Steroid compound and use thereof

Abstract

Provided are a steroid compound and a pharmaceutical composition comprising the steroid compound. The steroid compound has a structure as shown in formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure shown in formula (I). The compound or composition can be used for preparing drugs for preventing, dealing with, treating or alleviating eye diseases of patients.

Description

Steroid compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to the Chinese patent application with application number 202311223261.5 filed on September 20, 2023, and invention name “Steroid Compounds and Their Applications”. The entire contents of the above patent application are incorporated into this application in their entirety. Technical Field

[0003] The present application relates to a steroid compound, stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and uses thereof in the preparation of drugs for treating ophthalmic diseases. Background Art

[0004] Cataracts are eye diseases that develop in the lens of the eye. Any clouding of the lens is called a cataract. Aging, genetics, metabolic abnormalities, trauma, radiation, poisoning, and local malnutrition can damage the lens capsule, increasing its permeability and losing its barrier function. Alternatively, disturbances in lens metabolism can cause denaturation of lens proteins, resulting in clouding. If the transparent lens becomes opaque, limiting the ability of the eye to receive sunlight, vision can be affected. Mild clouding affects vision only slightly. As the cloudiness deepens, vision deteriorates, leading to blindness in severe cases. Cataracts are one of the most common causes of blindness and a leading cause of blindness. Because the mechanisms of cataract formation remain unclear, no breakthroughs in medical treatment have been achieved. Therefore, surgery is the only proven effective treatment.

[0005] Although continuous advancements in cataract surgery have greatly aided cataract treatment, the cure rate remains far lower than the incidence rate, and serious complications are a possibility. Furthermore, cataract surgery is extremely expensive, placing a significant burden on health insurance systems even in developed countries. Therefore, medication plays a crucial role in the prevention and treatment of cataracts. Currently, clinically available cataract treatments include: ① aldose reductase inhibitors, such as cataracts (catalin, kalinyou, and baineting), falconolactone, and benzyl lysine; ② antioxidants, such as glutathione, taurine, and aspirin; ③ nutritional and metabolic drugs, such as vitamins and carotenoids; and ④ traditional Chinese medicine formulas, including Shihu Yeguang Pills, Qiju Dihuang Pills, and Shijueming Powder. However, long-term clinical trials have confirmed that these cataract treatments can only slow the progression of cataracts, not reverse the condition. Furthermore, as my country enters an aging society, the number of cataract patients is increasing, further exacerbating the demand for cataract medications. Therefore, there is a great need in clinical practice for new types of ophthalmic topical anti-cataract drugs that are safe, effective, have strong intraocular penetration, and are stable in nature.

[0006] Lanosterol is an amphiphilic molecule that is abundant in the lens. It is synthesized by lanosterol synthase (LSS), a key cyclization reaction in the cholesterol biosynthesis pathway. It can reduce abnormal aggregation of lens proteins, causing them to rearrange regularly and thus restoring lens transparency. Previous studies have shown that lanosterol synthase can be detected in the lens. Furthermore, in studies of Shumiya cataract rats, specific combinations of homozygous mutations in lanosterol synthase and farnesyl diphosphate farnesyltransferase 1 (FDFT1) reduced cholesterol levels in the lens and led to cataracts. Furthermore, our recent research has shown that lanosterol can significantly reduce preformed lens protein aggregates in vitro and in cells. Lanosterol has also been shown to reverse cataracts in vivo, resulting in clear and transparent lenses. These results, recently published in Nature, have garnered widespread attention worldwide, proving it a promising new molecule for the prevention and treatment of cataracts.

[0007] Summary of the Invention

[0008] In one 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 shown in formula (I),

[0009] wherein Ring A is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring;

[0010] X is a bond, alkylene, -Oalkylene-, -alkyleneOC(=O)O-, -OalkyleneOC(=O)O-, -alkyleneOC(=O)-, or -OalkyleneOC(=O)-;

[0011] R 1 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0012] R 2 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0013] Optionally, R 1 and R 2 Together with the attached phosphorus atom, it forms a phosphorus-containing heterocyclic group;

[0014] R 3 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, or hydroxy-substituted alkoxy;

[0015] R 4 、R 5 and R 6 Each is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, R 11 C(=O)O-alkyl, R 12 C(=O)S-alkyl, monophosphate or diphosphate;

[0016] R 7 、R 8 、R 9 and R 10 are each independently hydrogen, deuterium, alkyl, cycloalkyl, aryl, heteroaryl or R 13 OC(=O)-alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle;

[0017] R 11 、R 12 and R 13are each independently alkyl, cycloalkyl, aryl, heteroaryl or arylalkyl;

[0018] R 14 is deuterium, alkyl, alkylOC(=O)-;

[0019] where R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 、R 13 or R 14 The alkyl, aryl, cycloalkyl, heteroaryl, phosphorus-containing heterocyclic group, heterocycle or heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic group, haloaryl, aryl and heteroaryl.

[0020] In some embodiments, Ring A is C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, C 3-10 Carbon ring or C 2-9 heterocyclic ring;

[0021] X is a bond, C 1-6 Alkylene, -C 1-6 Alkylene OC(=O)O- or -OC 1-6 Alkylene OC(=O)O-;

[0022] R 3 For hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy.

[0023] In some embodiments, X is -alkyleneOC(=O)- or -OalkyleneOC(=O)-.

[0024] In some embodiments, ring A is a benzene ring, a thiazole ring, a thiophene ring, a furan ring, a pyrrole ring, a pyridine ring, or a pyrimidine ring;

[0025] X is a bond or methylene, ethylene, propylene, or methylmethylene;

[0026] R 3 is hydrogen, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0027] In some embodiments, R 1 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0028] R 2 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0029] R 4 、R 5 and R 6 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, R 11 C(=O)OC 1-6 Alkyl, R12 C(=O)SC 1-6 Alkyl, monophosphate or diphosphate;

[0030] R 7 、R 8 、R 9 and R 10 are independently hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 Heteroaryl or R 13 C(=O)OC 1-6 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle;

[0031] R 11 、R 12 and R 13 Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 heteroaryl or benzyl;

[0032] R 14 Deuterium, C 1-6 Alkyl, C 1-6 AlkylOC(=O)-.

[0033] In other embodiments, R 1 For hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0034] R 2 For hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0035] R 4 、R 5 and R 6Each is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, R 11 C(=O)OC 1-3 Alkyl, R 12 C(=O)SC 1-3 Alkyl, monophosphate or diphosphate;

[0036] R 7 、R 8 、R 9 and R 10 are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, or R 13 C(=O)OC 1-3 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered nitrogen heterocycle;

[0037] R 11 、R 12 and R 13 each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl or benzyl;

[0038] R 14 For deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 AlkylOC(=O)-.

