Hz, 1H), 6.92 (dd, J = 8.0, 2.3 Hz, 1H), 6.84-6.81 (m, 1H), 6.74 (d, J = 7.7Hz, 1H), 6.21 (q, J = 7.2Hz, 1H), 5.05 (s, 2H), 3.72 (s, 3H), 1.83 (d, J = 7.2Hz, 3H).

[0642] Example 72: Preparation of ethyl 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 14-rac)

[0643] Ethyl 1H-imidazole-5-carboxylate (169.94 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (100.86 mg, 438.05 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (78 mg, 237.60 μmol). MS [ESI]: m / z = 329.1, [M+H] + ;

[0644] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=0.7Hz,1H),7.70(d,J=0.9Hz,1H),7.47(t,J=8.2Hz,1H),7.30-7.24(m,1H) ,7.16(d,J=7.0Hz,2H),6.25(q,J=7.2Hz,1H),4.24-4.07(m,2H),1.86(d,J=7.2Hz,3H),1.19(t,J=7.1Hz,3H).

[0645] Example 73: Preparation of methyl 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 109-rac)

[0646] Methyl 1H-imidazole-5-carboxylate (152.93 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (100.86 mg, 438.05 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (121 mg, 385.03 μmol). MS [ESI]: m / z = 315.1, [M+H] + ;

[0647] 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),7.71(d,J=0.8Hz,1H),7.48(dd,J=10.3,6.1Hz,1H),7.27(dd ,J=8.3,1.0Hz,1H),7.19-7.15(m,2H),6.25(q,J=7.1Hz,1H),3.71(s,3H),1.86(d,J=7.2Hz,3H).

[0648] Example 74: Preparation of (R)-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 113)

[0649] Referring to the operating procedures of Example 32, butanol was replaced by isopropanol (2 mL) to obtain the title compound (53 mg, 0.17 mmol). MS [ESI]: m / z = 304.3, [M+H] + ;

[0650] 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.16-8.11(m,1H),7.99(s,1H),7.69(s,1H),7.67-7.58(m, 2H), 6.32 (q, J = 7.1Hz, 1H), 5.04-4.91 (m, 1H), 1.90 (d, J = 7.2Hz, 3H), 1.17 (dd, J = 6.2, 2.2Hz, 6H).

[0651] Example 75: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 114)

[0652] Referring to the operating procedures of Example 33, compound 93 (52 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (37 mg, 0.14 mmol). MS [ESI]: m / z = 274.4, [M+H] + ;

[0653] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.68(s,1H),6.95(t,J=7.7Hz,1H),6.44(d,J=8.2Hz,1H),6.35-6.29(m,2H),6. 10(q,J=7.1Hz,1H),5.07(s,2H),4.18-4.02(m,2H),1.77(d,J=7.2Hz,3H),1.67-1.59(m,2H),0.89(t,J=7.4Hz,3H).

[0654] Example 76: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 115)

[0655] Referring to the operating procedures of Example 33, compound 113 (52 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (37 mg, 0.14 mmol). MS [ESI]: m / z = 274.4, [M+H] + ;

[0656] 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.62(s,1H),6.95(t,J=7.9Hz,1H),6.43(d,J=7.6Hz,1H),6.29-6.24( m, 2H), 6.07 (q, J = 7.0Hz, 1H), 5.07 (s, 2H), 5.03-4.95 (m, 1H), 1.76 (d, J = 7.1Hz, 3H), 1.22 (t, J = 5.6Hz, 6H).

[0657] Example 77: Preparation of butyl 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 116-rac)

[0658] Anhydrous butanol (2 mL) was added to a single-necked flask, and sodium hydride (57 mg, 1.42 mmol) was added under ice bath. After stirring for 5 minutes, a solution of compound 62-rac (130 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. After returning to room temperature naturally, stirring was continued. After the reaction was completed, acetic acid (120 mg, 2 mmol) was added dropwise under ice bath. The crude product was separated by Pre-HPLC to obtain the title compound (54 mg, 0.18 mmol). MS [ESI]: m / z = 303.4, [M+H] + ;

[0659] 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.67(s,1H),7.30-7.21(m,1H),7.01(d,J=8.2Hz,1H),6.88(t,J=7.4Hz,1H),6.69(d,J=6.8Hz,1H), 6.40(q,J=7.0Hz,1H),4.18-4.03(m,2H),3.78(s,3H),1.76(d,J=7.1Hz,3H),1.61-1.47(m,2H),1.37-1.22(m,2H),0.86(t,J=7.4Hz,3H).

[0660] Example 78: Preparation of 1-(1-(2-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 117-rac)

[0661] Referring to the operating procedures of Example 77, butanol was replaced by isobutanol (2 mL) to obtain the title compound (53 mg, 0.17 mmol). MS [ESI]: m / z = 303.4, [M+H] + ;

[0662] 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.67(s,1H),7.33-7.21(m,1H),7.01(d,J=8.2Hz,1H),6.88(t,J=7.5Hz,1H),6.6 9(d,J=7.5Hz,1H),6.40(q,J=7.1Hz,1H),4.2-4.07(m,2H),3.79(s,3H),1.76(d,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H).

[0663] Example 79: Preparation of (R)-butyl 1-(1-(4-methoxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 118)

[0664] Referring to the operating steps of Example 68, n-propanol was replaced with n-butanol to obtain the title compound (47 mg, 0.156 mmol, MS [ESI]: m / z = 303.1, [M+H] + ;

[0665] 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 7.65 (d, J = 0.7Hz, 1H), 7.19-7.08 (m, 2H), 6.97-6.81 (m, 2H), 6.18 (q, J = 7.2Hz, 1H), 4. 33-4.01(m,2H),3.71(s,3H),1.80(d,J=7.2Hz,3H),1.64-1.54(m,2H),1.32(dd,J=15.0,7.4Hz,2H),0.88(t,J=7.4Hz,3H).

[0666] Example 80: Preparation of (R) 1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 120)

[0667] To a round-bottom flask, add isobutyl 1H-imidazole-5-carboxylate (336 mg, 2.0 mmol), triphenylphosphine (1050 mg, 4 mmol), and diethyl ether (20 mL) and cool to -20°C. Then, add (S)-1-(2-methylphenyl)ethanol (272 mg, 2 mmol) and stir for 10 minutes. Then, add a solution of di-tert-butyl azodicarboxylate (1.19 g, 4 mmol) in diethyl ether (5 mL) dropwise. After nitrogen substitution and continued stirring, return the mixture to room temperature and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / MTBE = 35 / 65) to afford the title compound (210 mg, 0.73 mmol). MS [ESI]: m / z = 287.1, [M+H] + ;

[0668] 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.54 (s, 1H), 7.26-7.13 (m, 4H), 6.49 (q, J = 6.9Hz, 1H), 4.03 (tt, J = 10.6, 5. 3Hz, 2H), 2.25 (s, 3H), 2.05-1.96 (m, 1H), 1.82 (d, J = 6.9Hz, 3H), 0.99 (d, J = 1.9Hz, 3H), 0.97 (d, J = 1.9Hz, 3H).

[0669] Example 81: Preparation of (R)-ethyl 4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 121)

[0670] To a round-bottom flask, add ethyl 4-fluoro-1H-imidazole-5-carboxylate (338.48 mg, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL). The mixture was cooled to -20°C. (S)-1-(2-fluorophenyl)ethanol (300 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. After nitrogen substitution, the mixture was stirred while still warm. 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 afford the title compound (377 mg, 1.35 mmol). MS [ESI]: m / z = 281.3, [M+H] + ;

[0671] 1 H NMR(400MHz, DMSO-d6)δ8.08(d,J=1.7Hz,1H),7.41-7.30(m,1H),7.26-7.13(m,2H),6.90(td,J=7.8 ,1.5Hz,1H),6.32(q,J=7.1Hz,1H),4.24-4.06(m,2H),1.81(d,J=7.2Hz,3H),1.16(t,J=7.1Hz,3H).

[0672] Example 82: Preparation of (R)propyl 1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 122)

[0673] Referring to the operating procedures of Example 80, 1H-imidazole-5-carboxylic acid propyl ester (226 mg, 1.47 mmol) was substituted for 1H-imidazole-5-carboxylic acid isobutyl ester to obtain the title compound (150 mg, 0.55 mmol). MS [ESI]: m / z = 273.1, [M+H] + ;

[0674] 1H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.74(s,1H),7.24-7.12(m,3H),6.80(dd,J=7.5,5.0Hz,1H),6.34(q,J=7.0Hz,1H) ,4.10(qt,J=10.8,6.6Hz,2H),2.34(s,3H),1.78(d,J=7.1Hz,3H),1.60(dt,J=14.0,7.0Hz,2H),0.88(t,J=7.4Hz,3H).

[0675] Example 83: Preparation of (R)butyl 1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 123)

[0676] Referring to the operating procedures of Example 80, 1H-imidazole-5-carboxylic acid butyl ester (247 mg, 1.47 mmol) was used to replace 1H-imidazole-5-carboxylic acid isobutyl ester to obtain the title compound (160 mg, 0.56 mmol). MS [ESI]: m / z = 287.1, [M+H] + ;

[0677] 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.72(s,1H),7.23-7.14(m,3H),6.83-6.75(m,1H),6.34(q,J=7.0Hz,1H),4.20-4 .08(m,2H),2.34(s,3H),1.78(d,J=7.0Hz,3H),1.63-1.53(m,2H),1.30(dd,J=15.0,7.4Hz,2H),0.88(t,J=7.4Hz,3H).

[0678] Example 84: Preparation of (R)-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 124)

[0679] 1H-Imidazole-5-carboxylic acid propyl ester (252.99 mg, 1.64 mmol) and triphenylphosphine (860.84 mg, 3.28 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and (1S)-1-(3-fluorophenyl)ethanol (230 mg, 1.64 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (755.74 mg, 3.28 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After completion of the reaction, the solution was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (124 mg, 448.78 μmol). MS [ESI]: m / z = 277.1, [M+H] + ;

[0680] 1 H NMR (400MHz, DMSO-d6) δ8.35 (s, 1H), 7.70 (d, J = 0.8Hz, 1H), 7.37 (td, J = 8.0, 6.2Hz, 1H), 7.13-7.06 (m, 1H), 7.01 (ddd, J = 25.3 ,13.6,4.9Hz,2H),6.23(q,J=7.2Hz,1H),4.16-4.02(m,2H),1.85(d,J=7.2Hz,3H),1.65-1.55(m,2H),0.86(t,J=7.4Hz,3H).

[0681] Example 85: Preparation of (R)-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 125)

[0682] Isopropyl 1H-imidazole-5-carboxylate (274.99 mg, 1.78 mmol) and triphenylphosphine (935.70 mg, 3.57 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and (1S)-1-(3-fluorophenyl)ethanol (250 mg, 1.78 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (164.29 mg, 713.50 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (267 mg, 966.32 μmol). MS [ESI]: m / z = 277.1, [M+H] + ;

[0683] 1H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.66(s,1H),7.37(td,J=8.0,6.2Hz,1H),7.10(td,J=8.4,2.3Hz,1H),7.00(ddd, J=27.1,14.5,4.8Hz,2H),6.22(q,J=7.2Hz,1H),5.04-4.96(m,1H),1.84(d,J=7.2Hz,3H),1.19(dd,J=6.2,3.4Hz,6H).

[0684] Example 86: Preparation of (R)-butyl 1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 126)

[0685] Butyl 1H-imidazole-5-carboxylate (300.01 mg, 1.78 mmol) and triphenylphosphine (935.70 mg, 3.57 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and (1S)-1-(3-fluorophenyl)ethanol (250 mg, 1.78 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (164.29 mg, 713.50 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (207 mg, 712.98 μmol). MS [ESI]: m / z = 291.1, [M+H] + ;

[0686] 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.85(s,1H),7.38(td,J=8.0,6.2Hz,1H),7.12(td,J=8.4,2.1Hz,1H),7.05(d,J=10.2Hz,1H),6.98(d,J=7. 8Hz,1H),6.25(q,J=7.1Hz,1H),4.22-4.09(m,2H),1.86(d,J=7.2Hz,3H) ,1.61-1.52(m,2H),1.28(dt,J=14.0,7.0Hz,2H),0.86(t,J=7.4Hz,3H).

[0687] Example 87: Preparation of 1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 127-rac)

[0688] 1H-imidazole-5-carboxylic acid propyl ester (278.96 mg, 1.81 mmol) and triphenylphosphine (949.18 mg, 3.62 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 3-(1-hydroxyethyl)phenol (250 mg, 1.81 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (833.29 mg, 3.62 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the solution was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (157 mg, 572.34 μmol). MS [ESI]: m / z = 275.1, [M+H] + ;

[0689] 1 H NMR (400MHz, CDCl3) δ7.62-7.51(m,2H),7.24-7.16(m,1H),6.84(dd,J=8.1,1.7Hz,1H),6.73(d,J=7.6Hz,1H),6.52(t,J= 1.9Hz, 1H), 5.29 (q, J = 7.0Hz, 1H), 4.18 (t, J = 6.8Hz, 2H), 1.83 (d, J = 7.0Hz, 3H), 1.71-1.61 (m, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0690] Example 88: Preparation of 1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 128-rac)

[0691] Isopropyl 1H-imidazole-5-carboxylate (278.96 mg, 1.81 mmol) and triphenylphosphine (949.18 mg, 3.62 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 3-(1-hydroxyethyl)phenol (250 mg, 1.81 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (833.29 mg, 3.62 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (219 mg, 798.35 μmol). MS [ESI]: m / z = 275.1, [M+H] + ;

[0692] 1H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 8.26 (s, 1H), 7.65 (s, 1H), 7.11 (t, J = 7.9Hz, 1H), 6.66-6.55 (m, 2H), 6. 47(t,J=1.9Hz,1H), 6.13(q,J=7.2Hz,1H), 5.01(dt,J=12.5,6.3Hz,1H), 1.79(d,J=7.2Hz,3H), 1.20(m,6H).

[0693] Example 89: Preparation of 1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 129-rac)

[0694] Isobutyl 1H-imidazole-5-carboxylate (304.34 mg, 1.81 mmol) and triphenylphosphine (949.18 mg, 3.62 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 3-(1-hydroxyethyl)phenol (250 mg, 1.81 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (833.29 mg, 3.62 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (256 mg, 887.84 μmol). MS [ESI]: m / z = 289.1, [M+H] + ;

[0695] 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.28(s,1H),7.70(d,J=0.6Hz,1H),7.10(t,J=7.9Hz,1H),6.66-6.61(m,1H),6.59(d,J=7.7Hz,1H),6.48(t,J= 2.0Hz,1H),6.15(q,J=7.1Hz,1H),3.94(qd,J=10.6,6.6Hz,2H),1.90(tt, J=12.7, 6.3Hz, 1H), 1.78 (t, J= 11.1Hz, 3H), 0.88 (dt, J= 11.5, 5.8Hz, 6H).

[0696] Example 90: Preparation of ethyl 1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 13-rac)

[0697] Ethyl 1H-imidazole-5-carboxylate (169.94 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[2-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (100.86 mg, 438.05 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (118 mg, 359.44 μmol). MS [ESI]: m / z = 389.1, [M+H] + ;

[0698] 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.68(s,1H),7.48-7.42(m,1H),7.38(t,J=7.2Hz,2H),7.15(dd,J= 8.0, 1.5Hz, 1H), 6.50 (q, J = 7.1Hz, 1H), 4.23-4.12 (m, 2H), 1.82 (d, J = 7.1Hz, 3H), 1.20 (t, J = 7.1Hz, 3H).

[0699] Example 91: Preparation of methyl 1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 130-rac)

[0700] Methyl 1H-imidazole-5-carboxylate (152.93 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[2-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (100.86 mg, 438.05 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (138 mg, 439.13 μmol). MS [ESI]: m / z = 315.1, [M+H] + ;

[0701] 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.71(s,1H),7.48-7.42(m,1H),7.37(ddd,J=4.5,3.4,1.9 Hz, 2H), 7.14 (dd, J = 8.1, 1.5Hz, 1H), 6.49 (q, J = 7.1Hz, 1H), 3.32 (s, 3H), 1.82 (d, J = 7.1Hz, 3H).

