Compound and application thereof

Abstract

The invention relates to a compound and a composition containing the compound. The compound has a structure as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure as shown in the formula (I). The compound or the composition provided by the invention can be used for preparing medicines for treating ophthalmic diseases. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of the Chinese patent application with application number 202311678605.1 filed on December 7, 2023, and invention name “A compound and its application”. The entire contents of the above patent application are incorporated into this application as a whole. Technical Field

[0003] The present application relates to a compound, stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and use thereof in preparing drugs for treating ophthalmic diseases. Background Art

[0004] Presbyopia, also known as old eyesight, is a physiological condition that causes the hardening of the lens and the decline of the eye's visual accommodation function as people age. The initial symptoms are that the target needs to be kept at a certain distance to be seen clearly. If the light is insufficient, close reading will be more difficult, and these conditions will continue to worsen with age. In addition to age factors, the development of presbyopia is also related to refractive errors, physical fitness, medications and other factors.

[0005] At present, the main means of treating presbyopia include wearing frame reading glasses, wearing corneal contact lenses, corneal refraction, scleral refraction, and lens refractive surgery. In October 2021, the U.S. Food and Drug Administration (FDA) approved the ophthalmic drug Vuity (pilocarpine, 1.25% eye drops) of Allergan, a subsidiary of AbbVie, to treat presbyopia. As a topical medication, Vuity is dropped into both eyes once a day. It uses the eye's ability to reduce the size of the pupil to improve near and intermediate vision while maintaining some pupil response to light. It is the first FDA-approved presbyopia drug. The drops are delivered through proprietary technology and can quickly adjust to the natural pH of the tear film. The effect of constricting the pupil is usually achieved 15 minutes after administration and lasts up to 6 hours. However, Vuity eye drops cannot fundamentally cure presbyopia. It only improves the symptoms of presbyopia for a certain period of time. And based on the age range of its Phase III clinical trial participants, it may be more suitable for people aged 40-55 years old. For patients over 55 years old or older, the effect may not be ideal.

[0006] Therefore, there is an urgent need for other drugs that can prevent, relieve or treat presbyopia. Summary of the invention

[0007] In a first aspect, the present application provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I):

[0008]

[0009] in:

[0010] Ring A is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring;

[0011] R 1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkoxyalkyl substituted with halo or hydroxy;

[0012] R 2 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, ketoalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, alkynyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, alkylcarbonyl, or arylcarbonyl;

[0013] R 3 is deuterium, hydroxy, amino, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, ketoalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, alkynyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, alkylcarbonyl or arylcarbonyl.

[0014] In some embodiments, in formula (I), the A ring is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; the heteroaromatic ring and the heterocyclic ring each independently contain 1, 2, 3 or 4 identical or different N, O or S heteroatoms.

[0015] In some embodiments, in formula (I), the A ring is a benzene ring, a naphthalene ring, a cyclopropylene ring, a cyclobutylene ring, a cyclopentylene ring, a cyclohexylene ring, a tetrahydrofuran ring, a dihydrofuran ring, a tetrahydrothiophene ring, a dihydrothiophene ring, a 1,3-dioxolane ring, a dithiocyclopentyl ring, a tetrahydropyran ring, a dihydropyran ring, a 2H-pyran ring, a 4H-pyran ring, a tetrahydrothiopyran ring, a piperidine ring, a morpholine ring, a thiomorpholine ring, Piperazine ring, dioxane ring, dithiane ring, thioxane ring, homopiperazine ring, homopiperidine ring, oxepane ring, thiepane ring, indoline ring, 1,2,3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring, furan ring, imidazole ring, 3-isoxazole ring, isoxazole ring, oxazole ring, pyrrole ring, pyridine ring, pyrimidine ring, pyridazine ring, thiazole ring, tetrazole ring, triazole ring, 2-thiazole ring Phenyl ring, 3-thiophene ring, pyrazole ring, isothiazole ring, 1,2,3-oxadiazole ring, 1,2,5-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,3-triazole ring, 1,2,3-thiodiazole ring, 1,3,4-thiodiazole ring, 1,2,5-thiodiazole ring, pyrazine ring, 1,3,5-triazine ring, benzimidazole ring, benzofuran ring, benzothiophene ring, indole ring , purine ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyridine ring, pyrazolo[1,5-a]pyridine ring, pyrazolo[1,5-a]pyrimidine ring, imidazo[1,2-b]pyridazine ring, [1,2,4]triazolo[4,3-b]pyridazine ring, [1,2,4]triazolo[1,5-a]pyrimidine ring or [1,2,4]triazolo[1,5-a]pyridine ring.