[0039] In some embodiments, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 、R 13 or R 14 C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, C 2-9 Heteroaryl, C 2-9 Phosphorus-containing heterocyclic group or C2-9 The heterocyclic group is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10 Halogenated aryl and C 2-9 The heteroaryl group is substituted by a substituent.

[0040] In other embodiments, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 、R 13 or R 14 The methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl described in the above-mentioned group is optionally substituted by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

[0041] In some embodiments, the compound has a structure as shown in Formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in Formula (II),

[0042] On the other hand, the present application also provides a pharmaceutical composition comprising the compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0043] In another aspect, the present application provides a use of the compound or pharmaceutical composition described herein in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

[0044] In some embodiments, the eye disease is cataracts, floaters, or presbyopia.

[0045] In another aspect, the present application provides a method for preventing, managing, treating or alleviating eye diseases in patients, comprising administering an effective amount of the above-mentioned steroid compound or the above-mentioned pharmaceutical composition to the patient.

[0046] In some embodiments, the eye disease is cataracts, floaters, or presbyopia.

[0047] The foregoing description only summarizes certain aspects of the present application, but is not limited to these aspects. These and other aspects will be described in more detail and fully below. DETAILED DESCRIPTION

[0048] Definitions and General Terms

[0049] Unless otherwise stated, the terms used in the specification and claims of this application have the following definitions.

[0050] 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 application is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present application as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present application. The application is in no way limited to the methods and materials described herein. In the event that 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 technology, etc.), the present application shall prevail.

[0051] It should be further appreciated that certain features of the present application, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present application, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0052] 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.

[0053] Unless otherwise indicated, the following definitions as used herein shall apply. For the purposes of this application, the chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 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.

[0054] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles 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., more than one component may be contemplated for use or use in implementing the described embodiments.

[0055] The term "subject" as used herein refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., human, 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.

[0056] The term "patient" used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0057] The term "comprising" is an open expression, that is, including the contents specified in the application, but not excluding other contents.

[0058] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0059] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0060] Stereochemical definitions and conventions used herein 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.

[0061] Many organic compounds exist in optically active forms, meaning 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. A compound prefixed with (+) or d is right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. 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.

[0062] 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.

[0063] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or a mixture thereof, such as a racemate or a mixture of diastereomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can 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.

[0064] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0065] Unless otherwise indicated, the structural formulas described in the present application include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present application or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present application.

[0066] The term "prodrug" as used in this application refers to a compound that is converted into a compound shown in formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of this application can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in this application contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see 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.

[0067] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products 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).

[0068] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed 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.

[0069] 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, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarates, 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 such salts may be obtained by other methods described in the literature, such as ion exchange. 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 The present application also contemplates quaternary ammonium salts formed by any compound containing a N group. 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.

[0070] 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.

[0071] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0072] 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.

[0073] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0074] The term "protecting group" or "PG" refers to a substituent that blocks or protects a specific functionality when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl-protecting group" refers to a substituent attached to a carboxyl group that blocks or protects the carboxyl functionality. Typical carboxyl-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0075] A "pharmaceutical composition" refers to a mixture of one or more salts of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0076] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing down or preventing or alleviating the development of the disease or at least one clinical symptom thereof). 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 the 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 worsening of a disease or condition.

[0077] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated 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 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0078] 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 the context of radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein, using an appropriate isotopically labeled reagent in place of the previously used unlabeled reagent.

[0079] In addition, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in this application is considered a substituent of a compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the present application 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 herein include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0080] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as specifically exemplified in the Examples, subclasses, and classes of compounds encompassed herein. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position. The substituents can be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, thiol, 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, carboxylalkoxy and the like.

[0081] As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl radical may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl radicals 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), isobutyl (i-Bu, -CH2CH(CH3)2), 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 (-CH2CH2CH(CH3)2), 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. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0082] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to a main carbon chain via an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc., and the alkoxy group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0083] 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 C—C is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described in the present application, including groups with "trans", "cis" or "E", "Z" orientation, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0084] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an 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 (—CH2C≡CH), and the like.

[0085] The term "cycloalkyl" or "carbocycle" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including a monocyclic ring of 3-12 carbon atoms or a bicyclic ring of 7-12 carbon atoms. Bicyclic carbocycles of 7-12 atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocycles of 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 groups. Examples of cyclic aliphatic groups 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, and the like. And the "cyclic aliphatic group" or "carbocycle", "carbocyclic group", "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 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.

[0086] 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(s) are independently and optionally replaced by heteroatoms, wherein the heteroatoms have the meanings herein, the ring(s) may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, and have only one point of attachment to another molecule. One or more hydrogen atoms in the ring(s) 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, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom therein), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0087] Heterocyclic groups can be carbon groups or heteroatom groups. "Heterocyclic group" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, 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 yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinylimidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 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-triazin-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)ethan-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. The heterocyclic group may be substituted or unsubstituted, and the substituents may be, but are not limited to, oxo (=O), hydroxy, 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.

[0088] The term "aryl" or "aromatic ring" used alone or as part of an "aralkyl," "aralkyloxy," or "aryloxyalkyl" group refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6 to 14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 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," and examples of aromatic rings include phenyl, naphthyl, and anthracenyl. And the aryl group 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, 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.

[0089] The term "heteroaryl" or "heteroaromatic ring" refers to monocyclic, bicyclic, and tricyclic ring systems containing a total of 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 described herein, and 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" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound." And the heteroaryl group 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, 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.

[0090] In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, 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 dioxadiazolyl 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.

[0091] 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).

[0092] The term "halogen" refers to F, Cl, Br or I.

[0093] The term "halogenated" 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.

[0094] The term "hydroxy-substituted" as used herein means that the group following it is substituted with a hydroxy group, and the number of substitutions may be one or more.

[0095] When "substituted" in this application is used between two groups, it is preceded by a substituent, such as "aryl-substituted alkyl" means that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" means that the alkyl group has an alkoxycarbonyl substituent.

[0096] When multiple groups are used in combination in the present application, they are in a substitution relationship from left to right, such as "arylalkyl" represents an alkyl substituted by an aryl group, and "alkoxyalkoxy" represents an alkoxy substituted by an alkoxy group.