[0702] Example 92: Preparation of (R)-1-(1-(3-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 131)

[0703] Isobutyl 1H-imidazole-5-carboxylate (300.01 mg, 1.78 mmol) and triphenylphosphine (935.70 mg, 3.57 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and (1S)-1-(3-fluorophenyl)ethanol (250 mg, 1.78 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (821.45 mg, 3.57 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After completion of the reaction, the solution was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (108 mg, 371.99 μmol). MS [ESI]: m / z = 291.1, [M+H] + ;

[0704] 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=1.1Hz,1H),7.97(d,J=1.2Hz,1H),7.42(td,J=8.0,6.2Hz,1H),7.25(d,J=10.2Hz,1H),7.2 0-7.11(m,2H),5.63(q,J=7.1Hz,1H),3.94(d,J=6.7Hz,2H),1.99-1.89(m,1H),1.83(d,J=7.1Hz,3H),0.92(d,J=6.7Hz,6H).

[0705] Example 93: Preparation of (R)-butyl 1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 132)

[0706] Butyl 1H-imidazole-5-carboxylate (262.85 mg, 1.56 mmol) and triphenylphosphine (819.79 mg, 3.13 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and 4-[(1S)-1-hydroxyethyl]benzonitrile (230 mg, 1.56 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (143.94 mg, 625.11 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (157 mg, 558.02 μmol). MS [ESI]: m / z = 298.2, [M+H] + ;

[0707] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=0.6Hz,1H),7.84-7.79(m,2H),7.71(d,J=0.9Hz,1H),7.28(d,J=8.2Hz,2H),6.25(q,J=7 .2Hz, 1H), 4.10 (qt, J = 10.9, 6.5Hz, 2H), 1.86 (d, J = 7.2Hz, 3H), 1.59-1.48 (m, 2H), 1.32-1.19 (m, 2H), 0.85 (t, J = 7.4Hz, 3H).

[0708] Example 94: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 133)

[0709] Isobutyl 1H-imidazole-5-carboxylate (262.85 mg, 1.56 mmol) and triphenylphosphine (819.79 mg, 3.13 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was purged with nitrogen. 4-[(1S)-1-hydroxyethyl]benzonitrile (230 mg, 1.56 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (719.69 mg, 3.13 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction mixture. Stirring was performed at -30°C. After completion of the reaction, the mixture was concentrated under low temperature. The crude product was purified by preparative HPLC and lyophilized to afford the title compound (105 mg, 353.12 μmol). MS [ESI]: m / z = 298.1, [M+H] + ;

[0710] 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=0.6Hz,1H),7.83-7.78(m,2H),7.74(d,J=0.9Hz,1H),7.29(d,J=8.2Hz ,2H),6.25(q,J=7.2Hz,1H),3.90(qd,J=10.6,6.6Hz,2H),1.92-1.81(m,4H),0.85(dd,J=6.7,1.1Hz,6H).

[0711] Example 95: Preparation of (R)-butyl 1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 25)

[0712] Referring to the procedure of Example 58, (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) was substituted for (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) to obtain the title compound (104.19 mg, 0.38 mmol). MS [ESI]: m / z = 274.2, [M+H] + ;

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.50-8.48(m,1H),7.92(s,1H),7.80(td,J=7.7,1.8Hz,1H),7.31(ddd,J=7.6,4.8,1.0Hz,1H),7.24(d ,J=7.9Hz,1H),6.33(q,J=7.2Hz,1H),4.20-4.09(m,2H),1.86(d,J=7.2Hz,3H),1.60-1.49(m,2H),1.33-1.24(m,2H),0.86(t,J=7.4Hz,3H).

[0714] Example 96: Preparation of (R)-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 26)

[0715] Referring to the operating procedures of Example 60, (S)-1-(pyridin-2-yl)ethanol (99.6 mg, 0.81 mmol) was substituted for (S)-1-(p-tolyl)ethanol (110 mg, 0.81 mmol) to obtain the title compound (106.93 mg, 0.39 mmol). MS [ESI]: m / z = 274.2, [M+H] + ;

[0716] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.49(ddd,J=4.8,1.6,0.8Hz,1H),7.93(s,1H),7.79(td,J=7.7,1.8Hz,1H),7.30(ddd,J=7.5 ,4.8,1.0Hz,1H),7.23(d,J=8.0Hz,1H),6.33(q,J=7.2Hz,1H),3.96-3.89(m,2H),1.92-1.86(m,4H),0.87(dd,J=6.8,1.2Hz,6H).

[0717] Example 97: Preparation of (R)-ethyl 4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 42)

[0718] Referring to the operating procedures of Example 81, (S)-1-(4-trifluorophenyl)ethanol was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (52 mg, 0.156 mmol). MS [ESI]: m / z = 331.1, [M+H] + ;

[0719] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=1.7Hz,1H),7.71(d,J=8.2Hz,2H),7.36(d,J=8.2Hz,2H ), 6.21 (q, J = 7.2Hz, 1H), 4.25-4.00 (m, 2H), 1.85 (d, J = 7.2Hz, 3H), 1.16 (t, J = 7.1Hz, 3H).

[0720] Example 98: Preparation of (R)-1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylic acid methyl ester (Compound 134)

[0721] Referring to the operating procedures of Example 27, (S)-1-(2-cyclopropylphenyl)ethanol was used to replace compound 67-1 to obtain the title compound (42 mg, 0.156 mmol). MS [ESI]: m / z = 271.1, [M+H] + ;

[0722] 1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.72(s,1H),7.35-7.10(m,2H),7.05(dd, J=7.3,1.4Hz,1H),6.84(dd,J=7.5,1.4Hz,1H),6.66(q,J=7.0Hz,1H),3.70(s, 3H),2.00(tt,J=8.5,5.5Hz,1H),1.81(d,J=7.0Hz,3H),1.04-0.86(m,1H),0.8 6-0.75(m,1H),0.70(td,J=9.8,5.6Hz,1H),0.56(dtd,J=9.5,5.7,4.0Hz,1H).

[0723] Example 99: Preparation of (R)-ethyl 4-fluoro-1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 135)

[0724] Referring to the operating procedures of Example 81, (S)-1-(2-methylphenyl)ethanol (817 mg, 0.6 mmol) was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (660 mg, 2.39 mmol). MS [ESI]: m / z = 277.1, [M+H] + ;

[0725] 1 H NMR(400MHz, CDCl3)δ7.29(d,J=1.7Hz,1H),7.19-7.11(m,4H),6.25(q,J=7.1Hz, 1H), 4.36-4.25 (m, 2H), 2.35 (s, 3H), 1.83 (d, J = 7.1Hz, 3H), 1.35 (t, J = 7.1Hz, 3H).

[0726] Example 100: Preparation of (R)-methyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 52)

[0727] Anhydrous methanol (2 mL) was added to a round-bottom flask, followed by sodium hydride (56.98 mg, 1.42 mmol) under ice-cooling. After stirring, a solution of compound 47 (125 mg, 474.80 μmol) in anhydrous methanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (39 mg, 0.156 mmol). MS [ESI]: m / z = 250.3, [M+H] + ;

[0728] 1 H NMR(400MHz,DMSO-d6)δ8.49(d,J=4.3Hz,1H),8.07(s,1H),7.79(td,J=7.7,1.2Hz ,1H),7.36-7.17(m,2H),6.20(q,J=7.1Hz,1H),3.69(s,3H),1.83(d,J=7.2Hz,3H).

[0729] Example 101: Preparation of (R)-methyl 4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 136)

[0730] Anhydrous methanol (2 mL) was added to a round-bottom flask, followed by sodium hydride (30.76 mg, 1.34 mmol) under ice-cooling. After stirring, a solution of compound 121 (125 mg, 0.046 mmol) in anhydrous methanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, acetic acid (90 mg, 1.5 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 45 / 55) to obtain the title compound (95 mg, 0.36 mmol). MS [ESI]: m / z = 267.3, [M+H] + ;

[0731] 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=1.4Hz,1H),7.42-7.29(m,1H),7.26-7.11(m,2H),6 .94(td,J=7.7,1.1Hz,1H), 6.33(q,J=7.1Hz,1H), 3.69(s,3H), 1.81(d,J=7.2Hz,3H).

[0732] Example 102: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 54)

[0733] Synthesis was performed by referring to Example 100, using isopropanol (2 mL) instead of anhydrous methanol to obtain the title compound (55 mg, 0.2 mmol), MS [ESI]: m / z = 278.3, [M+H] + ;

[0734] 1 H NMR (400MHz, DMSO-d6) δ8.55-8.45(m,1H),8.03(d,J=1.8Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.36-7.25(m,1H),7 .20(d,J=7.8Hz,1H),6.17(q,J=7.2Hz,1H),5.11-4.83(m,1H),1.83(d,J=7.2Hz,3H),1.14(dd,J=9.8,6.2Hz,6H).

[0735] Example 103: Preparation of (R)-butyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 55)

[0736] Synthesis was performed by referring to Example 100, using n-butanol (2 mL) instead of anhydrous methanol to obtain the title compound (33 mg, 0.11 mmol), MS [ESI]: m / z = 292.3, [M+H] + ;

[0737] 1 H NMR (400MHz, DMSO-d6) δ8.56-8.45(m,1H),8.05(d,J=1.8Hz,1H),7.78(td,J=7.7,1.8Hz,1H),7.29(ddd,J=7.5,4.8,0.7Hz,1H),7.21(d,J=7.9 Hz, 1H), 6.19 (q, J=7.2Hz, 1H), 4.11 (qt, J=10.8, 6.5Hz, 2H), 1.83 (d, J= 7.2Hz, 3H), 1.60-1.47 (m, 2H), 1.35-1.20 (m, 2H), 0.85 (t, J = 7.4Hz, 3H).

[0738] Example 104: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 56)

[0739] Synthesis was performed by referring to Example 100, using isobutanol (2 mL) instead of anhydrous methanol to obtain the title compound (36 mg, 0.12 mmol), MS [ESI]: m / z = 292.3, [M+H] + ;

[0740] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.4Hz,1H),8.06(d,J=1.3Hz,1H),7.78(td,J=7.7,1.5Hz,1H),7.28(dd,J=7.1,5.0Hz,1H ),7.22(d,J=7.8Hz,1H),6.20(q,J=7.1Hz,1H),3.91(qd,J=10.6,6.5Hz,2H),1.93-1.78(m,4H),0.85(dd,J=6.7,1.2Hz,6H).

[0741] Example 105: Preparation of (R)-ethyl 4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 35)

[0742] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 4-fluoro-1H-imidazole-5-carboxylate (128 mg, 0.81 mmol), and diethyl ether (3 mL) were added, and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(3-nitrophenyl)ethanol (135 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added sequentially. After completion of the reaction at -30°C, the mixture was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 1 / 1) to obtain the title compound (127 mg, 0.41 mmol). MS [ESI]: m / z = 308.3, [M+H] + ;

[0743] 1 H NMR(400MHz,DMSO-d6)δ8.22(d,J=0.6Hz,1H),8.17-8.10(m,1H),8.05(s,1H),7.69-7.58(m ,2H),6.26(q,J=7.1Hz,1H),4.24-4.06(m,2H),1.89(d,J=7.2Hz,3H),1.16(t,J=7.1Hz,3H).

[0744] Example 106: Preparation of (R)-methyl 4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 137)

[0745] Anhydrous methanol (2 mL) was added to a single-necked flask. Sodium hydride (57 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 35 (144 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (54 mg, 0.18 mmol). MS [ESI]: m / z = 294.3, [M+H] + ;

[0746] 1 H NMR(400MHz,DMSO-d6)δ8.24(d,J=1.4Hz,1H),8.18-8.11(m,1H),8.05(s,1H) ,7.68-7.65(m,2H),6.26(q,J=7.1Hz,1H),3.70(s,3H),1.88(d,J=7.2Hz,3H).

[0747] Example 107: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester (Compound 31)

[0748] Referring to the operating procedures of Example 33, compound 35 (52 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (37 mg, 0.13 mmol). MS [ESI]: m / z = 278.3, [M+H] + ;

[0749] 1 H NMR(400MHz, DMSO-d6)δ8.00(d,J=1.6Hz,1H),6.96(t,J=7.7Hz,1H),6.46-6.44(m,1H),6.38-6.22(m,2 H), 6.01 (q, J = 7.1Hz, 1H), 5.08 (s, 2H), 4.25-4.11 (m, 2H), 1.76 (d, J = 7.2Hz, 3H), 1.21 (t, J = 7.1Hz, 3H).

[0750] Example 108: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid methyl ester (Compound 138)

[0751] Referring to the operating procedures of Example 33, compound 137 (50 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (37 mg, 0.14 mmol). MS [ESI]: m / z = 264.3, [M+H] + ;

[0752] 1 H NMR(400MHz,DMSO-d6)δ8.04(d,J=1.5Hz,1H),6.96(t,J=7.8Hz,1H),6.46-6.44(m,1H),6 .37-6.27(m,2H),6.01(q,J=7.1Hz,1H),5.10(s,2H),3.73(s,3H),1.76(d,J=7.2Hz,3H).

[0753] Example 109: Preparation of (R)-1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 139)

[0754] Anhydrous isopropanol (2 mL) was added to a single-necked flask. Sodium hydride (57 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 60 (133 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (49 mg, 0.16 mmol). MS [ESI]: m / z = 299.4, [M+H] + ;

[0755] 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.67(s,1H),7.25-7.15(m,2H),7.08-7.00(m,1H),6.88-6.84(m,1H),6.65(q,J=6.9Hz,1H),5.09-4.93(m, 1H),2.01-1.90(m,1H),1.82(d,J=7.0Hz,3H),1.19(t,J=8.0Hz,6H),0.9 9-0.89(m,1H),0.86-0.74(m,1H),0.73-0.63(m,1H),0.60-0.50(m,1H).

[0756] Example 110: Preparation of (R)-butyl 1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 108)

[0757] Referring to the preparation steps of Example 74, the title compound (50 mg, 0.16 mmol) was obtained by replacing isopropanol with butanol. MS [ESI]: m / z = 264.3, [M+H] + ;

[0758] 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.70(s,1H),7.22-7.14(m,2H),7.06-7.02( m,1H),6.88-6.82(m,1H),6.66(q,J=6.8Hz,1H),4.19-4.08(m,2H),2.03-1.94(m, 1H),1.81(d,J=7.0Hz,3H),1.60-1.53(m,2H),1.33-1.24(m,2H),0.96-0.90(m,1H ),0.86(t,J=7.4Hz,3H),0.81-0.75(m,1H),0.72-0.63(m,1H),0.58-0.52(m,1H).

[0759] Example 111: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 140)

[0760] Isopropyl 1H-imidazole-5-carboxylate (240.93 mg, 1.56 mmol) and triphenylphosphine (819.79 mg, 3.13 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and 4-[(1S)-1-hydroxyethyl]benzonitrile (230 mg, 1.56 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (719.69 mg, 3.13 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by pre-HPLC and lyophilized to give the title compound (201 mg, 709.43 μmol). MS [ESI]: m / z = 284.1, [M+H] + ;

[0761] 1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.90(s,1H),7.86-7.81(m,2H),7.32(d,J=8.3Hz,2H), 6.27(q,J=7.1Hz,1H),5.02-4.94(m,1H),1.87(d,J=7.2Hz,3H),1.17(dd,J=6.2,3.8Hz,6H).