[0016] In some embodiments, in formula (I), the R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 alkyl.

[0017] In some embodiments, in formula (I), the R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl or trifluoromethyl.

[0018] In some embodiments, in formula (I), the R 2 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Keto C1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Halogenated or hydroxy-substituted alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated or hydroxy substituted C 1-6 Alkylamino, C 1-6 Alkylthio, halogenated or hydroxy-substituted C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy, C 1-6 Alkylcarbonyl or C 6-10 Arylcarbonyl;

[0019] The R 3 Deuterium, hydroxyl, amino, cyano, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Keto C 1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Halogenated or hydroxy-substituted alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated or hydroxy substituted C 1-6 Alkylamino, C 1-6 Alkylthio, halogenated or hydroxy-substituted C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 2-9Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy, C 1-6 Alkylcarbonyl or C 6-10 Arylcarbonyl.

[0020] In some embodiments, in Formula (I), the R 2 is hydrogen, deuterium, hydroxyl, amino, cyano, mercapto, nitro, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, acetyl, benzoyl, trifluoromethyl, difluoromethyl, (2-oxocyclopentyl)methyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, butoxy, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3 -dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5 ...2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazolyl, 1,2,3-thiodiazolyl, 1,2,3-thiodiazoly azinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl;

[0021] The R 3deuterium, hydroxyl, amino, cyano, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, acetyl, benzoyl, trifluoromethyl, difluoromethyl, (2-oxocyclopentyl)methyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, butoxy, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, disulfide cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxanyl oxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0022] In some embodiments, in Formula (I), the R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, benzoyl, methoxy, ethoxy, propoxy, butoxy or (2-oxocyclopentyl)methyl;

[0023] The R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, benzoyl, methoxy, ethoxy, propoxy, butoxy or (2-oxocyclopentyl)methyl.

[0024] In a second aspect, the present application provides a compound having the structure shown below, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

[0025]

[0026]

[0028] In a third aspect, the present application provides a composition comprising the compound described in the first aspect or the second aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0029] In a fourth aspect, the present application provides use of the compound described in the first aspect, the second aspect, or the composition described in the third aspect in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

[0030] In some embodiments, the ocular disease is presbyopia.

[0031] Compared with the prior art, this application has the following beneficial effects:

[0032] The compounds provided in the present application have good miotic effect, and the miotic effect is long-lasting, increase the depth of field, effectively prevent and / or treat presbyopia, and have good clinical application prospects. DETAILED DESCRIPTION

[0033] Definitions and general terms

[0034] Unless otherwise stated, the terms used in the specification and claims of this application have the following definitions.

[0035] Some embodiments of the present application are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The present application is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present application as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present application. The present application is by no means limited to the methods and materials described herein. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0036] It should be further recognized that certain features of the present application, for clarity, are described in multiple independent embodiments, but can also be provided in combination in a single embodiment. Conversely, various features of the present application, for brevity, are described in a single embodiment, but can also be provided separately or in any suitable sub-combination.

[0037] Unless otherwise specified, all technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application belongs. All patents and publications involved in this application are incorporated herein by reference in their entirety.

[0038] Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of this application, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can 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.

[0039] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0040] The term "subject" as used herein refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0041] The term "patient" used in this application refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0042] The term "comprising" is an open expression, that is, including the contents specified in the present application but not excluding other contents.

[0043] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0044] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0045] The stereochemical definitions and conventions used in this application generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0046] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0047] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0048] Depending on the choice of starting materials and process, the compounds of the present application may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0049] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0050] Unless otherwise indicated, the structural formulas described in the present application include all isomeric forms (such as enantiomers, diastereomers), and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present application or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) all fall within the scope of the present application.