[0097] As used in this application, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0098] Description of the compounds of the present application

[0099] In one 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 shown in formula (I),

[0100] wherein Ring A is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring;

[0101] X is a bond, alkylene, -Oalkylene-, -alkyleneOC(=O)O-, -OalkyleneOC(=O)O-, -alkyleneOC(=O)-, or -OalkyleneOC(=O)-;

[0102] R 1 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0103] R 2 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0104] Optionally, R 1 and R 2 Together with the attached phosphorus atom, it forms a phosphorus-containing heterocyclic group;

[0105] R 3 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, or hydroxy-substituted alkoxy;

[0106] R 4 、R 5 and R 6Each is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, R 11 C(=O)O-alkyl, R 12 C(=O)S-alkyl, monophosphate or diphosphate;

[0107] R 7 、R 8 、R 9 and R 10 are each independently hydrogen, deuterium, alkyl, cycloalkyl, aryl, heteroaryl or R 13 OC(=O)alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle;

[0108] R 11 、R 12 and R 13 are each independently alkyl, cycloalkyl, aryl, heteroaryl or arylalkyl;

[0109] R 14 is deuterium, alkyl, alkylOC(=O)-;

[0110] where R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 、R 13 or R 14 The alkyl, aryl, cycloalkyl, heteroaryl, phosphorus-containing heterocyclic group, heterocycle or heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic group, haloaryl, aryl and heteroaryl.

[0111] In some embodiments, X is -alkyleneOC(=O)- or -OalkyleneOC(=O)-.

[0112] In some embodiments, wherein Ring A is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring;

[0113] X is a bond or an alkylene group;

[0114] R1 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0115] R 2 is hydroxy, hydroxyalkyl, alkoxyalkyl, haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0116] Optionally, R 1 and R 2 Together with the attached phosphorus atom, it forms a phosphorus-containing heterocyclic group;

[0117] R 3 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy, or hydroxy-substituted alkoxy;

[0118] R 4 、R 5 and R 6 Each is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, R 11 C(=O)O-alkyl, R 12 C(=O)S-alkyl, monophosphate or diphosphate;

[0119] R 7 、R 8 、R 9 and R 10 are each independently hydrogen, deuterium, alkyl, cycloalkyl, aryl, heteroaryl or R 13 OC(=O)-alkyl;

[0120] R 11 、R 12 and R 13 are each independently alkyl, cycloalkyl, aryl, heteroaryl or arylalkyl;

[0121] where R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R11 、R 11 、R 12 and R 13 The alkyl, aryl, cycloalkyl, heteroaryl, phosphorus-containing heterocyclic group, heterocycle or heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic group, haloaryl, aryl and heteroaryl.

[0122] In some embodiments, Ring A is C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, C 3-10 Carbon ring or C 2-9 heterocyclic ring;

[0123] X is a bond, C 1-6 Alkylene, -C 1-6 Alkylene OC(=O)O- or -OC 1-6 Alkylene OC(=O)O-;

[0124] R 3 For hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy.

[0125] In some embodiments, X is -C 1-6 Alkylene OC(=O)- or -OC 1-6 Alkylene OC(=O)-.

[0126] In some embodiments, ring A is a benzene ring, a thiazole ring, a thiophene ring, a furan ring, a pyrrole ring, a pyridine ring, or a pyrimidine ring;

[0127] X is a bond or methylene, ethylene, propylene, or methylmethylene;

[0128] R 3 is hydrogen, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0129] In some embodiments, R 1 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0130] R 2 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0131] R 4 、R 5 and R 6 Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, R 11 C(=O)OC 1-6 Alkyl, R 12 C(=O)SC 1-6 Alkyl, monophosphate or diphosphate;

[0132] R 7 、R 8 、R 9 and R 10 are independently hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 Heteroaryl or R13 C(=O)OC 1-6 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle;

[0133] R 11 、R 12 and R 13 Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 heteroaryl or benzyl;

[0134] R 14 Deuterium, C 1-6 Alkyl, C 1-6 AlkylOC(=O)-.

[0135] In other embodiments, R 1 For hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0136] R 2 For hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0137] R 4 、R 5 and R 6 Each is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, R 11 C(=O)OC 1-3 Alkyl, R 12 C(=O)SC 1-3 Alkyl, monophosphate or diphosphate;

[0138] R 7 、R 8 、R 9 and R 10are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, or R 13 C(=O)OC 1-3 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered nitrogen heterocycle;

[0139] R 11 、R 12 and R 13 each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl or benzyl;

[0140] R 14 For deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 AlkylOC(=O)-.

[0141] In some embodiments, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 and R 13 C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, C 2-9 Heteroaryl, C 2-9 Phosphorus-containing heterocyclic group or C 2-9 The heterocyclic group is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10 Halogenated aryl and C 2-9 The heteroaryl group is substituted by a substituent.

[0142] In some embodiments, R 14 C 1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10 Halogenated aryl and C 2-9 Substituted by a substituent in a heteroaryl group

[0143] In other embodiments, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 11 、R 12 and R 13The methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl described in the above-mentioned group is optionally substituted by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

[0144] In other embodiments, R 14 The methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl groups are optionally substituted by 1, 2, 3 or 4 substituents selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

[0145] In some embodiments, the compound has the structure shown in formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II),

[0146] In some embodiments, X is a bond or -OC 1-6 Alkylene OC(=O)-. In some embodiments, X is a bond, -Omethylene OC(=O)-, -Oethylene OC(=O)-, -O-n-propylene OC(=O)-, -O-isopropylene OC(=O)-, -O-n-butylene OC(=O)-, -O-isobutylene OC(=O)-, -O-tert-butylene OC(=O)-.

[0147] In some embodiments, R 1 For hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0148] R 2 For hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0149] R4 、R 5 and R 6 are independently hydrogen, C 1-6 Alkyl or C 6-10 aryl;

[0150] R 7 、R 8 、R 9 and R 10 are independently hydrogen, deuterium, C 1-6 Alkyl or -R 13 C(=O)OC 1-6 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered nitrogen heterocycle;

[0151] R 13 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 heteroaryl;

[0152] R 14 Deuterium, C 1-6 Alkyl, C 1-6 Alkyl OC(=O)-,

[0153] R 13 and R 14 C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, C 2-9 Heteroaryl is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10Halogenated aryl and C 2-9 The heteroaryl group is substituted by a substituent.

[0154] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl and the following groups:

[0155] In some embodiments, the compound has the structure shown in formula (III), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II),

[0156] Among them, R 1 、R 2 and R 3 Has the definitions given herein.