[0762] Example 112: Preparation of 1-(1-(4-(benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 141-rac)

[0763] 1H-Imidazole-5-carboxylic acid propyl ester (168.83 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (504.32 mg, 2.19 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title product (110 mg, 301.84 μmol). MS [ESI]: m / z = 365.2, [M+H] + ;

[0764] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=0.6Hz,1H),7.68(d,J=0.9Hz,1H),7.44-7. 31(m,5H),7.24(t,J=7.9Hz,1H),6.91(dd,J=8.1,2.1Hz,1H),6.83-6.81(m,1 H), 6.72 (d, J = 7.7Hz, 1H), 6.21 (q, J = 7.2Hz, 1H), 5.05 (s, 2H), 4.10 (qt, J = 10. 7, 6.6Hz, 2H), 1.83 (d, J = 7.2Hz, 3H), 1.67-1.56 (m, 2H), 0.88 (t, J = 7.4Hz, 3H).

[0765] Example 113: Preparation of Isopropyl 1-(1-(4-(Benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 142-rac)

[0766] Isopropyl 1H-imidazole-5-carboxylate (168.83 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2. 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (504.32 mg, 2.19 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (108 mg, 296.35 μmol). MS [ESI]: m / z = 365.2, [M+H] + ;

[0767] 1 H NMR(400MHz,DMSO-d6)δ8.29(d,J=0.5Hz,1H),7.64(d,J=0.8Hz,1H),7.44-7 .31(m,5H),7.24(t,J=8.0Hz,1H),6.91(dd,J=8.1,2.2Hz,1H),6.83-6.80(m, 1H),6.71(d,J=7.8Hz,1H),6.19(q,J=7.2Hz,1H),5.05(d,J=5.7Hz,2H),5.0 1(dt,J=12.5,6.2Hz,1H), 1.82(d,J=7.2Hz,3H), 1.20(dd,J=6.2,4.4Hz,6H).

[0768] Example 114: Preparation of butyl 1-(1-(4-(benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 111-rac)

[0769] Butyl 1H-imidazole-5-carboxylate (184.19 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2. 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (504.32 mg, 2.19 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was complete, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (98 mg, 258.94 μmol). MS [ESI]: m / z = 379.3, [M+H] + ;

[0770] 1H NMR(400MHz,DMSO-d6)δ8.31(d,J=0.8Hz,1H),7.67(d,J=0.9Hz,1H),7.45-7.30(m ,5H),7.24(t,J=8.0Hz,1H),6.94-6.89(m,1H),6.83-6.80(m,1H),6.72(d,J=7.7Hz ,1H),6.20(q,J=7.2Hz,1H),5.05(s,2H),4.14(qt,J=10.9,6.6Hz,2H),1.83(d,J= 7.2Hz, 3H), 1.62-1.53 ​​(m, 2H), 1.31 (dq, J = 14.6, 7.4Hz, 2H), 0.87 (t, J = 7.4Hz, 3H).

[0771] Example 115: Preparation of Isobutyl 1-(1-(4-(Benzyloxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 143-rac)

[0772] Isobutyl 1H-imidazole-5-carboxylate (184.19 mg, 1.10 mmol) and triphenylphosphine (574.47 mg, 2.19 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-(3-benzyloxyphenyl)ethanol (250 mg, 1.10 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (156.45 mg, 679.47 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (105 mg, 277.44 μmol). MS [ESI]: m / z = 379.3, [M+H] + ;

[0773] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=0.7Hz,1H),7.70(d,J=0.9Hz,1H),7.44-7.32( m,5H),7.24(t,J=8.0Hz,1H),6.91(dd,J=8.0,2.2Hz,1H),6.83-6.80(m,1H),6.72 (d,J=7.8Hz,1H),6.21(q,J=7.2Hz,1H),5.05(s,2H),3.94(qd,J=10.6,6.6Hz,2H) ,1.91(dt,J=13.3,6.7Hz,1H), 1.83(d,J=7.2Hz,3H), 0.88(dd,J=6.7,1.3Hz,6H).

[0774] Example 116: Preparation of Isopropyl 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 144-rac)

[0775] Isopropyl 1H-imidazole-5-carboxylate (186.95 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (156.45 mg, 679.47 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (98 mg, 286.29 μmol). MS [ESI]: m / z = 343.2, [M+H] + ;

[0776] 1 H NMR (400MHz, DMSO-d6) δ8.36(d,J=0.6Hz,1H),7.67(d,J=0.9Hz,1H),7.47(t,J=8.0Hz,1H),7.29-7.25(m,1H),7.14(d ,J=8.2Hz,2H),6.23(q,J=7.2Hz,1H),4.98(dt,J=12.5,6.2Hz,1H),1.86(d,J=7.2Hz,3H),1.17(dd,J=6.2,4.3Hz,6H).

[0777] Example 117: Preparation of butyl 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 145-rac)

[0778] Butyl 1H-imidazole-5-carboxylate (203.96 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (202 mg, 566.88 μmol). MS [ESI]: m / z = 357.1, [M+H] + ;

[0779] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=0.7Hz,1H),7.70(d,J=0.9Hz,1H),7.47(t,J=8.0Hz,1H),7.29-7.24(m,1H),7.17-7.11(m,2H),6.24(q, J=7.2Hz,1H),4.16-4.08(m,2H),1.86(d,J=7.2Hz,3H),1.55(dt,J=14.5,6.6Hz,2H),1.27(dq,J=14.7,7.4Hz,2H),0.85(t,J=7.4Hz,3H).

[0780] Example 118: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 146)

[0781] 1H-imidazole-5-carboxylic acid propyl ester (240.93 mg, 1.56 mmol) and triphenylphosphine (819.79 mg, 3.13 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 4-[(1S)-1-hydroxyethyl]benzonitrile (230 mg, 1.56 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (719.69 mg, 3.13 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (200 mg, 748.15 μmol). MS [ESI]: m / z = 284.1, [M+H] + ;

[0782] 1 H NMR (400MHz, DMSO-d6) δ8.38(d,J=0.6Hz,1H),7.83-7.80(m,2H),7.72(d,J=0.9Hz,1H),7.29(d,J=8.2Hz,2H),6. 25(q,J=7.2Hz,1H),4.06(qt,J=10.7,6.6Hz,2H),1.85(d,J=7.2Hz,3H),1.63-1.53(m,2H),0.84(t,J=7.4Hz,3H).

[0783] Example 119: Preparation of 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 147-rac)

[0784] 1H-imidazole-5-carboxylic acid propyl ester (186.95 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (157 mg, 458.65 μmol). MS [ESI]: m / z = 343.1, [M+H] + ;

[0785] 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.71(d,J=0.7Hz,1H),7.47(t,J=8.0Hz,1H),7.27(dd,J=8.2,1.1Hz,1H),7.16(d, J=8.2Hz,2H),6.25(q,J=7.2Hz,1H),4.13-4.02(m,2H),1.86(t,J=6.8Hz,3H),1.64-1.53(m,2H),0.84(t,J=7.4Hz,3H).

[0786] Example 120: Preparation of Isobutyl 1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 148-rac)

[0787] Isobutyl 1H-imidazole-5-carboxylate (203.96 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2. 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (217 mg, 608.97 μmol). MS [ESI]: m / z = 357.1, [M+H] + ;

[0788] 1H NMR (400MHz, DMSO-d6) δ8.37(t,J=4.0Hz,1H),7.73(d,J=0.9Hz,1H),7.47(t,J=8.0Hz,1H),7.30-7.25(m,1H), 7.19-7.11(m,2H),6.25(q,J=7.2Hz,1H),3.96-3.88(m,2H),1.87(d,J=7.2Hz,4H),0.85(dd,J=6.7,1.9Hz,6H).

[0789] Example 121: Preparation of (R)-4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 149)

[0790] Synthesis: Referring to Example 101, using n-propanol (2 mL) instead of anhydrous methanol to obtain the title compound (57 mg, 0.17 mmol), MS [ESI]: m / z = 295.3, [M+H] + ;

[0791] 1 H NMR(400MHz, DMSO-d6)δ8.07(d,J=1.7Hz,1H),7.35(ddd,J=15.3,5.4,1.7Hz,1H),7.26-7.13(m,2H),6.90(td,J=7.8, 1.5Hz, 1H), 6.32 (q, J = 7.1Hz, 1H), 4.16-3.99 (m, 2H), 1.81 (d, J = 7.1Hz, 3H), 1.63-1.49 (m, 2H), 0.83 (t, J = 7.4Hz, 3H).

[0792] Example 122: Preparation of (R)-butyl 4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 150)

[0793] Synthesis was performed by referring to Example 101, using n-butanol (2 mL) instead of anhydrous methanol to obtain the title compound (97 mg, 0.33 mmol), MS [ESI]: m / z = 309.3, [M+H] + ;

[0794] 1H NMR(400MHz, DMSO-d6)δ8.08(d,J=1.6Hz,1H),7.35(ddd,J=15.3,5.5,1.6Hz,1H),7.27-7.11(m,2H),6.89(td,J=7.8,1.4Hz,1H ), 6.32 (q, J = 7.1Hz, 1H), 4.21-4.03 (m, 2H), 1.81 (d, J = 7.2Hz, 3H), 1.59-1.46 (m, 2H), 1.33-1.19 (m, 2H), 0.84 (t, J = 7.4Hz, 3H).

[0795] Example 123: Preparation of (R)-4-fluoro-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 151)

[0796] Synthesis was performed by referring to Example 101, using n-butanol (2 mL) instead of anhydrous methanol to obtain the title compound (112 mg, 0.36 mmol), MS [ESI]: m / z = 309.3, [M+H] + ;

[0797] 1 H NMR(400MHz, DMSO-d6)δ8.08(d,J=1.6Hz,1H),7.35(ddd,J=15.3,5.4,1.6Hz,1H),7.26-7.12(m,2H),6.91(td,J=7 .8,1.4Hz,1H),6.33(q,J=7.1Hz,1H),3.91(qd,J=10.6,6.5Hz,2H),1.92-1.77(m,4H),0.85(dd,J=6.7,2.6Hz,6H).

[0798] Example 124: Preparation of (R) methyl 4-fluoro-1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 152)

[0799] Anhydrous methanol (2 mL) was added to a round-bottom flask, followed by sodium hydride (41 mg, 1.02 mmol) under ice-cooling. After stirring, a solution of compound 135 (141 mg, 510.30 μmol) in anhydrous methanol (1 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (ACN / water = 50 / 50) to obtain the title compound (17 mg, 64.82 μmol). MS [ESI]: m / z = 263.1, [M+H] + ;

[0800] 1 H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 7.22-7.19 (m, 3H), 6.79 (d, J = 6.7Hz, 1H), 6.26 (q, J = 6.8Hz, 1H), 3.71 (s, 3H), 2.37 (s, 3H), 1.76 (d, J = 6.9Hz, 3H).

[0801] Example 125: Preparation of (R) 4-fluoro-1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 220)

[0802] Referring to the operating procedures of Example 124, methanol was replaced with isopropanol (3 mL) to obtain the title compound (15 mg, 51.67 μmol). MS [ESI]: m / z = 291.1, [M+H] + ;

[0803] 1 H NMR (400MHz, CDCl3) δ7.32-7.17(m,4H),7.08(s,1H),6.44(q,J=6.8Hz,1H),5.26-5.17( m, 1H), 2.30 (s, 3H), 1.83 (d, J = 6.8Hz, 3H), 1.37 (d, J = 6.2Hz, 3H), 1.34 (d, J = 6.3Hz, 3H).

[0804] Example 126: Preparation of (R) 4-fluoro-1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 153)

[0805] Referring to the operating procedures of Example 124, methanol was replaced with isobutanol (3 mL) to obtain the title compound (23 mg, 75.57 μmol). MS [ESI]: m / z = 305.1, [M+H] + ;

[0806] 1 H NMR (400MHz, CDCl3) δ7.30-7.17(m,4H),7.11(d,J=1.5Hz,1H),6.45(q,J=6.9Hz,1H),4.07(qd,J=10.5,6.6Hz,2 H), 2.30 (s, 3H), 2.05 (dt, J = 6.6, 6.0Hz, 1H), 1.83 (d, J = 6.9Hz, 3H), 1.03 (d, J = 2.2Hz, 3H), 1.01 (d, J = 2.2Hz, 3H).

[0807] Example 127: Preparation of (R)butyl 4-fluoro-1-(1-(o-tolyl)ethyl)-1H-imidazole-5-carboxylate (Compound 154)

[0808] Referring to the operating procedures of Example 124, methanol was replaced with n-butanol (3 mL) to obtain the title compound (23 mg, 75.57 μmol). MS [ESI]: m / z = 305.1, [M+H] + ;

[0809] 1 H NMR (400MHz, CDCl3) δ7.31-7.23(m,3H),7.21-7.17(m,1H),7.10(d,J=1.6Hz,1H),6.44(q,J=6.9Hz,1H),4.29(qt,J =10.8, 6.6Hz, 2H), 2.30 (s, 3H), 1.83 (d, J = 6.9Hz, 3H), 1.76-1.66 (m, 2H), 1.50-1.45 (m, 2H), 0.99 (t, J = 7.4Hz, 3H).

[0810] Example 128: Preparation of (R)-1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 155)

[0811] Referring to the operating procedures of Example 74, isopropanol was replaced with isobutanol to obtain the title compound (51 mg, 0.16 mmol). MS [ESI]: m / z = 313.4, [M+H] + ;

[0812] 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.72(s,1H),7.22-7.14(m,2H),7.05-7.03(m,1H),6.91-6.86(m,1H),6.66(q,J=7.0Hz,1H),3.98-3.88(m, 2H),2.00-1.85(m,2H),1.81(d,J=7.0Hz,3H),0.98-0.90(m,1H),0.87(d ,J=6.7Hz,6H),0.83-0.73(m,1H),0.71-0.65(m,1H),0.58-0.52(m,1H).

[0813] Example 129: Preparation of (R)-1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 156)

[0814] Referring to the preparation steps of Example 74, the title compound (46 mg, 0.16 mmol) was obtained by replacing isopropanol with propanol. MS [ESI]: m / z = 299.4, [M+H] + ;

[0815] 1 H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.71(s,1H),7.24-7.12(m,2H),7.08-6 .99(m,1H),6.90-6.83(m,1H),6.66(q,J=7.0Hz,1H),4.15-4.03(m,2H),2.01 -1.94(m,1H),1.81(d,J=7.0Hz,3H),1.67-1.54(m,2H),0.97-0.90(m,1H),0. 86(t,J=7.4Hz,3H),0.82-0.75(m,1H),0.72-0.66(m,1H),0.58-0.52(m,1H).

[0816] Example 130: Preparation of (R)-propyl 4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 157)

[0817] Referring to the operating procedures of Example 106, methanol was replaced with propanol (2 mL) to obtain the title compound (53 mg, 0.16 mmol). MS [ESI]: m / z = 322.3, [M+H] + ;

[0818] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=1.5Hz,1H),8.16-8.09(m,1H),8.05(s,1H),7.69-7.61(m,2H),6.26(q,J =7.1Hz, 1H), 4.07 (qt, J = 10.7, 6.5Hz, 2H), 1.90 (d, J = 7.2Hz, 3H), 1.63-1.48 (m, 2H), 0.82 (t, J = 7.4Hz, 3H).

[0819] Example 131: Preparation of (R)-4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 158)

[0820] Referring to the operating procedures of Example 106, methanol was replaced with isopropanol (2 mL) to obtain the title compound (52 mg, 0.16 mmol). MS [ESI]: m / z = 322.3, [M+H] + ;

[0821] 1 H NMR(400MHz,DMSO-d6)δ8.20(d,J=1.6Hz,1H),8.16-8.10(m,1H),8.07-8.03(m,1H),7.70-7.56(m ,2H),6.24(q,J=7.1Hz,1H),5.07-4.90(m,1H),1.89(d,J=7.2Hz,3H),1.15(dd,J=6.1,4.5Hz,6H).