[0051] The term "prodrug" as used herein refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present application may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present application contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0052] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007)).

[0053] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0054] The salts mentioned in the present application are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, thiocarboxylates, and the like, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarate, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N+(C 1-4 alkyl) 4 The present application also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0055] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

[0056] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0057] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0058] The "solvate" of the present application refers to an association formed by one or more solvent molecules and the compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0059] "Pharmaceutical composition" means a mixture of one or more salts of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickeners. Pharmaceutical compositions facilitate administration of compounds to organisms. There are a variety of techniques for administering compounds in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration. In an embodiment of the present disclosure, the pharmaceutical composition of the present disclosure can be used for ocular administration.

[0060] As used herein, the term "treating" any disease or condition refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or at least one clinical symptom thereof) in some embodiments. In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or deterioration of a disease or condition.

[0061] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. An isotopically enriched compound has a structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0062] In another aspect, the compounds described herein include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparations in this application.

[0063] In addition, heavier isotopes, especially deuterium (i.e. 2 The substitution of H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present application is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present application refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include solvates in which the solvent of crystallization may be isotopically substituted, such as D 2 O, acetone-d 6 DMSO-d 6 Those solvates.

[0064] As described in the present application, the compounds of the present application may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples in the embodiments, subclasses, and a class of compounds contained in the present application. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not it is located before the term "substituted", indicates that one or more hydrogen atoms in the given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituted group can have a substituent substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner. The substituents may be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, sulfhydryl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy and the like.

[0065] The term "alkyl" as used herein refers to a saturated straight or branched monovalent hydrocarbon group of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

[0066] The term "ketoalkyl" refers to an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a keto group, wherein the keto group may be, but is not limited to, a cycloalkylketo group, a heterocycloalkylketo group, a straight or branched chain alkylketo group, and the like.

[0067] The term "alkoxy" as used in this application refers to an alkyl group, as defined in this application, connected to the main carbon chain through an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group can be substituted or unsubstituted, wherein the substituent can be, but are not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0068] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ),etc.

[0069] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is a sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), and so on.

[0070] The terms "cycloalkyl" and "carbocycle" refer to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated rings, and do not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocycles with 7-12 atoms may be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms may be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cyclic aliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. And the "cyclic aliphatic group" or "carbocycle" or "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy and the like.

[0071] The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings as described herein, the ring may be fully saturated or contain one or more unsaturations, but is never aromatic, and has only one point of attachment to other molecules. One or more hydrogen atoms in the ring are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to give, for example, SO, SO 2 ,PO,PO 2 When the ring is a three-membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give, for example, SO, SO 2 ,PO,PO 2 of groups).

[0072] Heterocyclic groups can be carbonyl or heteroatom groups. "Heterocyclic groups" also include groups formed by the combination of heterocyclic groups with saturated or partially unsaturated rings or heterocyclic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin 1-yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazine-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanon-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy and the like.

[0073] The terms "aryl" and "aromatic ring" can be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic rings can include phenyl, naphthyl and anthracenyl. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy, and the like.

[0074] The terms "heteroaryl" and "heteroaromatic ring" refer to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meanings as described herein, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic compound". And the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkoxy and the like.

[0075] The term "alkylcarbonyl" refers to -C(=O)alkyl, with the carbonyl carbon attached to the A ring, wherein the alkyl group is as defined above and may be, but is not limited to, acetyl, ethylcarbonyl, n-propylcarbonyl, and the like.

[0076] The term "arylcarbonyl" refers to a -C(=O)aryl group, with the carbonyl carbon attached to the A ring, wherein the aryl group is an aryl group as defined above, and may be, but is not limited to, benzoyl, 4-chlorobenzoyl, and the like.

[0077] In other embodiments, heteroaryl includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following di- ring, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0078] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).

[0079] The term "halogen" refers to F, Cl, Br or I.

[0080] The term "halogen" as used herein means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

[0081] The term "hydroxy substituted" as used herein means that the group following it is substituted with a hydroxy group, and the number of the substitution may be one or more.