[0157] In some embodiments, R 3 For hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 alkyl.

[0158] In some embodiments, R 1 For hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0159] R 2 For hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0160] R 4 、R 5 and R 6 are independently hydrogen, C 1-6 Alkyl or C 6-10 aryl;

[0161] R 7 、R 8 、R 9 and R 10 are independently hydrogen, deuterium, C1-6 Alkyl or R 13 C(=O)OC 1-6 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered nitrogen heterocycle;

[0162] R 13 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 heteroaryl;

[0163] R 14 Deuterium, C 1-6 Alkyl, C 1-6 Alkyl OC(=O)-,

[0164] R 13 and R 14 C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, C 2-9 Heteroaryl is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10 Halogenated aryl and C 2-9 The heteroaryl group is substituted by a substituent.

[0165] In some embodiments, R 1 is hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ;

[0166] R 2 is hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ;

[0167] R 4 、R 5 and R 6 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or phenyl;

[0168] R 7 、R 8 、R 9 and R 10 are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or R 13 C(=O)OC 1-3 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered nitrogen heterocycle;

[0169] R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl or benzyl, R 13 The methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl or benzyl group is optionally replaced by 1, 2, 3 or 4 substituents selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl;

[0170] R 14 For deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 AlkylOC(=O)-.

[0171] In some embodiments, R 1 and R 2 are each independently selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl and the following groups:

[0172] In some embodiments, the compounds of the present application have one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0173] Compositions, formulations and administration of the compounds of the present application

[0174] The pharmaceutical composition comprises any one of the compounds of the present application and may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0175] The pharmaceutical composition can be used to treat eye diseases, and in particular, has a good therapeutic effect on cataracts, floaters or presbyopia.

[0176] Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, 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, polyvinylpyrrolidone, 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 cellulose. sodium cellulose, ethylcellulose 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.

[0177] When used for treatment, a therapeutically effective amount of the compound of the present application can be given as a raw chemical or provided as an active ingredient of a pharmaceutical composition. Therefore, the present application also provides a pharmaceutical composition comprising 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" as used herein refers to the total amount of each active ingredient 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 that ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect, whether in combination, sequentially or simultaneously. In terms of compatibility with the 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, comprising 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 their intended use.

[0178] 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.

[0179] Uses of the compounds and compositions of the present application

[0180] The invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

[0181] Particularly, the eye disease is cataract, floaters or presbyopia.

[0182] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an amount effective to treat or alleviate the severity of one or more of the conditions mentioned herein. According to the methods of the present invention, the compounds and compositions thereof can be administered in any amount and by any route of administration to effectively treat or alleviate the severity of the disease. The exact amount required will vary depending on the patient's condition, which depends on race, age, general condition of the patient, severity of the infection, special factors, mode of administration, etc. The compounds or compositions of the present invention can be administered in combination with one or more other therapeutic agents, as discussed herein.

[0183] In order to enable those skilled in the art to better understand the technical solution of the present application, some non-limiting embodiments are further disclosed below to further illustrate the present application in detail.

[0184] General synthesis process

[0185] 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 provided to further illustrate the content of the present application.

[0186] 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 invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of compounds not exemplified herein can be successfully accomplished 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 herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0187] In the examples described below, all temperatures are set forth 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 used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0188] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0189] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0190] Silica gel columns were used for chromatography. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectra were performed using CDC13, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0191] Low-resolution mass spectrometry (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0192] Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0193] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; HPLC peaks were recorded at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phases consisted of 0.1% formic acid in acetonitrile (Phase A) and 0.1% formic acid in ultrapure water (Phase B). Gradient elution conditions are shown in Table a:

[0194] Table a

[0195] The process conditions for HPLC preparation are:

[0196] (1) Take an appropriate amount of a mixture of diastereoisomers containing a compound and dissolve it in a mobile phase;

[0197] (2) Set the flow rate of the mobile phase, detection wavelength and column temperature;

[0198] (3) Take an appropriate amount of the sample solution in step (1) and inject it into a high performance liquid chromatograph, record the chromatogram, and complete the separation and analysis of the isomers;

[0199] Chromatographic column: a normal phase chiral chromatographic column with a silica gel containing a polysaccharide derivative as the stationary phase; more specifically, the chromatographic column used is Daicel AD-H (10*250nm, 5um) or Daicel AD (20*250nm, 5um).

[0200] The mobile phase comprises a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid, and glacial acetic acid. More specifically, the volume ratio of n-hexane, n-pentane, isohexane, and n-heptane in the mobile phase mixture is 10-20%, the volume ratio of methanol, ethanol, isopropanol, and acetonitrile is 20-95%, the volume ratio of diethylamine, triethylamine, trifluoroacetic acid, and glacial acetic acid is 0-2%, and the total volume ratio of all components in the mobile phase is 100%. More specifically, the volume ratio of n-hexane in the mobile phase mixture is 15-20%, the volume ratio of isopropanol is 80-90%, the volume ratio of diethylamine and triethylamine is 0.5-1%, and the total volume ratio of all components in the mobile phase is 100%.

[0201] Detection wavelength: 250nm~320nm;

[0202] Flow rate: 0.5-10 mL / min; more specifically 2-5 mL / min;

[0203] Column temperature: 10~35℃.

[0204] The following abbreviations are used throughout this application:

[0205] AcOH: acetic acid

[0206] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0207] Boc: tert-butyloxycarbonyl

[0208] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0209] CH3CN: acetonitrile

[0210] DCM: dichloromethane

[0211] DIPEA: N,N-diisopropylethylamine

[0212] EA: ethyl acetate

[0213] HCl: hydrogen chloride

[0214] HCl / EA: Hydrogen chloride in ethyl acetate

[0215] H2O: water

[0216] NaOH: sodium hydroxide

[0217] NaI: sodium iodide

[0218] K2CO3: Potassium carbonate

[0219] rt, rt: room temperature

[0220] PE: Petroleum ether

[0221] DCC: dicyclohexylcarbodiimide

[0222] DMAP: dicyclohexylcarbodiimide

[0223] HP-β-CD: Hydroxypropyl-β-cyclodextrin

[0224] MC: methylcellulose

[0225] DMSO: dimethyl sulfoxide

[0226] Example

[0227] Example 1

[0228] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((((S)-1-isopropoxy)-1-oxopropan-2-yl)amino)(methoxymethyl)phosphoryl)oxy)benzoate (Compound 1)

[0229] Raw material 1a (0.46 g, 2.82 mmol) was dissolved in 10 mL of dry dichloromethane and cooled to -30°C under nitrogen. L-alanine isopropyl ester hydrochloride (0.457 g, 2.74 mmol) was added, followed by the slow dropwise addition of triethylamine (0.600 g, 5.94 mmol). Stirring was continued at -30°C for 1 hour. Raw material 1c (0.750 g, 1.41 mmol) and triethylamine (0.600 g, 5.94 mmol) were then added. After addition, the mixture was allowed to warm to room temperature and reacted for 2 hours. The mixture was diluted with 50 mL of dichloromethane and washed sequentially with saturated sodium dihydrogen phosphate solution (30 mL), saturated sodium bicarbonate solution (30 mL x 2), and saturated sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified on a silica gel column to yield compound 1 (0.324 g, white solid).