[0822] Example 132: Preparation of (R)-butyl 4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 159)

[0823] Referring to the operating procedures of Example 106, methanol was replaced with butanol (2 mL) to obtain the title compound (57 mg, 0.17 mmol). MS [ESI]: m / z = 336.3, [M+H] + ;

[0824] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=1.3Hz,1H),8.15-8.12(m,1H),8.07-8.05(m,1H),7.71-7.56(m,2H),6.25(q,J= 7.1Hz,1H),4.19-3.99(m,2H),1.89(d,J=7.2Hz,3H),1.58-1.43(m,2H),1.34-1.16(m,2H),0.82(t,J=7.4Hz,3H).

[0825] Example 133: Preparation of (R)-4-fluoro-1-(1-(3-nitrophenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 160)

[0826] Referring to the operating procedures of Example 106, methanol was replaced with isobutanol (2 mL) to obtain the title compound (54 mg, 0.16 mmol). MS [ESI]: m / z = 336.3, [M+H] + ;

[0827] 1H NMR(400MHz, DMSO-d6)δ8.23(d,J=1.6Hz,1H),8.16-8.10(m,1H),8.07-8.03(m,1H),7.67-7.22(m,2H ), 6.26 (q, J = 7.2Hz, 1H), 3.90 (qd, J = 10.6, 6.5Hz, 2H), 1.94-1.82 (m, 4H), 0.82 (dd, J = 6.7, 2.0Hz, 6H).

[0828] Example 134: Preparation of (R)-methyl 4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 161)

[0829] Anhydrous methanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 42 (157 mg, 474.80 μmol) in anhydrous methanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (38 mg, 0.121 mmol). MS [ESI]: m / z = 317.3, [M+H] + ;

[0830] 1 H NMR (400MHz, DMSO-d6) δ8.20 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 6.21 (q, J = 7.2 Hz, 1H), 3.69 (s, 3H), 1.85 (d, J = 7.2 Hz, 3H).

[0831] Example 135: Preparation of (R)-4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 162)

[0832] Referring to the operating procedures of Example 134, methanol was replaced with isopropanol to obtain the title compound (54 mg, 0.156 mmol). MS [ESI]: m / z = 345.2, [M+H] + ;

[0833] 1H NMR (400MHz, DMSO-d6) δ8.16(d,J=1.7Hz,1H),7.72(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H ), 6.18 (q, J = 7.2Hz, 1H), 5.07-4.87 (m, 1H), 1.85 (d, J = 7.2Hz, 3H), 1.14 (t, J = 6.2Hz, 6H).

[0834] Example 136: Preparation of (R)-propyl 4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 163)

[0835] Referring to the operating procedures of Example 134, methanol was replaced by propanol to obtain the title compound (46 mg, 0.133 mmol). MS [ESI]: m / z = 345.1, [M+H] + ;

[0836] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=1.4Hz,1H),7.71(d,J=8.2Hz,2H),7.36(d,J=8.1Hz,2H),6.20(q,J=7 .1Hz, 1H), 4.07 (qt, J = 10.7, 6.5Hz, 2H), 1.85 (d, J = 7.2Hz, 3H), 1.63-1.46 (m, 2H), 0.82 (t, J = 7.4Hz, 3H).

[0837] Example 137: Preparation of (R)-4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 164)

[0838] Referring to the operating procedures of Example 134, methanol was replaced with isobutanol to obtain the title compound (51 mg, 0.156 mmol). MS [ESI]: m / z = 359.2, [M+H] + ;

[0839] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=1.3Hz,1H),7.70(d,J=8.2Hz,2H),7.36(d,J=8.1Hz,2H),6.2 0(q,J=7.1Hz,1H),3.90(qd,J=10.6,6.5Hz,2H),1.90-1.77(m,4H),0.83(dd,J=6.7,1.1Hz,6H).

[0840] Example 138: Preparation of (R)-butyl 4-fluoro-1-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 165)

[0841] Referring to the operating procedures of Example 134, methanol was replaced by butanol to obtain the title compound (49 mg, 0.138 mmol). MS [ESI]: m / z = 359.1, [M+H] + ;

[0842] 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=1.6Hz,1H),7.71(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),6.19(q,J=7.1Hz,1H),4.10 (qt,J=10.9,6.5Hz,2H),1.85(d,J=7.2Hz,3H),1.50(dq,J=12.8,6.5Hz,2H),1.31-1.15(m,2H),0.82(t,J=7.4Hz,3H).

[0843] Example 139: Preparation of butyl 1-(1-(3-hydroxyphenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 166-rac)

[0844] Butyl 1H-imidazole-5-carboxylate (304.34 mg, 1.81 mmol) and triphenylphosphine (949.18 mg, 3.62 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 3-(1-hydroxyethyl)phenol (250 mg, 1.81 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (166.66 mg, 723.78 μmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (157 mg, 544.49 μmol). MS [ESI]: m / z = 289.1, [M+H] + ;

[0845] 1H NMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 8.28 (d, J = 0.8Hz, 1H), 7.67 (d, J = 1.0H z,1H),7.11(t,J=7.9Hz,1H),6.66-6.55(m,2H),6.48(t,J=2.0Hz,1H),6.14 (q,J=7.2Hz,1H),4.14(qt,J=10.9,6.6Hz,2H),1.80(d,J=7.2Hz,3H),1.58( dt,J=14.4,6.6Hz,2H), 1.30(dt,J=14.6,7.4Hz,2H), 0.88(t,J=7.4Hz,3H).

[0846] Example 140: Preparation of 1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 167-rac)

[0847] 1H-imidazole-5-carboxylic acid propyl ester (186.95 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2, and 1-[3-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (257 mg, 750.78 μmol). MS [ESI]: m / z = 343.1, [M+H] + ;

[0848] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=0.7Hz,1H),7.69(d,J=0.9Hz,1H),7.48-7.43(m,1H),7.37(dd,J=10.9,4.3Hz,2H),7.16(d ,J=7.8Hz,1H),6.50(q,J=7.1Hz,1H),4.09(t,J=6.6Hz,2H),1.82(d,J=7.1Hz,3H),1.66-1.55(m,2H),0.86(t,J=7.4Hz,3H).

[0849] Example 141: Preparation of Isopropyl 1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 168-rac)

[0850] Isopropyl 1H-imidazole-5-carboxylate (186.95 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were placed in a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was purged with nitrogen. 1-[2-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at 0°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction mixture. Stir at 25°C. After completion of the reaction, the mixture was concentrated at low temperature. The crude product was purified by preparative HPLC and lyophilized to afford the title compound (207 mg, 604.71 μmol). MS [ESI]: m / z = 343.1, [M+H] + ;

[0851] 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=0.7Hz,1H),7.64(d,J=1.0Hz,1H),7.48-7.43(m,1H),7.41-7.35(m,2H),7.18(dd, J=7.6,1.6Hz,1H),6.50(q,J=7.1Hz,1H),5.01(dt,J=12.5,6.2Hz,1H),1.82(d,J=7.1Hz,3H),1.20(t,J=6.3Hz,6H).

[0852] Example 142: Preparation of 1-(1-(2-(trifluoromethoxyphenyl)ethyl)-1H-imidazole-5-carboxylic acid butyl ester (Compound 169-rac)

[0853] Butyl 1H-imidazole-5-carboxylate (203.96 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was replaced with N2 and 1-[2-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction solution. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to give the title compound (234 mg, 656.68 μmol). MS [ESI]: m / z = 357.1, [M+H] + ;

[0854] 1H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.68(d,J=0.8Hz,1H),7.48-7.42(m,1H),7.37(t,J=7.3Hz,2H),7.15(dd,J=8.0,1.5Hz,1H),6.49(q,J =7.1Hz, 1H), 4.14 (t, J = 6.5Hz, 2H), 1.82 (d, J = 7.1Hz, 3H), 1.56 (dt, J = 14.5, 6.6Hz, 2H), 1.29 (dq, J = 14.6, 7.4Hz, 2H), 0.86 (t, J = 7.4Hz, 3H).

[0855] Example 143: Preparation of Isobutyl 1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 170-rac)

[0856] Isobutyl 1H-imidazole-5-carboxylate (203.96 mg, 1.21 mmol) and triphenylphosphine (636.12 mg, 2.43 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (8 mL). The atmosphere was purged with nitrogen. 1-[2-(trifluoromethoxy)phenyl]ethanol (250 mg, 1.21 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (558.45 mg, 2.43 mmol) was dissolved in tetrahydrofuran (8 mL) and added dropwise to the reaction mixture. Stirring was performed at -30°C. After completion of the reaction, the mixture was concentrated at low temperature. The crude product was purified by preparative HPLC and lyophilized to afford the title compound (254 mg, 712.80 μmol). MS [ESI]: m / z = 357.1, [M+H] + ;

[0857] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=0.6Hz,1H),7.71(d,J=0.9Hz,1H),7.48-7.42(m,1H),7.37(dd,J=12.8,5.2Hz,2H),7.19-7.15(m ,1H),6.50(q,J=7.1Hz,1H),3.93(d,J=6.6Hz,2H),1.90(dt,J=13.4,6.7Hz,1H),1.82(d,J=7.1Hz,3H),0.88(dd,J=6.7,0.8Hz,6H).

[0858] Example 144: Preparation of methyl 1-(1-(2-aminophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 171-rac)

[0859] Methyl 3-[1-(2-nitrophenyl)ethyl]imidazole-4-carboxylate (500 mg, 1.82 mmol) was added to a single-necked bottle and dissolved in methanol (10 mL). Palladium carbon (579.93 mg, 5.45 mmol) was added and replaced with hydrogen. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (125 mg, 509.63 μmol). MS [ESI]: m / z = 246.1, [M+H] + ;

[0860] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.70(s,1H),6.99-6.94(m,1H),6.65(dd,J=8.0,1.1Hz,1H),6.60(dd,J =7.7,1.4Hz,1H),6.53-6.48(m,1H),6.18(q,J=6.9Hz,1H),5.01(s,2H),3.71(s,3H),1.70(d,J=6.9Hz,3H).

[0861] Example 145: Preparation of ethyl 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 172-rac)

[0862] Referring to the operating procedures of Example 81, (S)-1-(3-trifluoromethoxyphenyl)ethanol was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (54 mg, 0.156 mmol). MS [ESI]: m / z = 347.4, [M+H] + ;

[0863] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=1.7Hz,1H),7.48(t,J=7.9Hz,1H),7.29-7.26(m,1H),7.25-7. 18(m,2H),6.17(q,J=7.2Hz,1H),4.22-4.09(m,2H),1.85(d,J=7.2Hz,3H),1.19(t,J=7.1Hz,3H).

[0864] Example 146: Preparation of ethyl 4-fluoro-1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 173-rac)

[0865] Referring to the operating procedures of Example 81, (S)-1-(2-trifluoromethoxyphenyl)ethanol was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (42 mg, 0.123 mmol). MS [ESI]: m / z = 347.1, [M+H] + ;

[0866] 1 H NMR(400MHz, DMSO-d6)δ7.96(d,J=1.7Hz,1H),7.49-7.41(m,1H),7.40-7.34(m,2H),7.15(dd,J=8.0 ,1.5Hz,1H),6.40(q,J=7.1Hz,1H),4.29-4.06(m,2H),1.81(d,J=7.1Hz,3H),1.17(t,J=7.1Hz,3H).

[0867] Example 147: Preparation of methyl 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 174-rac)

[0868] Anhydrous methanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 172-rac (164 mg, 474.80 μmol) in anhydrous methanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (42 mg, 0.125 mmol). MS [ESI]: m / z = 333.1, [M+H] + ;

[0869] 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=1.6Hz,1H),7.48(t,J=8.0Hz,1H),7.28(d,J=8.3H z,1H),7.24-7.16(m,2H),6.17(q,J=7.2Hz,1H),3.70(s,3H),1.85(d,J=7.2Hz,3H).

[0870] Example 148: Preparation of (R)-1-(1-(2-(dimethylamino)phenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 16)

[0871] To a round-bottom flask, add isopropyl 1H-imidazole-5-carboxylate (360 g, 2.14 mmol), triphenylphosphine (841.93 mg, 3.21 mmol), and diethyl ether (20 mL) and cool to -20°C. Then, add (S)-1-(2-(dimethylamino)phenyl)ethanol (353 mg, 2.14 mmol) and stir. Then, add a solution of di-tert-butyl azodicarboxylate (739.14 mg, 3.21 mmol) in diethyl ether (5 mL) dropwise. After nitrogen substitution and continued stirring, return the mixture to room temperature and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (PE / MTBE = 35 / 65) to obtain the title compound (381 mg, 1.33 mmol). MS [ESI]: m / z = 288.2, [M+H] + ;

[0872] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=0.5Hz,1H),7.67(d,J=0.9Hz,1H),7.34-7.24(m,2H),7.09(ddd,J=8.4,6.3,2.4Hz,1H ), 6.92-6.78 (m, 1H), 6.60 (q, J = 7.0Hz, 1H), 4.26-4.12 (m, 2H), 2.55 (s, 6H), 1.78 (d, J = 7.1Hz, 3H), 1.22 (t, J = 7.1Hz, 3H).

[0873] Example 149: Preparation of 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 175-rac)

[0874] Referring to the operating procedures of Example 147, methanol was replaced by propanol to obtain the title compound (45 mg, 0.126 mmol). MS [ESI]: m / z = 361.2, [M+H] + ;

[0875] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=1.7Hz,1H),7.48(t,J=7.9Hz,1H),7.28(d,J=8.2Hz,1H),7.25-7.16(m,2H ), 6.17 (q, J = 7.2Hz, 1H), 4.21-3.88 (m, 2H), 1.85 (d, J = 7.2Hz, 3H), 1.67-1.46 (m, 2H), 0.83 (t, J = 7.4Hz, 3H).

[0876] Example 150: Preparation of 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 176-rac)

[0877] Referring to the operating procedures of Example 147, methanol was replaced with isopropanol to obtain the title compound (42 mg, 0.123 mmol). MS [ESI]: m / z = 361.4, [M+H] + ;

[0878] 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=1.7Hz,1H),7.48(t,J=8.0Hz,1H),7.28(dd,J=8.2,1.0Hz,1H),7.2 3-7.07(m,2H),6.15(q,J=7.2Hz,1H),5.11-4.79(m,1H),1.85(d,J=7.2Hz,3H),1.15(t,J=6.6Hz,6H).

[0879] Example 151: Preparation of butyl 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 177-rac)

[0880] Referring to the operating procedures of Example 147, methanol was replaced with n-butanol to obtain the title compound (42 mg, 0.111 mmol). MS [ESI]: m / z = 375.2, [M+H] + ;

[0881] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=1.5Hz,1H),7.47(t,J=8.2Hz,1H),7.26(d,J=8.3Hz,1H),7.23-7.16(m,2H),6.17(q ,J=7.1Hz,1H),4.35-3.98(m,2H),1.85(d,J=7.2Hz,3H),1.60-1.40(m,2H),1.31-1.16(m,2H),0.82(t,J=7.4Hz,3H).

[0882] Example 152: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid propyl ester (Compound 178)

[0883] Referring to the procedure of Example 33, compound 157 (50 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (40 mg, 0.14 mmol). MS [ESI]: m / z = 292.3, [M+H] + ;

[0884] 1 H NMR(400MHz, DMSO-d6)δ8.00(d,J=1.5Hz,1H),6.96(t,J=7.7Hz,1H),6.52-6.42(m,1H),6.34-6.30(m,2H),6.02( q,J=7.1Hz,1H),5.08(s,2H),4.17-4.06(m,2H),1.76(d,J=7.2Hz,3H),1.66-1.56(m,2H),0.89(t,J=7.4Hz,3H).

[0885] Example 153: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 179)

[0886] Referring to the operating procedures of Example 33, compound 158 (50 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (41 mg, 0.14 mmol). MS [ESI]: m / z = 292.3, [M+H] + ;

[0887] 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=1.6Hz,1H),6.96(t,J=7.7Hz,1H),6.49-6.41(m,1H),6.34-6.28(m,2H) ,5.99(q,J=7.1Hz,1H),5.08(s,2H),5.05-4.99(m,1H),1.76(d,J=7.2Hz,3H),1.20(dd,J=8.0,6.3Hz,6H).