[0082] When the term “substituted” is used between two groups, it is preceded by a substituent, such as “aryl-substituted alkyl” means an alkyl group having an aryl substituent, and “alkoxycarbonyl-substituted alkyl” means an alkyl group having an alkoxycarbonyl substituent.

[0083] When multiple groups are used in combination in the present application, they are in a substitution relationship from left to right, such as "arylalkyl" means an alkyl substituted with an aryl group, and "alkoxyalkoxy" means an alkoxy substituted with an alkoxy group.

[0084] As used in this application, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0085] In the present application, substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0086] When it can be used for treatment, the therapeutically effective amount of the compound of the present application can be given as a raw chemical drug, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present application also provides a pharmaceutical composition, which includes a therapeutically effective amount of the compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" used herein refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction). When a separate active ingredient is administered alone, the term refers only to the ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, sequential or simultaneous administration. In terms of compatibility with other ingredients of the preparation and harmlessness to its recipient, the carrier, diluent or excipient must be acceptable. According to another aspect of the present application, a method for preparing a pharmaceutical preparation is also provided, which includes mixing the compound of the present application with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effectively used for the intended purpose.

[0087] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0088] The "effective amount" or "effective dose" of the compound or pharmaceutically acceptable composition of the present application refers to an effective amount for treating or alleviating the severity of one or more of the conditions mentioned in the present application. According to the methods of the present application, the compound and its composition can be effectively used to treat or alleviate the severity of the disease in any dosage and any route of administration. The exact amount required will vary according to the patient's condition, which depends on the age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compound or composition of the present application can be co-administered with one or more other therapeutic agents, as discussed in the present application.

[0089] Generally, the compounds of the present application can be prepared by the methods described in the present application. The following reaction schemes and examples are used to further illustrate the content of the present application.

[0090] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present application, and other methods for preparing the compounds of the present application are considered to be within the scope of the present application. For example, the synthesis of the non-exemplified compounds according to the present application can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described in the present application, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed in the present application or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present application.

[0091] In the examples described below, all temperatures are set in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0092] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application is further described in detail below in conjunction with the embodiments. The specific embodiments described herein are only used to explain the present application and are not intended to constitute any limitation to the present application. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0093] Example 1: Synthesis of Compound 1

[0094]

[0095] Step 1:

[0096]

[0097] 3-Quinuclide hydrochloride (12.91 g, 80.0 mmol) was added to a 250 mL two-necked bottle and dissolved in 100 mL of ethanol at room temperature. The mixture was cooled in an ice water bath. 2Sodium borohydride (3.63 g, 96.0 mmol) was added in batches under protection. After the addition was completed, the mixture was kept in an ice-water bath for 0.5 h and then transferred to room temperature for reaction for 4 h. The reaction was completed by TLC detection (dichloromethane: methanol = 9:1). After suction filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a white solid. 60 mL of acetone was added and heated to reflux for 10 min. After the mixture naturally cooled to room temperature, it was cooled in an ice-water bath, stirred for 0.5 h, suction filtered, the filter cake was rinsed with a small amount of acetone, and dried to obtain a white solid (9.25 g, 72.7 mmol, 91%).

[0098] 1 H NMR(500MHz,Chloroform-d)δ3.85(dt,J=7.8,3.6Hz,1H),3.13(ddd,J=14.1,8.3,2.4Hz,1 H),2.91(tdd,J=10.4,5.6,2.4Hz,1H),2.77(ddddd,J=13.2,10.4,8.3,5.3,2.3Hz,2H),2.7 0–2.55(m,2H),1.94(dddt,J=13.4,10.8,5.4,3.1Hz,1H),1.81(h,J=3.3Hz,1H),1.68(ddt ,J=14.3,9.4,4.4Hz,1H),1.46(dddt,J=13.2,10.8,5.6,2.8Hz,1H),1.40–1.31(m,1H)ppm.