[0230] LCMS (ESI), m / z, [M+H] + =768.4;

[0231] 1 H NMR (500MHz, CDCl3) δ7.86–7.79(m,1H),7.52–7.43(m,2H),7.24–7.18(m,1H),5.11( t,1H),5.02–4.81(m,1H),4.78–4.72(m,1H),4.33–4.16(m,1H),4.09–4.03(m,1H),3 .96–3.88(m,2H),3.50(s,3H),2.10–2.00(m,5H),1.97–1.72(m,8H),1.69(s,3H),1. 61(s,3H),1.60–1.45(m,3H),1.45–1.15(m,9H),1.15–0.90(m,21H),0.70(s,3H)ppm;

[0232] 31 P NMR (202MHz, CDCl3) δ24.06, 23.37ppm.

[0233] Example 2

[0234] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((ethoxycarbonyl)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 2)

[0235] Raw material 2a (0.431 g, 2.27 mmol) (synthesis method described in CN112390821) was dissolved in 20 mL of dry dichloromethane and cooled to -60°C under nitrogen. A dichloromethane mixture (20 mL) of raw material 1c (1.24 g, 2.27 mmol) and triethylamine (0.460 g, 0.454 mmol) was slowly added dropwise. After addition, the mixture was incubated for 40 minutes. L-alanine isopropyl ester hydrochloride (0.380 g, 2.27 mmol) and triethylamine (0.460 g, 0.454 mmol) were then added. The mixture was allowed to warm to room temperature and reacted for 2 hours. 30 mL of water was added, the layers separated, and the organic layer was washed once with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified on a silica gel column to yield compound 2 (0.379 g, white solid, 21% yield).

[0236] LCMS (ESI), m / z, [M+H] + =796.3.

[0237] Example 3

[0238] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((ethoxycarbonyl)((1-isopropoxy-2-methyl-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 3)

[0239] Raw material 2a (0.431 g, 2.27 mmol) (synthesis method described in CN112390821) was dissolved in 20 mL of dry dichloromethane and cooled to -60°C under nitrogen. A dichloromethane mixture (20 mL) of raw material 1c (1.24 g, 2.27 mmol) and triethylamine (0.460 g, 0.454 mmol) was slowly added dropwise. After addition, the mixture was incubated for 40 minutes. Subsequently, isopropyl 2-amino-2-methylpropanoate hydrochloride (0.412 g, 2.27 mmol) and triethylamine (0.460 g, 0.454 mmol) were added. After addition, the mixture was naturally warmed to room temperature and reacted for 4 hours. 30 mL of water was added, the layers separated, and the organic layer was washed once with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified on a silica gel column to yield compound 3 (0.276 g, white solid).

[0240] LCMS (ESI), m / z, [M+H] +=810.5.

[0241] Example 4

[0242] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 4)

[0243] Step 1: Preparation of L-alanine isopropyl ester (4c)

[0244] Triethylamine (6.7 g, 65.8 mmol) was added dropwise to a solution of L-alanine isopropyl ester hydrochloride 4b (10.0 g, 59.9 mmol) in dichloromethane (100 mL) at 0°C under nitrogen. The mixture was returned to room temperature and stirred for 1 h. The mixture was filtered, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 4c (4.0 g, colorless oil).

[0245] 1 HNMR (500MHz, CDCl3) δ4.89(m,1H),3.38(q,1H),2.56(s,2H),1.22–1.14(m,9H)ppm.

[0246] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 4)

[0247] Under nitrogen, phosphorus oxychloride (0.36 g, 2.4 mmol) was added dropwise to dichloromethane (5 mL) at -78°C. Compound 1c (1.0 g, 1.8 mmol) and triethylamine (0.24 g, 2.4 mmol) in dichloromethane (5 mL) were then added dropwise. The mixture was stirred and allowed to react for 1 hour. A solution of compound 4c (0.53 g, 4.0 mmol) and triethylamine (0.41 g, 4.0 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture. Stirring was continued for 2 hours. A solution of sodium bicarbonate (1.5 g, 18.0 mmol) in water (10 mL) was added dropwise. The mixture was allowed to return to room temperature and stirred for 2 hours. The reaction was monitored for completion by TLC. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high pressure preparative separation to give compound 4 (0.31 g, white solid).

[0248] LCMS(ESI),m / z,[MH] ― =738.9;

[0249] 1 H NMR(500MHz, CDCl3)δ7.70(dd,2H),7.29(t,1H),6.90(t,1H),5.10(t,1H),4.84–4.71(m,1H),4. 55(d,1H),3.86(d,1H),3.49(d,1H),3.06–3.01(m,1H),2.04(s,3H),1.93(d,3H),1.88–1.77(m, 2H),1.73–1.66(m,5H),1.60(s,5H),1.49(dd,2H),1.43–1.36(m,2H),1.32–1.25(m,3H),1.18(d d,2H),1.11–1.02(m,11H),0.98(s,3H),0.95(s,3H),0.92(d,3H),0.87(d,6H),0.68(s,3H)ppm;

[0250] 31 PNMR(202MHz,CDCl3)δ2.50(s)ppm.

[0251] Example 5

[0252] Preparation of methyl (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy((1-isopropoxy-2-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 5)

[0253] Step 1: Preparation of 2-amino-2-methylpropionic acid isopropyl ester (Compound 5b)

[0254] At 0°C, under nitrogen, a solution of sodium bicarbonate (1.9 g, 22.0 mmol) in water (20 mL) was added dropwise to a solution of isopropyl 2-amino-2-methylpropanoate hydrochloride (Compound 5a) (2.0 g, 11.0 mmol) in dichloromethane (20 mL). The mixture was returned to room temperature and stirred for 1 h. The layers were separated, and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield Compound 5b (0.6 g, a colorless oil).