[0888] Example 154: Preparation of (R)-butyl 1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 180)

[0889] Referring to the operating procedures of Example 33, compound 159 (57 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (41 mg, 0.13 mmol). MS [ESI]: m / z = 306.4, [M+H] + ;

[0890] 1 H NMR (400MHz, DMSO-d6) δ8.00(d,J=1.5Hz,1H),6.96(t,J=7.7Hz,1H),6.49-6.37(m,1H),6.38-6.26(m,2H),6.00(q,J=7.1H z,1H),5.08(s,2H),4.28-4.05(m,2H),1.75(d,J=7.2Hz,3H),1.61-1.53(m,2H),1.38-1.27(m,2H),0.87(t,J=7.4Hz,3H).

[0891] Example 155: Preparation of (R)-1-(1-(3-aminophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 181)

[0892] Referring to the operating procedures of Example 33, compound 160 (57 mg, 0.17 mmol) was substituted for compound 72 to obtain the title compound (41 mg, 0.13 mmol). MS [ESI]: m / z = 306.4, [M+H] + ;

[0893] 1 H NMR(400MHz, DMSO-d6)δ8.01(d,J=1.6Hz,1H),6.96(t,J=7.9Hz,1H),6.50-6.43(m,1H),6.35-6.31(m,2H),6.02(q, J=7.1Hz,1H),5.08(s,2H),4.00-3.90(m,2H),1.97-1.86(m,1H),1.76(d,J=7.2Hz,3H),0.89(dd,J=6.7,0.7Hz,6H).

[0894] Example 156: Preparation of ethyl 1-(1-(2-(dimethylamino)phenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 46-rac)

[0895] Compound 46-rac-1 (100 mg, 0.38 mmol) and cesium carbonate (371.6 mg, 0.11 mmol) were dissolved in 3 mL of anhydrous DMF, cooled to 0°C, and iodomethane (107.9 mg, 0.76 mmol) was added dropwise. After nitrogen substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered and concentrated. The crude product was separated by Pre-HPLC to obtain the title compound (88.2 mg, 0.28 mmol). MS [ESI]: m / z = 306.2, [M+H] + ;

[0896] 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=1.5Hz,1H),7.38-7.28(m,2H),7.16-7.12(m,1H),6.89(d,J=7.6Hz,1 H), 6.56 (q, J = 7.2Hz, 1H), 4.27-4.18 (m, 2H), 2.59 (s, 6H), 1.80 (d, J = 7.2Hz, 3H), 1.23 (t, J = 7.2Hz, 3H).

[0897] Example 157: Preparation of (R)-ethyl 4-fluoro-1-(1-(4-nitrophenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 182)

[0898] To a three-necked flask, triphenylphosphine (425 mg, 1.62 mmol), ethyl 4-fluoro-1H-imidazole-5-carboxylate (128 mg, 0.81 mmol), and diethyl ether (3 mL) were added, and the atmosphere was replaced with nitrogen. The temperature was lowered to -10°C, and a solution of (S)-1-(4-nitrophenyl)ethanol (135 mg, 0.81 mmol) in diethyl ether and a solution of di-tert-butyl azodicarboxylate (373 mg, 1.62 mmol) in diethyl ether were added sequentially. The reaction was allowed to proceed at -30°C. After completion, the reaction was quenched with water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (PE / MTBE = 1 / 4) to afford the title compound (203 mg, 0.66 mmol). MS [ESI]: m / z = 308.2, [M+H] + ;

[0899] 1 H NMR (400MHz, DMSO-d6) δ8.21-8.19(m,3H),7.43-7.38(m,2H),6.23(q,J=7.2Hz,1H),4.20-4.07(m,2H),1.86(d,J=7.2Hz,3H),1.16(t,J=7.2Hz,3H).

[0900] Example 158: Preparation of 4-fluoro-1-(1-(3-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 183-rac)

[0901] Referring to the operating procedures of Example 147, methanol was replaced with isobutanol to obtain the title compound (47 mg, 0.123 mmol). MS [ESI]: m / z = 375.6, [M+H] + ;

[0902] 1 H NMR(400MHz, DMSO-d6)δ8.18(d,J=1.7Hz,1H),7.48(t,J=8.2Hz,1H),7.32-7.22(m,1H),7.24-7.1 7(m,2H),6.17(q,J=7.2Hz,1H),4.07-3.71(m,2H),2.00-1.69(m,4H),0.85(dd,J=6.7,2.8Hz,6H).

[0903] Example 159: Preparation of methyl 4-fluoro-1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 184-rac)

[0904] Anhydrous methanol (2 mL) was added to a round-bottom flask. Sodium hydride (56.98 mg, 1.42 mmol) was added under ice-cooling. After stirring, a solution of compound 173-rac (164 mg, 474.80 μmol) in anhydrous methanol (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was purified by Pre-HPLC (acetonitrile / water = 50 / 50) to obtain the title compound (42 mg, 0.125 mmol). MS [ESI]: m / z = 333.1, [M+H] + ;

[0905] 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J=1.6Hz,1H),7.52-7.43(m,1H),7.41-7.35(m,2 H),7.19-7.09(m,1H),6.39(q,J=7.1Hz,1H),3.70(s,3H),1.81(d,J=7.1Hz,3H).

[0906] Example 160: Preparation of 4-fluoro-1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester (Compound 185-rac)

[0907] Referring to the operating procedures of Example 159, methanol was replaced by propanol to obtain the title compound (44 mg, 0.123 mmol). MS [ESI]: m / z = 361.3, [M+H] + ;

[0908] 1 H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.53-7.44(m,1H),7.42-7.33(m,2H),7.23-7.13(m,1H),6.41( q,J=6.9Hz,1H),4.27-3.88(m,2H),1.81(d,J=7.1Hz,3H),1.68-1.49(m,2H),0.85(t,J=7.4Hz,3H).

[0909] Example 161: Preparation of 4-fluoro-1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester (Compound 186-rac)

[0910] Referring to the operating procedures of Example 159, methanol was replaced with isopropanol to obtain the title compound (36 mg, 0.111 mmol). MS [ESI]: m / z = 361.2, [M+H] + ;

[0911] 1 H NMR (400MHz, DMSO-d6) δ7.91 (d, J = 1.7Hz, 1H), 7.53-7.46 (m, 1H), 7.45-7.37 (m, 2H), 7.23-7.16 (m ,1H),6.41(q,J=7.1Hz,1H),5.10-4.97(m,1H),1.80(d,J=7.1Hz,3H),1.17(dd,J=6.0,5.3Hz,6H).

[0912] Example 162: Preparation of 4-fluoro-1-(1-(2-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylic acid isobutyl ester (Compound 187-rac)

[0913] Referring to the operating procedures of Example 159, methanol was replaced with isobutanol to obtain the title compound (54 mg, 0.144 mmol). MS [ESI]: m / z = 375.4, [M+H]+ ;

[0914] 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 1.6Hz, 1H), 7.54-7.44 (m, 1H), 7.43-7.36 (m, 2H), 7.23-7. 17(m,1H),6.41(q,J=7.1Hz,1H),4.03-3.80(m,2H),1.94-1.70(m,4H),0.85(d,J=6.7Hz,6H).

[0915] Example 163: Preparation of ethyl 4-fluoro-1-(1-(pyrimidin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 51-rac)

[0916] Referring to the operating procedures of Example 81, (S)-1-(2-fluorophenyl)ethanol was replaced with 1-(pyrimidin-2-yl)ethanol (1.41 g, 11.32 mmol) to obtain the title compound (950 mg, 3.6 mmol). MS [ESI]: m / z = 265.1, [M+H] + ;

[0917] 1 H NMR (400MHz, CDCl3) δ8.74(d,J=4.9Hz,2H),7.64(d,J=1.5Hz,1H),7.24(t,J=4.9Hz,1H) ,6.45(q,J=7.3Hz,1H),4.34-4.20(m,2H),1.98(d,J=7.3Hz,3H),1.32(t,J=7.1Hz,3H).

[0918] Example 164: Preparation of (R)-propyl 1-(1-(3-(dimethylamino)phenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 188)

[0919] Compound 178 (130 mg, 0.45 mmol), 30% aqueous formaldehyde solution (893 mg, 29.77 mmol), and methanol (5 mL) were added to a single-necked flask and stirred at room temperature. Sodium cyanoborohydride (141 mg, 2.25 mmol) was then added. After the reaction was complete, the reaction solution was directly subjected to Pre-HPLC to obtain the title compound (72 mg, 0.23 mmol). MS [ESI]: m / z = 320.4, [M+H] + ;

[0920] 1H NMR (400MHz, DMSO-d6) δ8.08(d,J=1.5Hz,1H),7.12(t,J=7.9Hz,1H),6.64-6.52(m,2H),6.43(d,J=7.6Hz,1H),6.0 9(q,J=7.1Hz,1H),4.15-4.05(m,2H),2.85(s,6H),1.81(d,J=7.2Hz,3H),1.63-1.58(m,2H),0.87(t,J=7.4Hz,3H).

[0921] Example 165: Preparation of ethyl 4-fluoro-1-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 219)

[0922] Referring to the procedure of Example 81, (S)-1-(2-fluorophenyl)ethanol was replaced with 1-(4-(trifluoromethoxy)phenyl)ethanol (618 mg, 3.0 mmol) to obtain the title compound (420 mg, 1.21 mmol). MS [ESI]: m / z = 347.1, [M+H] + ;

[0923] 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 1.3Hz, 1H), 7.28-7.19 (m, 4H), 6.33 (q, J = 7.1Hz, 1H), 4.35-4.25 (m, 2H), 1.88 (d, J = 7.1Hz, 3H), 1.34 (t, J = 7.1Hz, 3H).

[0924] Example 166: Preparation of (R)-1-(1-(4-cyanophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester (Compound 33)

[0925] Ethyl 4-fluoro-1H-imidazole-5-carboxylate (537.22 mg, 3.40 mmol) and triphenylphosphine (1.78 g, 6.79 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (10 mL). The atmosphere was replaced with N2 and compound 33-1 (500 mg, 3.40 mmol) was added at -30°C. Di-tert-butyl azodicarboxylate (1.56 g, 6.79 mmol) was dissolved in tetrahydrofuran (10 mL) and added dropwise to the reaction solution. The mixture was stirred at -30°C. After the reaction was completed, the mixture was concentrated at low temperature. The crude product was purified by Pre-HPLC and lyophilized to obtain the title compound (812 mg, 2.83 mmol). MS [ESI]: m / z = 288.1, [M+H] + ;

[0926] 1 H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.7Hz,1H),7.84-7.80(m,2H),7.32(d,J=8.2Hz,2H) ,6.17(q,J=7.2Hz,1H),4.20-4.07(m,2H),1.83(d,J=7.2Hz,3H),1.16(t,J=7.1Hz,3H).

[0927] Example 167: Preparation of ethyl 4-fluoro-1-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 37)

[0928] Referring to the operating procedures of Example 81, (S)-1-(p-tolyl)ethanol (680 mg, 4.99 mmol) was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (560 mg, 2.03 mmol). MS [ESI]: m / z = 277.1, [M+H] + ;

[0929] 1 H NMR (400MHz, CDCl3) δ7.32 (d, J = 1.4Hz, 1H), 7.17-7.10 (m, 4H), 6.28 (q, J = 7.1Hz, 1H), 4.35-4.29 (m, 2H), 2.38 (s, 3H), 1.86 (d, J = 7.1Hz, 3H), 1.37 (t, J = 7.1Hz, 3H).

[0930] Example 168: Preparation of (R)-ethyl 4-fluoro-1-(1-(2-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 189)

[0931] Referring to the procedure of Example 81, (S)-1-(2-(trifluoromethyl)phenyl)ethanol (760 mg, 4.0 mmol) was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (480 mg, 1.45 mmol). MS [ESI]: m / z = 331.1, [M+H] + ;

[0932] 1H NMR (400MHz, CDCl3) δ7.78(d,J=7.8Hz,1H),7.64(t,J=7.6Hz,1H),7.52(t,J=7.6Hz,1H),7.32(d,J=7.7Hz,1H) ,7.22(d,J=1.5Hz,1H),6.66(q,J=6.8Hz,1H),4.37-4.26(m,2H),1.91(d,J=6.9Hz,3H),1.34(t,J=7.1Hz,3H).

[0933] Example 169: Preparation of (R)-ethyl 1-(1-(3-bromophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylate (Compound 190)

[0934] Referring to the operating procedures of Example 105, (S)-1-(3-bromophenyl)ethanol (162 mg, 0.81 mmol) was substituted for (S)-1-(3-nitrophenyl)ethanol to obtain the title compound (148 mg, 0.44 mmol). MS [ESI]: m / z = 342.2, [M+H] + ;

[0935] 1 H NMR(400MHz, DMSO-d6)δ8.16(d,J=1.5Hz,1H),7.50-7.39(m,2H),7.30(t,J=7.9Hz,1H),7.15(d,J= 7.8Hz, 1H), 6.12 (q, J = 7.1Hz, 1H), 4.20-4.11 (m, 2H), 1.83 (d, J = 7.2Hz, 3H), 1.18 (t, J = 7.1Hz, 3H).

[0936] Example 170: Preparation of (R)-1-(1-(3-bromophenyl)ethyl)-4-fluoro-1H-imidazole-5-carboxylic acid methyl ester (Compound 191)

[0937] Referring to the procedure of Example 106, compound 190 (160 mg, 474.80 μmol) was substituted for compound 35 to obtain the title compound (56 mg, 0.17 mmol). MS [ESI]: m / z = 328.2, [M+H] + ;

[0938] 1H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.7Hz,1H),7.50-7.39(m,2H),7.31(t,J=7.9Hz,1 H), 7.16 (d, J = 7.8Hz, 1H), 6.13 (q, J = 7.2Hz, 1H), 3.71 (s, 3H), 1.83 (d, J = 7.2Hz, 3H).

[0939] Example 171: Preparation of (R)-ethyl 4-fluoro-1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 192)

[0940] Referring to the procedure of Example 105, (S)-1-(3-(trifluoromethyl)phenyl)ethanol (154 mg, 0.81 mmol) was substituted for (S)-1-(3-nitrophenyl)ethanol to obtain the title compound (135 mg, 0.41 mmol). MS [ESI]: m / z = 331.3, [M+H] + ;

[0941] 1 H NMR(400MHz,DMSO-d6)δ8.21(d,J=1.6Hz,1H),7.67-7.55(m,3H),7.45(d,J=7.7Hz,1H) ,6.22(q,J=7.2Hz,1H),4.20-4.10(m,2H),1.87(d,J=7.2Hz,3H),1.15(t,J=7.1Hz,3H).

[0942] Example 172: Preparation of (R)-methyl 4-fluoro-1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-imidazole-5-carboxylate (Compound 193)

[0943] Referring to the procedure of Example 106, compound 192 (155 mg, 474.80 μmol) was substituted for compound 35 to obtain the title compound (53 mg, 0.19 mmol). MS [ESI]: m / z = 317.3, [M+H] + ;

[0944] 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=0.6Hz,1H),7.68-7.54(m,3H),7.46(d,J=7.7Hz,1H),6.22(q,J=7.1Hz,1H),3.70(s,3H),1.87(d,J=7.2Hz,3H).

[0945] Example 173: Preparation of 2-fluoroethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 194)

[0946] 2-Fluoroethanol (2 mL) was added to a single-necked flask, followed by sodium hydride (57 mg, 1.42 mmol) under ice-cooling. After stirring, a solution of compound 47 (124 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (49 mg, 0.17 mmol). MS [ESI]: m / z = 282.3, [M+H] + ;

[0947] 1 H NMR (400MHz, DMSO-d6) δ8.55-8.47(m,1H),8.10(d,J=1.8Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.30(ddd,J=7.6,4.8,0.9Hz,1H ),7.25(d,J=7.9Hz,1H),6.19(q,J=7.2Hz,1H),4.69-4.63(m,1H),4.59-4.51(m,1H),4.45-4.29(m,2H),1.84(d,J=7.2Hz,3H).