[0099] Step 2:

[0100]

[0101] In a 100 mL two-necked bottle, add (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid (0.46 g, 2.0 mmol) and dissolve in 20 mL of dichloromethane at room temperature. 2 Under protection, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46g, 2.4mmol) and 4-dimethylaminopyridine (0.03g, 0.24mmol) were added respectively, and stirred at room temperature for 0.5h. Quinuclidine-3-ol (0.31g, 2.4mmol) was dissolved in 10mL of dichloromethane at room temperature and then added to the system at constant pressure. After the addition was completed, the reaction was allowed to proceed at room temperature for 4h. TLC detection (dichloromethane: methanol = 9:1) showed that the reaction was complete. 20mL of purified water and 2mL of 1N dilute hydrochloric acid were added to the system to extract and separate the liquids. The aqueous phase was separated twice with 20mL*2 of dichloromethane. The organic phases were combined and washed with 20mL*2 of saturated brine. The organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain an oily crude product. Purification by flash chromatography column gave a yellow oily solid (0.46g, 1.4mmol, 68%).

[0102] 1 H NMR(500MHz,Chloroform-d)δ7.77–7.67(m,2H),7.64(s,1H),7.39–7.32(m,1H),7 .20–7.08(m,2H),5.00(ddt,J=16.3,7.7,3.1Hz,1H),3.92(s,3H),3.87(q,J=7.1H z,1H),3.53–3.40(m,1H),3.15–2.94(m,4H),2.86(d,J=14.3Hz,1H),2.33–2.18(m ,1H),1.98–1.73(m,2H),1.59(t,J=6.5Hz,3H),1.54–1.39(m,1H),1.26(s,1H)ppm.

[0103] Example 2: Synthesis of Compound 2

[0104]

[0105] According to the method of Example 1, compound 2 was prepared by using 2-(3-benzoylphenyl)propionic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to obtain a yellow oily solid.

[0106] 1 H NMR(500MHz,Chloroform-d)δ7.81–7.75(m,3H),7.68(d,J=7.6Hz,1H),7.59(t,J=7.5Hz,1H),7. 55(d,J=7.8Hz,1H),7.47(dt,J=18.1,7.7Hz,3H),4.80(dq,J=7.8,3.9,3.5Hz,1H),3.82(q,J=7. 2Hz,1H),3.26–3.15(m,1H),2.85–2.65(m,4H),2.52(dt,J=14.7,2.7Hz,1H),1.97(dq,J=31.0,3 .5Hz,1H),1.70(dtd,J=17.6,9.8,4.4Hz,1H),1.56(dd,J=7.1,2.2Hz,4H),1.41–1.22(m,2H)ppm.

[0107] Example 3: Synthesis of Compound 3

[0108]

[0109] According to the method of Example 1, compound 3 was prepared by using 2-(2-fluoro-[1,1′-biphenyl]-4-yl)propionic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to obtain a yellow oily solid.

[0110] 1 H NMR (500MHz, Chloroform-d) δ7.54(t,J=8.0Hz,2H),7.43(q,J=7.8Hz,3H),7.37(t,J=7. 4Hz,1H),7.11(ddt,J=16.1,11.2,2.5Hz,2H),5.02(ddt,J=12.1,7.8,3.3Hz,1H),3.78( q,J=7.2Hz,1H),3.55–3.45(m,1H),3.22–2.88(m,5H),2.28(dq,J=31.7,3.4Hz,1H),1.9 3(dqd,J=17.6,9.6,8.3,4.2Hz,2H),1.85–1.64(m,2H),1.55(dd,J=7.2,4.0Hz,3H)ppm.

[0111] Example 4: Synthesis of Compound 4

[0112]

[0113] Compound 4 was prepared according to the method of Example 1 using 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid to give a yellow oily solid.

[0114] 1 H NMR(500MHz,Chloroform-d)δ7.20–7.10(m,4H),5.01(dq,J=7.6,4.0,3.2Hz,1H),3.71(q,J=7.2Hz,1H),3.56–3.45(m,1H),3.22–3.09(m ,5H),2.90(d,J=13.6Hz,1H),2.54(qd,J=8.8,4.3Hz,1H),2.39–2.25(m,3H),2.16–2.04(m,2H),2.02–1.66(m,5H),1.61–1.48(m,5H)ppm.