[0255] 1 H NMR (500MHz, CDCl3) δ4.85 (m, 1H), 1.79 (s, 2H), 1.18 (t, 12H) ppm.

[0256] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy((1-isopropoxy-2-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoic acid methyl ester (Compound 5)

[0257] Under nitrogen, phosphorus oxychloride (0.45 g, 2.96 mmol) was added dropwise to dichloromethane (5 mL) at -78°C. Compound 1c (0.9 g, 1.6 mmol) and triethylamine (0.30 g, 2.96 mmol) in dichloromethane (5 mL) were then added dropwise. The mixture was stirred and allowed to react for 1 hour. A solution of isopropyl 2-amino-2-methylpropionate (compound 5b) (0.52 g, 3.6 mmol) and triethylamine (0.37 g, 3.6 mmol) in dichloromethane (5 mL) was added dropwise to the reaction mixture. Stirring was continued for 2 hours. A solution of sodium bicarbonate (1.3 g, 16.0 mmol) in water (10 mL) was added dropwise. The mixture was allowed to return to room temperature and stirred for 2 hours. TLC monitored the reaction for completion. The liquids were separated, the aqueous phase was extracted with dichloromethane (50 mL x 2), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to high pressure preparative separation to obtain compound 5 (78 mg, white solid).

[0258] LCMS(ESI),m / z,[MH] ― =753.0;

[0259] 1 H NMR(500MHz, CDCl3)δ7.69(t,2H),7.21(s,1H),6.84(s,1H),5.10(t,1H),4.83–4.74(m,1H),4 .60(s,1H),3.65(s,1H),2.58(s,1H),2.05(d,3H),2.00(d,2H),1.96–1.81(m,3H),1.74(d,2H ),1.69(s,6H),1.63–1.58(m,5H),1.53–1.47(m,2H),1.43–1.37(m,2H),1.30(dd,2H),1.17(t ,8H),1.06(t,6H),1.00(s,3H),0.96(s,3H),0.93–0.90(m,6H),0.86(s,3H),0.69(s,3H)ppm;

[0260] 31 P NMR (202MHz, CDCl3) δ0.78(s)ppm.

[0261] Example 6

[0262] Preparation of ethyl (hydroxy (2-((((3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)phenoxy)phosphoryl)-L-proline ester (Compound 6)

[0263] Step 1: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(phosphonooxy)benzoate (6a)

[0264] Under nitrogen, phosphorus oxychloride (6.17 g, 40.2 mmol) was added dropwise to a dichloromethane (50 mL) solution at -78°C. Compound 1c (10.0 g, 18.3 mmol) and triethylamine (4.3 g, 42.1 mmol) in dichloromethane (50 mL) were then added dropwise. The mixture was stirred and allowed to react for 1 hour. A solution of sodium bicarbonate (7.7 g, 91.5 mmol) in water (100 mL) was added dropwise, and the mixture was allowed to return to room temperature and stirred for 2 hours. The liquids were separated, and the aqueous phase was extracted with dichloromethane (300 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by acetonitrile slurrying to afford compound 6a (10.2 g, white solid).

[0265] LCMS (ESI), m / z, [M+H] ― =625.5;

[0266] 1 HNMR(500MHz, CDCl3)δ10.73(s,2H),7.73(d,1H),7.48(d,1H),7.38(t,1H),7.08(t,1H),5.10(t,1H),4.75–4.57(m,1H),2.03(d,3H),1.94(s,2 H),1.83(d,2H),1.74–1.63(m,6H),1.60(s,3H),1.53–1.26(m,6H),1.1 6(dd,7H),0.97(d,6H),0.94–0.89(m,6H),0.87(s,3H),0.68(s,3H)ppm;

[0267] 31 PNMR(202MHz,CDCl3)δ-3.57(s)ppm.

[0268] Step 2: Preparation of ethyl (hydroxy (2-((((3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)phenoxy)phosphoryl)-L-proline ester (Compound 6)

[0269] Under nitrogen, compound 6a (3.2 g, 5.1 mmol), dichloromethane (60 mL), 4A molecular sieves, L-proline ethyl ester (2.2 g, 15.3 mmol), and N,N'-dicyclohexylcarbodiimide (3.1 g, 15.3 mmol) were added sequentially to a reaction flask and stirred at 45°C for 6 hours. The mixture was filtered, and the filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-pressure preparative separation to obtain compound 6 (0.8 g, white solid).

[0270] LCMS(ESI),m / z,[MH] ― =750.6;

[0271] 1 HNMR(400MHz, CDCl3)δ7.87(d,1H),7.72(d,1H),7.38(t,1H),7.00(t,1H),5.13(t,1H), 4.70(dd,1H),4.32(dd,1H),4.07(q,2H),3.36(dd,1H),2.06(d,4H),1.93(dd,2H),1.84 –1.75(m,5H),1.71(s,5H),1.63(s,3H),1.52(dd,2H),1.41(d,2H),1.31(m,10H),1.21( t,5H),1.05(s,3H),1.01(s,3H),0.98(s,3H),0.95(d,3H),0.92(s,3H),0.73(s,3H)ppm;

[0272] 31 PNMR (162MHz, CDCl3) δ1.06(s)ppm.

[0273] Example 7

[0274] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((((R)-1-isopropoxy)-1-oxopropan-2-yl)amino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 7)

[0275] Step 1: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((((R)-1-isopropoxy)-1-oxopropan-2-yl)amino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 7)

[0276] Under nitrogen protection, phosphorus oxychloride (0.50 g, 3.3 mmol) was added dropwise to dichloromethane (5 mL) at -78°C, followed by a dichloromethane (5 mL) solution of compound 1c (1.0 g, 1.8 mmol) and triethylamine (0.33 g, 3.3 mmol). The mixture was stirred and heated for 1 hour. L-alanine isopropyl ester (compound 4c) was added dropwise to obtain a 5-nitrogen phosphate ester. A solution of 2-[ ...

[0277] LCMS (ESI), m / z, [M+H] + =853.5;

[0278] 1HNMR(500MHz, CDCl3)δ7.79(d,1H),7.49–7.44(m,2H),7.19–7.14(m,1H),5.10(t,1H),4 .97(m,2H),4.77(dd,1H),4.19(t,1H),4.11–3.96(m,3H),2.04(dd,5H),1.90–1.83(m,2 H),1.82–1.72(m,4H),1.68(s,4H),1.59(d,4H),1.57–1.46(m,2H),1.44–1.35(m,6H),1 .31(t,4H),1.20(m,15H),1.04(s,4H),0.98(d,6H),0.93–0.87(m,6H),0.70(s,3H)ppm;

[0279] 31 PNMR(202MHz,CDCl3)δ8.98(s)ppm.