[0948] Example 174: Preparation of 2-methoxyethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 195)

[0949] Ethylene glycol methyl ether (2 mL) was added to a single-necked flask, followed by sodium hydride (57 mg, 1.42 mmol) under ice-cooling. After stirring, a solution of compound 47 (157 mg, 474.80 μmol) in tetrahydrofuran (0.5 mL) was added dropwise. The mixture was allowed to return to room temperature and continued stirring. After the reaction was complete, acetic acid (120 mg, 2 mmol) was added dropwise under ice-cooling. The crude product was separated by Pre-HPLC to obtain the title compound (53 mg, 0.17 mmol). MS [ESI]: m / z = 294.2, [M+H] + ;

[0950] 1H NMR (400MHz, DMSO-d6) δ8.52-8.47(m,1H),8.08(d,J=1.6Hz,1H),7.78(td,J=7.7,1.7Hz,1H),7.31-7.23( m, 2H), 6.19 (q, J = 7.2Hz, 1H), 4.30-4.16 (m, 2H), 3.51 (t, J = 4.8Hz, 2H), 3.23 (s, 3H), 1.83 (d, J = 7.2Hz, 3H).

[0951] Example 175: Preparation of 2-hydroxyethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 196)

[0952] Synthesize Reference Example 100 by replacing anhydrous methanol with ethylene glycol (2 mL) to obtain the title compound (27 mg, 0.10 mmol); MS [ESI]: m / z = 280.1, [M+H] + ;

[0953] 1 H NMR(400MHz, DMSO-d6)δ8.50(dd,J=4.7,0.6Hz,1H),8.06(d,J=1.8Hz,1H),7.79(td,J=7.7,1.8Hz,1H) ,7.33-7.22(m,2H),6.21(q,J=7.2Hz,1H),4.17-4.07(m,2H),3.62-3.52(m,2H),1.83(d,J=7.2Hz,3H).

[0954] Example 176: Preparation of 3-hydroxypropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 197)

[0955] Reference Example 100 was synthesized by replacing anhydrous methanol with 1,3-propylene glycol (2 mL) to obtain the title compound (36 mg, 0.12 mmol). MS [ESI]: m / z = 294.3, [M+H] + ;

[0956] 1H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.2Hz,1H),8.05(d,J=1.7Hz,1H),7.78(td,J=7.7,1.8Hz,1H),7.32-7.26(m,1H),7.23(d,J=7.9Hz,1H) ,6.19(q,J=7.2Hz,1H),4.51(t,J=5.2Hz,1H),4.15(pt,J=7.4,5.9Hz,2H),3.47-3.40(m,2H),1.83(d,J=7.2Hz,3H),1.70(p,J=6.3Hz,2H).

[0957] Example 177: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 198)

[0958] Synthesize Reference Example 100, using n-pentanol (2 mL) instead of anhydrous methanol to obtain the title compound (33 mg, 0.11 mmol), MS [ESI]: m / z = 306.3, [M+H] + ;

[0959] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.3Hz,1H),8.05(d,J=1.7Hz,1H),7.78(td,J=7.7,1.7Hz,1H),7.29(dd,J=6.9,4.9Hz,1H),7.21(d,J=7.9Hz, 1H),6.19(q,J=7.2Hz,1H),4.10(qt,J=10.8,6.5Hz,2H),1.83(d,J=7.2 Hz, 3H), 1.54 (p, J = 6.7 Hz, 2H), 1.31-1.17 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H).

[0960] Example 178: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid allyl ester (Compound 199)

[0961] Synthesis: Referring to Example 186, allyl bromide (0.85 g, 7 mmol) was used to replace 3-bromoprop-1-yne to obtain the title compound (1.1 g, 3.76 mmol). MS [ESI]: m / z = 276.3, [M+H] + ;

[0962] 1H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.6Hz,1H),8.10(d,J=1.3Hz,1H),7.78(td,J=7.7,1.6Hz,1H),7.29(dd,J=7.3,5.0Hz,1H),7.23(d,J=7.8Hz ,1H),6.19(q,J=7.1Hz,1H),5.89(ddd,J=22.4,10.5,5.2Hz,1H),5.23(ddd,J=13.9,11.6,1.3Hz,2H),4.76-4.57(m,2H),1.83(d,J=7.2Hz,3H).

[0963] Example 179: Preparation of 3-fluoropropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 200)

[0964] Synthesize Reference Example 100, using 3-fluoropropanol (2 ml) instead of anhydrous methanol to obtain the title compound (38 mg, 0.13 mmol), MS [ESI]: m / z = 296.3, [M+H] + ;

[0965] 1 H NMR (400MHz, CDCl3) δ8.58 (dd, J=5.3, 1.7Hz, 1H), 7.70-7.62 (m, 2H), 7.24-7.19 (m, 2H), 6.36 (q, J=7.1Hz, 1H), 4. 62(t,J=5.8Hz,1H), 4.51(t,J=5.8Hz,1H), 4.43-4.27(m,2H), 2.08(dp,J=25.6,6.0Hz,2H), 1.89(d,J=7.2Hz,3H).

[0966] Example 180: Preparation of 3-methoxypropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 201)

[0967] Synthesis was performed by referring to Example 100, using 3-methoxypropanol (2 mL) instead of anhydrous methanol to obtain the title compound (35 mg, 0.113 mmol). MS [ESI]: m / z = 308.1, [M+H] + ;

[0968] 1H NMR (400MHz, DMSO-d6) δ8.52(d,J=4.0Hz,1H),8.09(d,J=1.7Hz,1H),7.82(td,J=7.7,1.8Hz,1H),7.32(ddd,J=7.5,4.8,0.8Hz,1H),7.25 (d,J=7.9Hz,1H),6.22(q,J=7.2Hz,1H),4.23-4.12(m,2H),3.34(d,J=6.2Hz,2H),3.21(s,3H),1.86(d,J=7.2Hz,3H),1.80-1.75(m,2H).

[0969] Example 181: Preparation of dodecyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 202)

[0970] Synthesis was performed by referring to Example 100, using n-dodecanol (2 mL) instead of anhydrous methanol to obtain the title compound (25 mg, 0.069 mmol). MS [ESI]: m / z = 404.3, [M+H] + ;

[0971] 1 H NMR (400MHz, DMSO-d6) δ8.52(dd,J=4.8,0.8Hz,1H),8.08(d,J=1.7Hz,1H),7.81(td,J=7.7,1.8Hz,1H),7.32(ddd,J=7.5,4.8,0.9Hz,1H),7.24(d,J= 7.9Hz,1H),6.22(q,J=7.2Hz,1H),4.13(qt,J=10.8,6.5Hz,2H),1.86(d,J =7.2Hz,3H),1.74-1.40(m,2H),1.29-1.26(m,18H),0.88(t,J=6.8Hz,3H).

[0972] Example 182: Preparation of 2-((tert-Butoxycarbonyl)(methyl)amino)ethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 203)

[0973] Synthesis was performed by referring to Example 100, using N-Boc-N-methylaminoethanol (2 mL) instead of anhydrous methanol to obtain the title compound (42 mg, 0.107 mmol). MS [ESI]: m / z = 393.2, [M+H] + ;

[0974] 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=4.1Hz,1H),8.08(d,J=1.2Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.34-7.28(m,1H),7.25(d,J= 7.8Hz, 1H), 6.22 (q, J = 7.1Hz, 1H), 4.35-4.20 (m, 2H), 3.51-3.35 (m, 2H), 2.76 (s, 3H), 1.83 (d, J = 7.2Hz, 3H), 1.43-1.18 (m, 9H).

[0975] Example 183: Preparation of 3-((tert-Butoxycarbonyl)amino)propyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 204)

[0976] Synthesis was performed by referring to Example 100, using tert-butyl (3-hydroxypropyl) aminocarboxylate (2 mL) instead of anhydrous methanol to obtain the title compound (38 mg, 0.0713 mmol). MS [ESI]: m / z = 393.2, [M+H] + ;

[0977] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=4.2Hz,1H),8.08(d,J=1.2Hz,1H),7.81(td,J=7.7,1.7Hz,1H),7.31-7.28(m,1H),7.26(d,J=7.8Hz,1 H), 6.84 (s, 1H), 6.23 (q, J = 7.1Hz, 1H), 4.16-4.05 (m, 2H), 3.00 (q, J = 6.5Hz, 2H), 1.86 (d, J = 7.2Hz, 3H), 1.71-1.65 (m, 2H), 1.38 (s, 9H).

[0978] Example 184: Preparation of 3-((tert-Butoxycarbonyl)(methyl)amino)propyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 205)

[0979] Synthesize Reference Example 100, using N-(3-hydroxypropyl)-N-methylaminocarboxylic acid tert-butyl ester (4 ml) instead of anhydrous methanol to obtain the title compound (111 mg, 0.27 mmol), MS [ESI]: m / z = 407.4, [M+H] + ;

[0980] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,1H),8.12(s,J=0.9Hz,1H),7.84(td,J=7.7,1.8Hz,1H),7.35(ddd,J=7.6,4.8,0.8Hz,1H),7.29(d,J=7.9Hz,1 H), 6.26 (q, J = 7.2Hz, 1H), 4.22-4.08 (m, 2H), 3.31-3.20 (m, 2H), 2.78 (s, 3H), 1.89 (d, J = 7.2Hz, 3H), 1.82 (p, J = 6.5Hz, 2H), 1.46-1.34 (m, 9H).

[0981] Example 185: Preparation of 3-bromopropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 206)

[0982] Synthesize Reference Example 100, using 3-bromopropanol (2 ml) instead of anhydrous methanol to obtain the title compound (46 mg, 0.13 mmol), MS [ESI]: m / z = 357.2, [M+H] + ;

[0983] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,1H),8.14(d,J=1.8Hz,1H),7.86(td,J=7.7,1.8Hz,1H),7.39-7.34(m,1H),7.30(d,J=7 .9Hz, 1H), 6.25 (q, J = 7.2Hz, 1H), 4.35-4.20 (m, 2H), 3.58 (t, J = 6.6Hz, 2H), 2.17 (p, J = 6.3Hz, 2H), 1.90 (d, J = 7.2Hz, 3H).

[0984] Example 186: Preparation of prop-2-yn-1-yl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 207)

[0985] Step 1: Synthesis of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid (Compound 207-2)

[0986] A mixed solution of (R)-ethyl 4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (1 g, 6.32 mmol) and lithium hydroxide monohydrate (1 g, 23.81 mmol) (25 mL of methanol, 25 mL of tetrahydrofuran, and 10 mL of water) was added to a round-bottom flask and stirred. After the reaction was complete, the mixture was concentrated under reduced pressure and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was concentrated. The crude product was purified by preparative column chromatography (H2O / MeCN=95 / 5) to give the title compound (832 mg, 4.25 mmol). MS [ESI]: m / z=234.2, [MH] - ;

[0987] Step 2: Synthesis of prop-2-yn-1-yl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 207)

[0988] Compound 207-2 (100 mg, 0.43 mmol) and potassium carbonate (293 mg, 2.13 mmol) were added to a round-bottom flask and dissolved in DMF (2 mL). 3-bromoprop-1-yne (157 mg, 1.28 mmol) was added and stirred. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic phase was concentrated and the crude product was purified by preparative column chromatography (H2O / MeCN=45 / 55) to give the title compound (97 mg, 0.35 mmol). MS [ESI]: m / z=274.3, [M+H] + ;

[0989] 1 H NMR (400MHz, DMSO-d6) δ8.56(dd,J=4.7,0.6Hz,1H),8.17(d,J=1.8Hz,1H),7.85(td,J=7.7,1.8Hz,1H),7 .39-7.30(m,2H),6.24(q,J=7.2Hz,1H),4.92-4.82(m,2H),3.60(t,J=2.4Hz,1H),1.90(d,J=7.2Hz,3H).

[0990] Example 187: Preparation of 4-fluorobutyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 208)

[0991] Synthesize Reference Example 100, using 4-fluoro-1-butanol (2 mL) instead of anhydrous methanol to obtain the title compound (25 mg, 0.08 mmol), MS [ESI]: m / z = 310.2, [M+H] + ;

[0992] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.2Hz,1H),8.05(s,1H),7.81-7.75(m,1H),7.29(dd,J=7.0,5.1Hz,1H),7.22(d,J=7.8Hz,1H) ,6.18(q,J=7.1Hz,1H),4.48(t,J=5.5Hz,1H),4.36(t,J=5.5Hz,1H),4.21-4.08(m,2H),1.83(d,J=7.2Hz,3H),1.68-1.62(m,4H).

[0993] Example 188: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid hexyl ester (Compound 209)

[0994] Synthesize Reference Example 100, using hexanol (2 mL) instead of anhydrous methanol to obtain the title compound (40 mg, 0.12 mmol); MS [ESI]: m / z = 320.2, [M+H] + ;

[0995] 1 H NMR (400MHz, DMSO-d6) δ8.49(dd,J=4.7,0.6Hz,1H),8.05(d,J=1.7Hz,1H),7.78(td,J=7.7,1.8Hz,1H),7.29(ddd,J=7.6,4.8,0.8Hz,1H),7.21 (d,J=7.9Hz,1H),6.19(q,J=7.2Hz,1H),4.16-4.04(m,2H),1.83(d,J=7.2Hz,3H),1.57-1.49(m,2H),1.28-1.19(m,6H),0.83(t,J=6.8Hz,3H).

[0996] Example 189: Preparation of 4-methoxybutyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 210)

[0997] Synthesize Reference Example 100, using 4-methoxybutane-1-ol (2 ml) instead of anhydrous methanol to obtain the title compound (46 mg, 0.14 mmol), MS [ESI]: m / z = 322.4, [M+H] + ;

[0998] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=7.7,3.8Hz,1H),8.11(d,J=1.7Hz,1H),7.84(td,J=9.4,4.7Hz,1H),7.37-7.33(m,1H),7.28(d, J=7.9Hz,1H),6.25(q,J=7.2Hz,1H),4.25-4.11(m,2H),3.55-3.45(m,2H),3.25(s,3H),1.89(d,J=7.2Hz,3H),1.69-1.50(m,4H).

[0999] Example 190: Preparation of 3-(methylamino)propyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 211)

[1000] Compound 205 (62 mg, 0.15 mmol) was added to a round-bottom flask and dissolved in DCM (2 ml). 4 M hydrochloric acid solution in dioxane was added and stirred. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic phase was concentrated and the crude product was purified by Pre-HPLC (H2O / MeCN = 42 / 58) to give the title compound (42 mg, 0.14 mmol); MS [ESI]: m / z = 307.3, [M+H] + ;

[1001] 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.63(d,J=4.3Hz,1H),8.15(d,J=1.6Hz,1H),8.01(td,J=7.8,1.5Hz,1H),7.50(dd,J=7.0,5.3Hz,1H),7. 36(d,J=7.9Hz,1H),6.28(q,J=7.1Hz,1H),4.31-4.13(m,2H),2.97-2. 80(m,2H),2.53-2.48(m,3H),2.04-1.93(m,2H),1.91(d,J=7.2Hz,3H).

[1002] Example 191: Preparation of 3,3,3-trifluoropropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 212)

[1003] Reference Example 100 was synthesized by replacing anhydrous methanol with 3,3,3-trifluoropropanol (2 ml) to obtain the title compound (43 mg, 0.13 mmol); MS [ESI]: m / z = 332.3, [M+H] + ;

[1004] 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.15(s,1H),7.92-7.78(m,1H),7.42-7.23(m,2H ), 6.25 (q, J = 7.1Hz, 1H), 4.57-4.35 (m, 2H), 2.87-2.60 (m, 2H), 1.89 (d, J = 6.4Hz, 3H).