[0115] Example 5: Synthesis of Compound 5

[0116]

[0117] According to the method of Example 1, using 2-(4-isobutylphenyl)propionic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to prepare compound 5, a yellow oily solid was obtained.

[0118] 1 H NMR(500MHz,Chloroform-d)δ7.16(dd,J=8.1,3.9Hz,2H),7.13–7.07(m,2H),5.05–4 .96(m,1H),3.71(qd,J=7.2,2.4Hz,1H),3.47(dtd,J=14.5,8.0,2.5Hz,1H),3.26–2. 96(m,4H),2.94–2.85(m,1H),2.45(dd,J=7.2,5.6Hz,2H),2.36–2.25(m,1H),2.03–1 .61(m,4H),1.51(dd,J=7.2,5.4Hz,3H),1.48–1.44(m,1H),0.88(t,J=7.2Hz,6H)ppm.

[0119] Example 6: Synthesis of Compound 6

[0120]

[0121] According to the method of Example 1, compound 6 was prepared by using 2-(p-tolyl)propionic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to obtain a yellow oily solid.

[0122] 1 H NMR(500MHz,Chloroform-d)δ7.19(d,J=7.8Hz,2H),7.12(dd,J=8.0,3.8Hz,2H),4.76(dq,J=8.4,4.4,3.9Hz,1H),3.69(q,J =7.2Hz,1H),3.22–3.09(m,1H),2.82–2.43(m,5H),2.32(s,3H),1.97–1.87(m,1H),1.76–1.46(m,6H),1.38–1.28(m,1H)ppm.

[0123] Example 7: Synthesis of Compound 7

[0124]

[0125] Compound 7 was prepared according to the method of Example 1 using 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to give a yellow oily solid.

[0126] 1 H NMR(500MHz,Chloroform-d)δ7.70–7.64(m,2H),7.53–7.45(m,2H),6.95(d,J=2.5Hz,1H),6 .85(d,J=8.9Hz,1H),6.68(dd,J=9.1,2.6Hz,1H),4.98(dt,J=8.1,3.5Hz,1H),3.83(s,3H), 3.70(s,2H),3.42(ddd,J=14.7,8.5,2.4Hz,1H),3.03(ddt,J=43.4,35.4,12.3Hz,5H),2.41 (s,3H),2.26–2.21(m,1H),1.93–1.82(m,2H),1.80–1.69(m,1H),1.59(q,J=10.8Hz,1H)ppm.

[0127] Example 8: Synthesis of Compound 8

[0128]

[0129] Compound 8 was prepared according to the method of Example 1 using 2-(4-isopropylphenyl)acetic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid to give a yellow oily solid.

[0130] 1 H NMR(500MHz,Chloroform-d)δ7.19(q,J=8.2Hz,4H),4.82–4.73(m,1H),3.59(s,2H),3.23–3.15(m,1H),2.89(p,J=7.0Hz,1H),2.83–2.66(m,4H),2.6 3(dt,J=14.7,2.8Hz,1H),1.97(q,J=3.3Hz,1H),1.77–1.60(m,2H),1.52( dtt,J=13.4,7.1,2.8Hz,1H),1.38–1.29(m,1H),1.24(d,J=6.9Hz,6H)ppm.

[0131] Example 9: Synthesis of Compound 9

[0132]

[0133] According to the method of Example 1, using 2-(4-propylphenyl)acetic acid instead of (S)-2-(6-methoxynaphthalen-2-yl)propionic acid to prepare compound 9, a yellow oily solid was obtained.

[0134] 1 H NMR(500MHz,Chloroform-d)δ7.19(d,J=7.7Hz,2H),7.13(d,J=7.8Hz,2H),4.79(dt, J=7.7,3.5Hz,1H),3.59(s,2H),3.18(dd,J=14.8,8.3Hz,1H),2.82–2.66(m,4H),2.62 (dt,J=14.7,2.8Hz,1H),2.56(t,J=7.7Hz,2H),1.97(p,J=3.3Hz,1H),1.74–1.59(m, 4H), 1.52 (dtt, J=13.4, 6.4, 2.6Hz, 1H), 1.37–1.29 (m, 1H), 0.93 (t, J=7.3Hz, 3H) ppm.