[0280] Example 8

[0281] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-3-methyl-1-oxobutan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 8)

[0282] Step 1: Preparation of L-valine isopropyl ester (Compound 8b)

[0283] At 0°C, under nitrogen, thionyl chloride (26.4 g, 221.9 mmol) was added dropwise to isopropanol (100 mL) and stirred for 20 minutes. A solution of L-valine (compound 8a) (20.0 g, 170.7 mmol) in isopropanol (100 mL) was added dropwise, and the temperature was raised to 85°C and stirred for 12 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by slurrying with ethyl acetate (200 mL). The product was filtered and dissolved in water (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10 / 1 (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was subjected to medium-pressure preparative separation to obtain compound 8b (12.7 g, 47% yield, colorless oil).

[0284] 1 HNMR (500MHz, CDCl3) δ5.02(dq,1H),3.21(d,1H),1.99(dq,1H),1.41(s,2H),1.25–1.19(m,6H),0.95(d,3H),0.87(d,3H)ppm.

[0285] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-3-methyl-1-oxobutan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 8)

[0286] Under nitrogen, compound 6a (3.0 g, 4.8 mmol), dichloromethane (60 mL), 4A molecular sieves, L-valine isopropyl ester (compound 8b), and N,N'-dicyclohexylcarbodiimide (2.0 g, 9.6 mmol) were added sequentially to a reaction flask and stirred at 45°C for 8 hours. The mixture was filtered, and the filtrate was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-pressure preparative separation to obtain compound 8 (0.49 g, white solid).

[0287] LCMS (ESI), m / z, [M+H] + =767.1;

[0288] 1 HNMR(400MHz, CDCl3)δ7.72(d,1H),7.61(d,1H),7.21(t,1H),6.85(t,1H),5.11(t, 1H),4.74–4.55(m,2H),3.60(d,1H),3.30(s,1H),2.21(s,2H),2.04(s,2H),1.98(s ,2H),1.89–1.78(m,3H),1.67(d,7H),1.61(s,4H),1.52–1.37(m,4H),1.31–1.10(m ,6H),1.03(d,4H),0.99(d,6H),0.96(s,3H),0.92(d,3H),0.89(d,6H),0.69(t,9H);

[0289] 31 PNMR (162MHz, CDCl3) δ3.64(s)ppm.

[0290] Example 9

[0291] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-4-methyl-1-oxopentan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 9)

[0292] Step 1: Preparation of L-leucine isopropyl ester (Compound 9b)

[0293] At 0°C, under nitrogen, thionyl chloride (23.6 g, 198.2 mmol) was added dropwise to isopropanol (100 mL) and stirred for 20 minutes. A solution of L-leucine (compound 9a) (20.0 g, 152.5 mmol) in isopropanol (100 mL) was added dropwise, and the temperature was raised to 85°C and stirred for 4 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by slurrying with ethyl acetate (200 mL). The product was filtered and dissolved in water (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10 / 1 (200 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was subjected to medium-pressure preparative separation to obtain compound 10b (6.5 g, colorless oil).

[0294] 1 HNMR (500MHz, CDCl3) δ4.97(dt,1H),3.39–3.26(m,1H),1.72(dt,1H),1.41(m,4H),1.19(t,6H),0.90–0.84(m,6H)ppm.

[0295] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-2-((hydroxy(((S)-1-isopropoxy-4-methyl-1-oxopentan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 9)

[0296] Under nitrogen, compound 6a (3.0 g, 4.8 mmol), dichloromethane (60 mL), 4A molecular sieves, L-leucine isopropyl ester (compound 9b) (1.7 g, 9.6 mmol), and N,N'-dicyclohexylcarbodiimide (2.0 g, 9.6 mmol) were added sequentially to a reaction flask and stirred at 45°C for 4 hours. The mixture was filtered, and the filtrate was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-pressure preparative separation to obtain compound 9 (0.39 g, white solid).

[0297] LCMS(ESI),m / z,[MH] ― =781.0;

[0298] 1 HNMR(400MHz, CDCl3)δ7.71(dd,2H),7.33(dd,1H),6.94(t,1H),5.10(t,1H),5. 02(dd,1H),4.87–4.80(m,1H),4.69(dd,1H),4.00–3.90(m,2H),2.03(s,2H),1. 91–1.80(m,3H),1.71(dt,7H),1.60(s,4H),1.45–1.32(m,4H),1.26(d,5H),1.1 9(d,3H),1.03–0.95(m,10H),0.93–0.85(m,15H),0.81(dd,6H),0.69(s,3H)ppm;

[0299] 31 PNMR (162MHz, CDCl3) δ1.47(s)ppm.

[0300] Example 10

[0301] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((2S,3S)-1-isopropoxy-3-methyl-1-oxopentan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 10)

[0302] Step 1: Preparation of L-isoleucine isopropyl ester (Compound 10b)

[0303] At 0°C, under nitrogen, thionyl chloride (23.6 g, 198.2 mmol) was added dropwise to isopropanol (100 mL) and stirred for 20 minutes. A solution of L-isoleucine (compound 10a) (20.0 g, 152.5 mmol) in isopropanol (100 mL) was added dropwise, and the temperature was raised to 85°C and stirred for 4 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by slurrying with ethyl acetate (200 mL). The product was filtered, and the solid was dissolved in water (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10 / 1 (200 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was subjected to medium-pressure preparative separation to obtain the title compound, L-isoleucine isopropyl ester (10b) (5.2 g, colorless oil).

[0304] 1 HNMR (500MHz, CDCl3) δ5.00(dq,1H),3.24(d,1H),1.74–1.64(m,1H),1.41(dd,2H),1.28(dd,2H),1.23–1.18(m,6H),0.91–0.82(m,6H)ppm.

[0305] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-((hydroxy(((2S,3S)-1-isopropoxy-3-methyl-1-oxopentan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 10)

[0306] Under nitrogen, compound 6a (3.0 g, 4.8 mmol), dichloromethane (60 mL), 4A molecular sieves, L-isoleucine isopropyl ester (compound 10b) (1.7 g, 9.6 mmol), and N,N'-dicyclohexylcarbodiimide (2.0 g, 9.6 mmol) were added to the reaction flask in sequence and stirred at 45°C for 6 hours. The mixture was filtered and the filtrate was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high pressure preparative separation to obtain compound 10 (0.42 g, white solid).