[1005] Example 192: Preparation of 3-chloropropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 213)

[1006] Synthesis was performed by referring to Example 100, using 3-chloropropanol (2 mL) instead of anhydrous methanol to obtain the title compound (28 mg, 0.0898 mmol). MS [ESI]: m / z = 311.1, [M+H] + ;

[1007] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=4.1Hz,1H),8.11(d,J=1.7Hz,1H),7.82(td,J=7.7,1.8Hz,1H),7.33(ddd,J=7.5,4.8,0.8Hz,1H), 7.26(d,J=7.9Hz,1H), 6.21(q,J=7.2Hz,1H), 4.36-4.17(m,2H), 3.67(t,J=6.5Hz,2H), 2.05(p,J=6.3Hz,2H), 1.87(d,J=7.2Hz,3H).

[1008] Example 193: Preparation of 2-(trifluoromethoxy)ethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 214)

[1009] Synthesis was performed by referring to Example 100, replacing anhydrous methanol with 2-(trifluoromethoxy)ethanol (2 mL) to obtain the title compound (44 mg, 0.126 mmol). MS [ESI]: m / z = 348.1, [M+H] + ;

[1010] 1 H NMR (400MHz, CDCl3) δ8.64-8.54(m,1H),7.69-7.64(m,2H),7.33-7.29(m,2H),6.3 6(q,J=7.1Hz,1H),4.53-4.41(m,2H),4.25(t,J=4.8Hz,2H),1.94(d,J=7.1Hz,3H).

[1011] Example 194: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester hydrochloride (Compound 53 hydrochloride)

[1012] Synthesis Step 1: Referring to Example 186, 3-iodopropane (217 mg, 1.28 mmol) was used to replace 3-bromoprop-1-yne to obtain the title compound 53 (93 mg, 0.36 mmol). MS [ESI]: m / z = 278.3, [M+H] + ;

[1013] Step 2: Synthesis of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid propyl ester hydrochloride (Compound 53 hydrochloride)

[1014] Compound 53 (92 mg, 0.36 mmol) was added to a round-bottom flask, acidified with 4 M hydrochloric acid and ethyl acetate, stirred, and the organic phase was concentrated to obtain the hydrochloride salt of the title compound 53 (97 mg, 0.33 mmol). MS [ESI]: m / z = 278.3, [M+H] + .

[1015] Example 195: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid isopropyl ester hydrochloride (Compound 215 hydrochloride)

[1016] Synthesize Reference Example 194 by replacing compound 53 with compound 54 (100 mg, 0.38 mmol) to obtain the title compound (112 mg, 0.36 mmol). MS [ESI]: m / z = 264.1, [M+H] + ;

[1017] 1H NMR (400MHz, DMSO-d6) δ8.49 (s, 1H), 8.03 (s, 1H), 7.78 (t, J = 7.0Hz, 1H), 7.32-7.16 (m, 2H), 6.19 (q, J = 7.2Hz, 1H), 5.04-4.89 (m, 1H), 1.83 (d, J = 6.7Hz, 3H), 1.18-1.08 (m, 6H).

[1018] Example 196: Preparation of 3-iodopropyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 216)

[1019] Synthesize Reference Example 186 by replacing 3-bromoprop-1-yne with 1,3-diiodopropane (516 mg, 1.28 mmol) to obtain the title compound (132 mg, 0.32 mmol). MS [ESI]: m / z = 404.2, [M+H] + ;

[1020] 1 H NMR (400MHz, DMSO-d6) δ8.48(d,J=4.5Hz,1H),8.06(d,J=1.6Hz,1H),7.77(td,J=7.7,1.7Hz,1H),7.28(dd,J=7.3,5.0Hz,1H),7 .21(d,J=7.8Hz,1H),6.16(q,J=7.2Hz,1H),4.23-4.04(m,2H),3.20(t,J=6.9Hz,2H),2.10-1.96(m,2H),1.82(d,J=7.2Hz,3H).

[1021] Example 197: Preparation of 2,2-difluoroethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 217)

[1022] Synthesize Reference Example 186 by replacing 3-bromoprop-1-yne with 2-bromo-1,1-difluoroethane (187 mg, 1.28 mmol) to obtain the title compound (16 mg, 0.05 mmol). MS [ESI]: m / z = 300.3, [M+H] + ;

[1023] 1H NMR (400MHz, CDCl3) δ8.62 (d, J = 4.5Hz, 1H), 7.78-7.66 (m, 2H), 7.29-7.22 (m, 2H), 6.33 ( q, J=7.1Hz, 1H), 6.03 (tt, J=55.1, 4.1Hz, 1H), 4.54-4.37 (m, 2H), 1.93 (d, J=7.1Hz, 3H).

[1024] Example 198: Preparation of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid fluoromethyl ester (Compound 215)

[1025] Step 1: Synthesis of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid (Compound 207-2)

[1026] Compound 47 (1.00 g, 3.78 mmol), lithium hydroxide (452 ​​mg, 18.90 mmol), tetrahydrofuran (10 mL), methanol (10 mL), and water (4 mL) were added to a round-bottom flask. After the reaction was completed at room temperature, 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 (705 mg, 3.00 mmol). MS [ESI]: m / z = 236.0, [M+H] + ;

[1027] Step 2: Synthesis of (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylic acid fluoromethyl ester (Compound 215)

[1028] To compound 207-2 (250 mg, 1.06 mmol) were added iodomethane (254 mg, 1.59 mmol), potassium carbonate (220 mg, 1.59 mmol), and anhydrous DMF (6 mL). After the reaction was completed at room temperature, purified water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The mixture was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC (acetonitrile / water = 45 / 55) to obtain the title compound (14 mg, 0.052 mmol). MS [ESI]: m / z = 268.1, [M+H] + ;

[1029] 1H NMR (400MHz, DMSO-d6) δ8.52(dd,J=5.1,1.8Hz,1H),8.24(d,J=1.7Hz,1H),7.82(td,J=7.7,1.8Hz,1H ),7.36-7.27(m,2H),6.20(q,J=7.2Hz,1H),5.86(ddd,J=51.0,9.4,2.5Hz,2H),1.88(d,J=7.2Hz,3H).

[1030] Example 199: Preparation of but-2-yn-1-yl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 68)

[1031] Compound 207-2 (100 mg, 0.42 mmol), 1-bromo-2-butyne (113.08 mg, 0.85 mmol), potassium carbonate (176.27 mg, 1.28 mmol), and N,N-dimethylformamide (0.5 mL) were added to a three-necked flask. After the reaction was completed at room temperature, the reaction solution was filtered. The crude product was separated by Pre-HPLC to obtain the title compound (29.56 mg, 0.074 mmol). MS [ESI]: m / z = 288.2, [M+H] + ;

[1032] 1 H NMR (400MHz, DMSO-d6) δ8.54-8.43(m,1H),8.10(d,J=1.7Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.32-7.28(m,1H ), 7.26 (d, J = 7.9Hz, 1H), 6.18 (q, J = 7.2Hz, 1H), 4.86-4.65 (m, 2H), 1.83 (d, J = 7.2Hz, 3H), 1.81 (t, J = 2.4Hz, 3H).

[1033] Example 200: Preparation of (R)-1-(1-(2-bromophenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 221)

[1034] Referring to the procedure of Example 81, (S)-1-(2-bromophenyl)ethanol was substituted for (S)-1-(2-fluorophenyl)ethanol to obtain the title compound (502 mg, 1.56 mmol); MS [ESI]: m / z = 323.3, [M+H] + ;

[1035] 1H NMR(400MHz, DMSO-d6)δ7.82(s,1H),7.69(s,1H),7.60(dd,J=7.8,1.0Hz,1H),7.29–7.23(m,1H),7.19–7.15(m,1H) ,6.84(dd,J=7.6,1.2Hz,1H),6.49(q,J=7.0Hz,1H),4.32–4.19(m,2H),1.86(d,J=7.0Hz,3H),1.27(d,J=7.2Hz,3H).

[1036] Example 201: Preparation of (R)-1-(1-(2-cyclopropylphenyl)ethyl)-1H-imidazole-5-carboxylic acid ethyl ester (Compound 60)

[1037] To a round-bottom flask was added dioxane / water (5 mL), followed by compound 221 (50 mg, 0.155 mmol), cyclopropylboronic acid (66.6 mg, 0.775 mmol), potassium phosphate (98.7 mg, 0.465 mmol), and Pd(dppf)Cl2 (12.6 mg, 0.155 mmol). The reaction mixture was stirred at 100°C under nitrogen. LCMS confirmed the reaction was complete, and the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield the crude product. The crude product was purified by Pre-HPLC (ACN / water = 50 / 50) to afford the title compound (20 mg, 0.07 mmol). MS [ESI]: m / z = 285.3, [M+H] + ;

[1038] 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.71(s,1H),7.28–7.14(m,2H),7.10–6.99(m,1H),6.93–6.81(m,1H),6.69–6 .64(m,1H),4.27–4.10(m,2H),2.03–1.97(m,1H),1.81(d,J=7.0Hz,3H),1.20(t,J=7.0Hz,3H),0.97–0.53(m,4H).

[1039] Example 202: Preparation of (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-2-(tert-butoxy)-2-oxoethyl-5-carboxylate (Compound 223)

[1040] (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.43 mmol) and potassium carbonate (293 mg, 2.13 mmol) were dissolved in DMF (2 ml), tert-butyl 2-bromoacetate (250 mg, 1.28 mmol) was added, and the mixture was 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 obtain the title compound (124 mg, 0.36 mmol). MS [ESI]: m / z = 349.3, [M+H] + ;

[1041] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.80(s,1H),7.33(td,J=7.3,1.4Hz,1H),7.17(dt,J=15.4,8.4Hz,2H) ,6.93(dd,J=7.5,6.8Hz,1H),6.40(q,J=7.1Hz,1H),4.72-4.52(m,2H),1.83(d,J=7.1Hz,3H),1.33(s,9H).

[1042] Example 203: Preparation of 2-(tert-Butoxy)-2-oxoethyl (R)-4-fluoro-1-(1-(pyridin-2-yl)ethyl)-1H-imidazole-5-carboxylate (Compound 222)

[1043] Reference Example 202 was synthesized by replacing (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid with 5-fluoro-3-((1R)-1-(2-pyridyl)ethyl)imidazole-4-carboxylic acid (300 mg, 1.28 mmol) to give the title compound (122 mg, 0.35 mmol); MS [ESI]: m / z = 350.3, [M+H] + ;

[1044] 1 H NMR (400MHz, DMSO-d6) δ8.49(dd,J=4.1,0.7Hz,1H),8.12(d,J=1.7Hz,1H),7.77(td,J=7.7,1.8Hz,1H),7.29(ddd,J=7. 5,4.8,0.9Hz,1H),7.25(d,J=7.8Hz,1H),6.18(q,J=7.2Hz,1H),4.69-4.56(m,2H),1.83(d,J=7.2Hz,3H),1.34(s,9H).

[1045] Example 204: Preparation of (R)-1-(1-phenylethyl)-1H-imidazole-2-(tert-butoxy)-2-oxoethyl-5-carboxylate (Compound 224)

[1046] Reference Example 202 was synthesized by replacing (R)-1-(1-(2-fluorophenyl)ethyl)-1H-imidazole-5-carboxylic acid with 1-((1R)-1-phenylethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.41 mmol) to obtain the title compound (121 mg, 0.37 mmol). MS [ESI]: m / z = 331.2, [M+H] + ;

[1047] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.77(s,1H),7.32-7.26(m,3H),7.18(d,J=7.3H z, 2H), 6.22 (q, J = 7.1Hz, 1H), 4.71-4.59 (m, 2H), 1.85 (d, J = 7.2Hz, 3H), 1.36 (s, 9H).

[1048] The remaining compounds of this application can be prepared by referring to the methods of Examples 1-204.

[1049] Experimental Example 1: ED in mice or rats 50 and LD 50 test

[1050] Weigh an appropriate amount of the compound of the invention and add DMSO to a final volume of 5%. Once the test 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%. Ultrasonicate for several minutes to create a homogeneous, clear solution for later use. For mice or rats, a fixed dosage volume is used, while the dosage concentration varies depending on the actual situation.

[1051] Sequential method to measure LORR ED in mice 50 LD 50 and rat LORR ED 50 Healthy 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. The test compound was divided into 5 groups according to the dose, 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 dose.

[1052] Compounds in mice and rats LORR ED 50 Test results and mouse LD50 The test results are shown in Tables 1-3 below.

[1053] Table 1. Mouse LORR ED 50 Test results (n=10)

[1054] Table 2. Mouse LD 50 Test results (n=10)

[1055] Table 3. LORR ED in rats 50 Test results (n=10)

[1056] It can be seen that the compounds of the present invention, such as compound 17, compound 25-26, compound 47, compound 52-56, compound 66, compound 68, compound 121, compound 146, compound 194, compound 199-200, compound 206-207, compound 213, compound 216-217, etc., can exert anesthetic effects and have good anesthetic efficacy and safety window.

[1057] Experimental Example 2: Determination of the latency and duration of anesthesia in rats and mice

[1058] 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 was calculated according to Experimental Example 1. 50 , refer to the method of Experimental Example 1 to calculate and measure the ED of rats 50 .

[1059] Using 3×ED 50 The drug was injected into the tail vein at a constant speed, and the injection was completed within 10 seconds. The maintenance time (persistence period) and walking time (recovery period) were recorded.

[1060] The results of the anesthesia duration and recovery period of the compounds in rats and mice are shown in Tables 4-5 below.

[1061] Table 4. Results of the compound's effect on the duration of anesthesia and recovery period in mice (group method, n=10)

[1062] Table 5. Results of the compound's effect on the duration of anesthesia and recovery period in rats (group method, n=10)

[1063] It can be seen that the compounds of the present invention can rapidly exert anesthetic effects (for example, at 3×ED 50The compounds 26, 47, 52-56, 66, 68, 121, 146, 194, 199-200, 206-207, 213, and 216-217 exhibited excellent anesthetic effects and faster recovery effects.

[1064] Experimental Example 3: Continuous infusion experiment in rats

[1065] SD rats were grouped according to the test compound, with 10 rats per group (half male and half female). Anesthesia was induced using the doses shown in Table 6. The test drug was injected into the tail vein at a constant rate over 10 seconds. Anesthesia was then maintained at an appropriate infusion rate based on the animal's condition for 1 or 4 hours. The onset of anesthesia (latency) and ambulation time (recovery) were recorded. The results of the continuous infusion assay of the compounds in rats are shown in Table 6 below.

[1066] Table 6. Results of continuous infusion in rats (mg / kg / h, grouping method n=10)

[1067] It can be seen from this that the compounds of the present invention, such as Compound 47, Compounds 52-56, Compound 199, etc., can maintain stable anesthesia in rats.

[1068] Experimental Example 4: Experiment on the inhibition of corticosterone secretion in rats

[1069] The degree of inhibition of rat corticosterone secretion by the compounds of the present invention was determined according to the method 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.

[1070] SD rats were selected and divided into groups according to each test compound, with 10 rats in each group. 0.2 mg / kg dexamethasone (dosing concentration was 0.04 mg / mL, dosing volume was 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). Except for the negative control group, the other groups were given the test compound of the present invention according to the dosage of Table 7-8. After that, 25 μg / kg of adrenocorticotropic hormone ACTH1-24 (dosing concentration was 5 μg / mL, dosing volume was 5 mL / kg) was immediately injected into the tail vein of each group of rats. Blood was collected from the carotid artery 15 and 30 minutes later to measure the corticosterone concentration (corticosterone C 15min 、C 30min ), calculate the inhibition rate C 15min (%) and C 30min The results of the inhibition test on rat corticosterone secretion are shown in Tables 7-8 below.