[0135] Example 10: Pharmacological Test

[0136] Purpose:

[0137] The compounds of Examples 1-9 were prepared into eye drops of different concentrations, and Holland rabbits were selected for pharmacodynamic screening, mainly to investigate the pupil changes of Holland rabbits.

[0138] Experimental Materials:

[0139] Male Dutch rabbits, aged 4-6 months and weighing 1.5-3.0 kg, were purchased from Pizhou Dongfang Breeding Co., Ltd.

[0140] Eye drops preparation:

[0141] The blank solvents used were polyoxyethylene hydrogenated castor oil, sodium chloride, benzalkonium chloride, and sterile water for injection.

[0142] Experimental operation 1: Test on the irritation of the compound to the eyes of Dutch rabbits

[0143] Twelve male Dutch rabbits, totaling 24 eyes, were administered single topical eye drops of the test products of Examples 1-9, blank solvent, pilocarpine hydrochloride eye drops, and acetocarpine hydrochloride eye drops, with a volume of 50 μL / eye, and detailed clinical observations were performed 0.5h and 2h after eye drops administration. Scoring was performed according to the criteria in Table 1, and the concentrations of the compounds in each example are shown in Table 2.

[0144] Table 1 Eye irritation response scores

[0145]

[0146]

[0147] Table 2 Compound preparation concentration

[0148] sample Concentration (w / v) Example 1 2.90％ Example 2 3.10％ Example 3 6.00％ Example 4 6.00％ Example 5 5.40％ Example 6 2.33％ Example 7 7.90％ Example 8 2.45％ Example 9 2.45％ solvent / Clidine hydrochloride 1.75％ Pilocarpine Hydrochloride 1.25％

[0149] Conclusion: Under the experimental conditions, the test products of Examples 1-9 had no irritation to the eyes of Dutch rabbits at all concentrations.

[0150] Experimental operation 2: Investigate the effect of compounds on pupil constriction in Dutch rabbits

[0151] 27 male Dutch rabbits were randomly divided into 9 groups, 3 rabbits / group, and the test sample was administered by topical eye drops in both eyes. The vehicle group was administered with the vehicle, and the positive control group was administered with pilocarpine hydrochloride and acetocarpine hydrochloride. The administration volume was 50 μL / eye, and the drug concentrations were shown in Table 2. The blank control group was not administered. The effect of the test sample on the pupil diameter of Dutch rabbits was investigated. Animals will be randomly grouped according to body weight in Provantis or Excel. The pupil measurement data of all animals will be collected on 3 different days during the quarantine period. The pupil diameter data of the experimental animals will be collected once before the start of administration, 15min, 30min, 1h, 3h, 6h, 8h and 10h after administration. The test results are shown in Table 3.

[0152] Table 3 Effects of compounds on pupil size of Dutch rabbit eyes

[0153]

[0154] Conclusion: Through the miotic test, it was found that the compounds of the examples all had certain miotic effects, especially Example 5 had the best miotic effect. The miotic effect of this example was significantly better than that of pilocarpine hydrochloride at 3-10 hours after administration, and significantly better than that of acetochloride hydrochloride at 6-10 hours after administration, which shows that the miotic effect of the compounds provided in this application was more lasting.

[0155] Although the present application has been described in detail above by means of general description, specific implementation methods and experiments, it is obvious to those skilled in the art that some modifications or improvements may be made to the present application. Therefore, these modifications or improvements made without departing from the spirit of the present application are within the scope of protection claimed in the present application.

Claims

1. A compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I): in: Ring A is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring; R 1 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkoxyalkyl substituted with halo or hydroxy; R 2 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, ketoalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, alkynyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, alkylcarbonyl, or arylcarbonyl; R 3 is deuterium, hydroxy, amino, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, ketoalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, alkynyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, alkylcarbonyl or arylcarbonyl.

2. The compound according to claim 1, wherein The A ring is a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; The heteroaromatic ring and the heterocyclic ring each independently contain 1, 2, 3 or 4 identical or different N, O or S heteroatoms.

3. The compound according to claim 2, wherein In formula (I), the ring A is a benzene ring, a naphthalene ring, a cyclopropylene ring, a cyclobutylene ring, a cyclopentylene ring, a cyclohexylene ring, a tetrahydrofuran ring, a dihydrofuran ring, a tetrahydrothiophene ring, a dihydrothiophene ring, a 1,3-dioxolane ring, a dithiocyclopentyl ring, a tetrahydropyran ring, a dihydropyran ring, a 2H-pyran ring, a 4H-pyran ring, a tetrahydrothiopyran ring, a piperidine ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a dioxane ring, ring, dithiane ring, thioxane ring, homopiperazine ring, homopiperidine ring, oxepane ring, thiepane ring, indoline ring, 1,2,3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring, furan ring, imidazole ring, 3-isoxazole ring, isoxazole ring, oxazole ring, pyrrole ring, pyridine ring, pyrimidine ring, pyridazine ring, thiazole ring, tetrazole ring, triazole ring, 2-thiophene ring, 3- Thiophene ring, pyrazole ring, isothiazole ring, 1,2,3-oxadiazole ring, 1,2,5-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,3-triazole ring, 1,2,3-thiodiazole ring, 1,3,4-thiodiazole ring, 1,2,5-thiodiazole ring, pyrazine ring, 1,3,5-triazine ring, benzimidazole ring, benzofuran ring, benzothiophene ring, indole ring, purine ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyridine ring, pyrazolo[1,5-a]pyridine ring, pyrazolo[1,5-a]pyrimidine ring, imidazo[1,2-b]pyridazine ring, [1,2,4]triazolo[4,3-b]pyridazine ring, [1,2,4]triazolo[1,5-a]pyrimidine ring or [1,2,4]triazolo[1,5-a]pyridine ring.

4. The compound according to any one of claims 1 to 3, wherein In formula (I), R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 alkyl; Preferably, the R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl or trifluoromethyl.

5. The compound according to any one of claims 1 to 4, wherein In formula (I), R 2 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Keto C 1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Halogenated or hydroxy-substituted alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated or hydroxy substituted C 1-6 Alkylamino, C 1-6 Alkylthio, halogenated or hydroxy-substituted C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy, C 1-6 Alkylcarbonyl or C 6-10 Arylcarbonyl; The R 3 Deuterium, hydroxyl, amino, cyano, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Keto C 1-6 Alkyl, C 1-6 Halogenated or hydroxy substituted alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen or hydroxy substituted C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Halogenated or hydroxy-substituted alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated or hydroxy substituted C 1-6 Alkylamino, C 1-6 Alkylthio, halogenated or hydroxy-substituted C 1-6 Alkylthio, C 3-8 Cycloalkyl, C 2-10 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy, C 1-6 Alkylcarbonyl or C 6-10 Arylcarbonyl.

6. The compound according to any one of claims 1 to 5, wherein In formula (I), R 2 is hydrogen, deuterium, hydroxyl, amino, cyano, mercapto, nitro, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, acetyl, benzoyl, trifluoromethyl, difluoromethyl, (2-oxocyclopentyl)methyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, butoxy, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl , isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, phenyl imidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl; The R 3 deuterium, hydroxyl, amino, cyano, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, acetyl, benzoyl, trifluoromethyl, difluoromethyl, (2-oxocyclopentyl)methyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, butoxy, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl , dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, Oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazole yl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

7. The compound according to any one of claims 1 to 6, wherein In formula (I), R 2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, benzoyl, methoxy, ethoxy, propoxy, butoxy or (2-oxocyclopentyl)methyl; The R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, benzoyl, methoxy, ethoxy, propoxy, butoxy or (2-oxocyclopentyl)methyl.

8. A compound having the structure shown below, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

9. A composition comprising the compound according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

10. Use of the compound according to any one of claims 1 to 8 or the composition according to claim 9 in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient; Preferably, the eye disease is presbyopia.

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