[1071] Table 7. Inhibition of corticosterone secretion by the compounds in rats NA means not involved.

[1072] Table 8. Inhibition of the compounds on rat corticosterone secretion

[1073] It can be seen that the compounds of the present invention, such as Compounds 25-26, Compound 47, Compounds 52-56, Compound 66, Compound 68, Compound 121, Compound 146, Compound 194, Compound 200, Compounds 206-207, Compound 213, Compounds 215-217, etc., have no obvious inhibitory effect on adrenal cortex function and do not inhibit corticosterone secretion.

[1074] Experimental Example 5: Continuous Infusion Experiment in Dogs

[1075] Beagle dogs were grouped according to the test compound, with three males per group. The induction dose of each test compound was determined through pre-testing, and the test drug was injected intravenously at a constant rate over 30 seconds. Anesthesia was then maintained for 1 hour using an appropriate infusion rate adjusted based on the animal's condition. The onset of anesthesia (latency), recovery time after cessation of infusion (persistence), and ambulation time (recovery) were recorded.

[1076] The results of the continuous infusion assay of the compounds are shown in Table 9 below.

[1077] Table 9. Results of continuous infusion assay in dogs

[1078] Therefore, the compounds of the present invention, such as Compound 47, Compounds 53-56, Compound 199, etc., can maintain stable anesthesia in dogs.

[1079] In summary, the compounds of the present invention not only have better pharmacodynamics (i.e., the compounds of the present invention have better anesthetic activity, faster onset, shorter duration and recovery time; 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.

[1080] 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

A compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has a structure as shown in Formula I: in: R 1 is halogen or H; 1) When R 1 When it is a 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, 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, C 3-6 Cycloalkyl, hydroxy C 1-6 Alkyl, C 1-14 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl, -C 1-6 Alkylene-NH-C(=O)OC 1-6 Alkyl, -C 1- 6-alkylene-N(C 1-6 alkyl)-C(=O)OC 1-6 Alkyl and -C 1-6 Alkylene-NH-C 1-6 substituted by an alkyl substituent; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; R 3 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; 2) When R 1 When it is H: 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, 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; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl; R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6 cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, halogen, C 6-10 Aryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkylene-, 5-10 membered heteroaryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-C 1-6 Alkyleneoxy-, C 6-10 Aryl-O-, 5-10 membered heteroaryl-C 1-6 Alkylene-NH- and C 6-10 Aryl-C 1-6 Alkylene-NH-. The compound according to claim 1, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled substances, or metabolites, prodrugs, or pharmaceutically acceptable salts or esters, wherein: The compound has the structure of Formula II: Among them, R 1 、R 2 、X 1 、X 2 、X 3 、X 4 and X 5 As defined in claim 1. The compound according to any one of claims 1 to 2, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: The compound satisfies one or more of the following characteristics: 1) R 1 is H; 2) 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, 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- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 substituted by a cycloalkyl substituent; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 is not methyl; and / or, 4) R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogen, C 6-10 Aryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkylene-, 5-10 membered heteroaryl-C 1-4 Alkyleneoxy- and C 6-10 Aryl-C 1-4 Alkyleneoxy-; or, The compound satisfies one or more of the following characteristics: 1) R 1 is a halogen; 2) R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, 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- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl (e.g. C 1-10 Alkyl, C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl), -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1- 4 alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; and / or, 4) R 3 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. The compound according to any one of claims 1 to 3, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: The compound satisfies one or more of the following characteristics: 1) R 1 is H; 2) R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl, the C 1-4 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, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -C(=O)-OC 1-4 Alkyl, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH 3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH 3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2C H3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3), -N(CH2CH -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl substituents; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 is not methyl; and / or, 4) R 3 Each independently selected from H, hydroxy, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and C 6-10 Aryl-C 1-4 Alkyleneoxy-; or, The compound satisfies one or more of the following characteristics: 1) R 1 is a halogen; 2) R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more selected from H, halogen, hydroxyl, amino, cyano, 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 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, hydroxy C 1-4 Alkyl, C 1-12 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl, -C 1-4 Alkylene-NH-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-N(C 1-4 alkyl)-C(=O)OC 1-4 Alkyl and -C 1-4 Alkylene-NH-C 1-4 substituted by an alkyl substituent; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; and / or, 4) R 3 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. The compound according to any one of claims 1 to 4, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: The compound satisfies one or more of the following characteristics: 1) R 1 is H; 2) R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I, -CH2-C(=O)-OC(CH3)3 and -CH2CHF2; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 is not methyl; and / or, 4) R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, methoxy, ethyl, isopropyl, cyclopropyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)2, halogen and phenyl-C 1-4 Alkyleneoxy-; or, The compound satisfies one or more of the following characteristics: 1) R 1 is a halogen; 2)R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, isobutyl, sec-butyl and tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hexyl, n-butyl, sec-butyl, isobutyl and tert-butyl are each independently optionally substituted by one or more groups selected from the group consisting of H, F, Cl, Br, I, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, - NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), - N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(C H3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2C -H2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)2, -C(=O)CH(CH3)CH2CH3, -C(=O)CH2CH2(CH3)2, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, tert-butenyl, ethynyl, propynyl, isopropynyl, n-butynyl, isobutynyl, tert-butynyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, -CH2OH, -CH2CH2OH,-CH(OH)CH3, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2CH2OH, -CH2CH2CH(OH)CH3, -CH2CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(CH3)CH2OH, -CH2C(CH3)2OH, -CHOHCH(CH3)2, -CH(CH3)CH2CH2OH, -CH(CH3)CHOHCH3, -C(CH3)(OH)CH2CH3, -C(CH2OH)CH2CH, 3、 -C(CH2OH)(CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, tert-butoxycarbonyl, methoxymethyl, methoxyethyl, methoxy-n-propyl, methoxyisopropyl, methoxy-n-butyl, methoxyisobutyl, methoxy-tert-butyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, n-butyloxymethyl, isobutyloxymethyl, tert-butyloxymethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, ethoxypropyl, propoxypropyl, -N(CH3)(Boc), -N(CH3)-C(=O)O-isobutyl, -N(CH3)-C(=O)O-n-butyl, -N(CH3)-C(=O)O-isopropyl, -N(CH3)-C(=O)O-n-propyl, -N(CH3)-C(=O)O-ethyl, -N(CH 3) -C(=O)O-methyl, -N(CH2CH3)(Boc), -N(CH2CH2CH3)(Boc), -N(CH(CH3)2)(Boc), -N(n-butyl)(Boc), -N(isobutyl)(Boc), -N(tert-butyl)(Boc), -CH2NH(Boc), -CH2CH2NH(Boc), -CH(CH3)NH(Boc), -n-propyl-NH(Boc), -isopropyl-NH(Boc), -n-butyl-NH(Boc), -isobutyl-NH(Boc), -tert-butyl-NH(Boc), -CH2NH-C(=O)O-isobutyl, -CH2NH-C(=O)O-n-butyl , -CH2NH-C(=O)O-isopropyl, -CH2NH-C(=O)O-n-propyl, -CH2NH-C(=O)O-ethyl, -CH2NH-C(=O)O-methyl, -CH2N(CH3)(Boc), -CH2CH2N(CH3)(Boc), -CH(CH3)N(CH3)(Boc), -n-propyl-N(CH3)(Boc), -isopropyl-N(CH3)(Boc), -n-butyl-N(CH3)(Boc), -isobutyl-N(CH3)(Boc), -tert-butyl-N(CH3)(Boc), -CH2N(CH3)-C(=O)O-isobutyl, -CH2N(CH3)-C(= O) O-n-butyl, -CH2N(CH3)-C(=O)O-isopropyl, -CH2N(CH3)-C(=O)O-n-propyl, -CH2N(CH3)-C(=O)O-ethyl, -CH2N(CH3)-C(=O)O-methyl, -CH2N(CH2CH3)(Boc), -CH2N(CH2CH2CH3)(Boc), -CH2Br, -CH2CH2Br, -CHBrCH3, -CH2CH2CH2Br, -CH2CHBrCH3, -CHBrCH2CH3, -CBr(CH3)2, -CH2CH2CH2CH2Br, -CH2CH2F, -CHFCH3, -CH2F,-CH2CH2CH2F, -CH2CHFCH3, -CHFCH2CH3, -CF(CH3)2, -CH2Cl, -CH2CH2Cl, -CHClCH3, -CH2CH2CH2Cl, -CH2CHClCH3, -CHClCH2CH3, -CCl(CH3)2, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH(CH3)NHCH3, -CH(CH3)2NHCH3, -CH(CH3)CH2NHCH3, -CH2NHCH2CH3, -CH2NHCH2CH2CH3, -CH2NHCH(CH3)2, -CF3, -CH2CF3, -CH2CH2CF3, -CH(CF3)CH3, -CH2CH2CH2CF3, -CH(CH3)CH2CF3, -C(CH3)2CF3, -CH2CH(CF3)CH3, -CH(CF3)CH2CH3, -C(CF3)(CH3)2, -CH2I, -CH2CH2I, -CHICH3, -CH2CH2CH2I, -CH2CHICH3, -CHICH2CH3, -CI(CH3)2, -CHF2, -CH2CHF2, -CF2CH3, -CH2CH2CHF2, -CH2CF2CH3, -CF2CH2CH3 and -CH2CF2(CH3); 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; and / or, 4) R 3 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. The compound according to any one of claims 1 to 5, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: The compound satisfies one or more of the following characteristics: 1) R 1 is H; 2) R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2-C(=O)-OC(CH3)3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I and -CH2CHF2; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 or X 4 One of them is N, and X 1 、X 3 and X 5 When both are CH, R 2 is not methyl; and / or, 4) R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -NH-CH2-CH3, -NH-(CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(C H(CH3)2)(CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(C H2CH2CH2CH3)(CH2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH 2CH3)2, -N(CH(CH3)CH2CH3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 3), -N(CH(CH3)CH2CH3)(CH2CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2 CH3)(CH(CH3)CH2CH3), -N(CH2CH(CH3)2)2, F, Cl, Br, I, benzyloxy, phenoxy, -O-CH2CH2-phenyl and -O-CH(CH3)-phenyl; or, The compound satisfies one or more of the following characteristics: 1) R 1 is a halogen; 2) R 2 is selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2-C(=O)-OC(CH3)3, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(C H3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2; 3)X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; and / or, 4) R 3 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. The compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: R 1 is H; R 2 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2I, -CH2-C(=O)-OC(CH3)3 and -CH2CHF2; X 1 Selected from CR 3 、N + -O - and N; X 2 Selected from CR 3 and N; X 3 Selected from CR 3 and N; X 4 Selected from CR 3 ; X 5 Selected from CR 3 and N; The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl; R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH 3、 -N(CH3)2, F, Br and benzyloxy; or, R 1 For halogens: R 2 is selected from the group consisting of methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2-C(=O)-OC(CH3)3, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; R 3 each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trifluoro-n-butyl, trifluoroisobutyl, trifluoro-tert-butyl, trifluoromethoxy, trifluoroethoxy, trifluoro-n-propoxy, trifluoroisopropoxy, trifluoro-n-butoxy, trifluoroisobutoxy, trifluoro-tert-butoxy, -NH-CH3, -NH-CH2-CH3, -NH-( CH2)2-CH3, -NH-CH(CH3)2, -NH-(CH2)3-CH3, -NH-CH2-CH(CH3)2, -NH-CH(CH3)-CH2-CH3, -N(CH3)2, -N(CH 2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH3)(CH2CH2CH3), -N(CH2CH2CH3)2, -N(CH(CH3)2)(CH3), -N(CH(CH3)2) (CH2CH3), -N(CH(CH3)2)2, -N(CH2CH2CH2CH3)(CH3), -N(CH2CH2CH2CH3)(CH2CH3), -N(CH2CH2CH2CH3)(CH 2CH2CH3), -N(CH2CH2CH2CH3)(CH2(CH3)2), -N(CH2CH2CH2CH3)2, -N(CH(CH3)CH2CH3)2, -N(CH(CH3)CH2CH 3)(CH3), -N(CH(CH3)CH2CH3)(CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH 2CH3), -N(CH(CH3)CH2CH3)(CH2CH2CH(CH3)2), -N(CH(CH3)CH2CH3)(CH(CH3)CH2CH3) and -N(CH2CH(CH3)2)2. The compound according to any one of claims 1 to 7, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: R 1 is H; R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2-C(=O)-OC(CH3)3 and isobutyl; X 1 Selected from CR 3 、N + -O - and N; X 2 Selected from CR 3 and N; X 3 Selected from CR 3 and N; X 4 Selected from CR 3 ; X 5 Selected from CR 3 and N; The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl; R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -N(CH3)2, F, Br and benzyloxy; or, R 1 is a halogen; R 2 is selected from methyl, ethyl, butyl, n-propyl, isopropyl, cyclopropyl, isobutyl, hexyl, -CH2-C(=O)-OC(CH3)3, -CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(C H3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2-vinyl, -CH2-ethynyl, -CH2F, -CH2-ethynyl-CH3, -CH2CH2CH2F, -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2; X 1 、X 2 、X 3 、X 4 and X 5 Each independently selected from N, N + -O - and CR 3 , the condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2. The compound according to any one of claims 1 to 8, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: R 1 is H; R 2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2-C(=O)-OC(CH3)3 and isobutyl; X 1 Selected from CR 3 、N + -O - and N; X 2 Selected from CR 3 and N; X 3 Selected from CR 3 and N; X 4 Selected from CR 3 ; X 5 Selected from CR 3 and N; The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time, and when X 2 is N, and X 1 、X 3 and X 5 When both are CH, R 2 Not methyl; R 3 Each is independently selected from H, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, trifluoromethoxy, -NH-CH3, -N(CH3)2, F, Br and benzyloxy; or, R 1 is F; R 2 is selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, cyclopropyl, -CH2-C(=O)-OC(CH3)3, isobutyl, n-hexyl, -CH2CH2F, -CH2CH2CH2F, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2(CH2)9CH3, -CH2CH2N(CH3)(Boc), -CH2CH2CH2NH(Boc), -CH2CH2CH2N(CH3)(Boc), -CH2CH2CH2Br, -CH2CH2CH2CH2F, -CH2CH2(CH2)3CH3, -CH2CH2CH2Cl, -CH2CH2OCF3, -CH2F、 -CH2CH2CH2CH2OCH3, -CH2CH2CH2NHCH3, -CH2CH2CF3, -CH2CH2CH2I and -CH2CHF2; X 1 Selected from CR 3 、N + -O - and N; X 2 Selected from CR 3 and N; X 3 Selected from CR 3 and N; X 4 Selected from CR 3 ; X 5 Selected from CR 3 and N; The condition is X 1 、X 2 、X 3 、X 4 and X 5 Cannot be CH at the same time; R 3 Each is independently selected from H, F, Br, hydroxy, amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, -NH-CH3 and -N(CH3)2. The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, 2-fluorophenyl, 3-fluorophenyl, 3-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-benzyloxy, 2-methylphenyl, 2-ethylphenyl, 2-cyclopropylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, The compound according to any one of claims 1 to 10, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, wherein: The compound is selected from: The compound according to claim 11, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled substances, or metabolites, prodrugs, or pharmaceutically acceptable salts or esters, wherein: The compound is selected from: A pharmaceutical composition comprising a preventively and / or therapeutically effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled substance thereof, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers. A kit comprising a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled substance thereof, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition according to claim 13. Use of the compound according to any one of claims 1 to 12, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled substances, or metabolites or prodrugs or pharmaceutically acceptable salts or esters, or the pharmaceutical composition according to claim 13, or the kit according to claim 14 in the preparation of anesthetics, especially intravenous anesthetics and sedatives. A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label thereof, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition according to claim 13, or a kit according to claim 14 for use in anesthesia, particularly intravenous anesthesia and sedation. A method of anesthesia or sedation, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled form thereof, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition according to claim 13, or a pharmaceutical kit according to claim 14.

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