[0307] LCMS(ESI),m / z,[MH] ― =780.5;

[0308] 1HNMR(500MHz, CDCl3)δ8.85(s,1H),7.74(dd,2H),7.35(t,1H),6.96(t,1H),5.09(dq,1H),4.85(dt, 1H),4.69(d,1H),3.96–3.81(m,2H),2.04(d,2H),1.87(s,3H),1.76(d,4H),1.70(s,4H),1.62(s,3H ),1.59–1.50(m,3H),1.47–1.40(m,4H),1.29(d,4H),1.26–1.17(m,5H),1.12(d,3H),1.04(s,3H),1 .01(s,3H),0.97(s,3H),0.94(d,3H),0.93(d,3H),0.91(s,3H),0.86–0.78(m,6H),0.71(s,3H)ppm;

[0309] 31 PNMR(202MHz,CDCl3)δ1.57(s)ppm.

[0310] Example 11

[0311] Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-1-oxo-3-phenylpropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 11)

[0312] Step 1: Preparation of L-phenylalanine isopropyl ester (Compound 11b)

[0313] At 0°C, under nitrogen, thionyl chloride (18.7 g, 157.0 mmol) was added dropwise to isopropanol (100 mL) and stirred for 20 minutes. A solution of L-phenylalanine (compound 11a) (20.0 g, 121.0 mmol) in isopropanol (100 mL) was added dropwise, and the temperature was raised to 85°C and stirred for 10 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by slurrying with ethyl acetate (200 mL). The product was filtered and dissolved in water (200 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane / methanol (v / v) = 10 / 1 (200 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was subjected to medium-pressure preparative separation to obtain compound 11b (14 g, colorless oil).

[0314] 1 HNMR (500MHz, CDCl3) δ7.28(t,2H),7.21(dd,3H),4.99(dq,1H),3.65(t,1H),3.04(dd,1H),2.84(dd,1H),1.46(s,2H),1.22(d,3H),1.17(d,3H)ppm.

[0315] Step 2: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((hydroxy(((S)-1-isopropoxy-1-oxo-3-phenylpropan-2-yl)amino)phosphoryl)oxy)benzoate (Compound 11)

[0316] Under nitrogen, compound 6a (3.0 g, 4.8 mmol), dichloromethane (60 mL), 4A molecular sieves, L-phenylalanine isopropyl ester (compound 11b) (2.0 g, 9.6 mmol), and N,N'-dicyclohexylcarbodiimide (2.0 g, 9.6 mmol) were added sequentially to a reaction flask and stirred at 45°C for 5 hours. The mixture was filtered, and the filtrate was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-pressure preparative separation to obtain compound 13 (0.45 g, white solid).

[0317] LCMS(ESI),m / z,[MH] ― =814.5;

[0318] 1HNMR(500MHz, CDCl3)δ8.66(s,1H),7.80(d,1H),7.73(d,1H),7.36(t,1H),7.18–7.13(m,5H),6.98(t,1H),5 .13(t,1H),4.77–4.66(m,1H),4.52(d,1H),4.35(s,1H),3.25–3.16(m,1H),3.09(dd,1H),2.91(dd,1H),2.1 0–1.99(m,5H),1.97–1.83(m,3H),1.71(m,5H),1.62(d,4H),1.52(dd,4H),1.46–1.35(m,5H),1.31(dd,2H), 1.20(dt,7H),1.14(dd,4H),1.10–1.05(m,1H),1.04–0.98(m,4H),0.95(t,3H),0.91(s,3H),0.71(s,3H)ppm;

[0319] 31 PNMR(202MHz, CDCl3)δ0.65(s)ppm.

[0320] Example 12

[0321] Step 1: Synthesis of (S)-1-((tert-butyldimethylsilyl)oxy)-propan-2-ol (Compound 12a)

[0322] Dissolve 5 g of (2S)-propane-1,2-diol and 4.47 g of imidazole in 40 mL of dichloromethane. Under nitrogen, slowly add a solution of 9.9 g of TBSCl in 20 mL of dichloromethane while maintaining an ice bath. Stir for 2.5 hours. After the reaction is complete, filter the mixture under reduced pressure and wash with 20 mL of dichloromethane. Concentrate the filtrate under reduced pressure to yield 12.4 g of a colorless oil, which is used directly in the next step without purification.

[0323] 1 H NMR (500MHz, CDCl3) δ4.53(s,1H),3.98–3.92(m,1H),3.72(dd,1H),3.50–3.47(m,1H),1.25(d,3H),1.04(s,9H),0.20(s,6H).

[0324] Step 2: Synthesis of (S)-1-((tert-butyldimethylsilyl)oxy)-propan-2-yl-(4-nitrophenyl) carbonate (Compound 12b)

[0325] Dissolve 16.94 g of phenyl 4-nitrochloroformate in 50 mL of dichloromethane. Add 8 g of compound 12a in 25 mL of dichloromethane and 8.76 g of triethylamine, followed by stirring in an ice bath for 10 h. After the reaction is complete, the system is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (PE / EA = 10 / 1) to afford 8 g of a yellow oil.

[0326] 1 H NMR (500MHz, CDCl3) δ8.29(d,2H),7.39(d,2H),5.01–4.95(m,1H),3.75(d,2H),1.37(d,3H),0.92(s,9H),0.11(s,6H)ppm.

[0327] Step 3: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-2-(((((S)-1-((tert-butyldimethylsilyl)oxy)prop-2-yl)oxy)carbonyl)oxy)benzoate (12c)

[0328] 7.38 g of compound 1c was dissolved in tetrahydrofuran (50 mL), and 1.89 g of potassium tert-butoxide was added. The system was protected by nitrogen and stirred at room temperature for 10 minutes. A solution of 4 g of compound 12b in tetrahydrofuran (25 mL) was added in an ice bath, and the system was stirred at room temperature for 5 hours. After the reaction was complete, the system was quenched by adding 20 mL of water and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed sequentially with saturated brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 20 / 1) to obtain 8 g of compound 12c as a colorless viscous substance.

[0329] LCMS (ESI), m / z, [M+Na] + =785;

[0330] 1H NMR(500MHz, CDCl3)δ7.98(t,1H),7.53(t,1H),7.33–7.29(m,1H),7.18(d,1H),5.10(t,1H),4.91 –4.85(m,1H),4.80–4.72(m,1H),3.80(dd,1H),3.68(dd,1H),2.07–2.03(m,6H),1.68(s,6H),1.6 1(s,5H),1.37(d,2H),1.21(d,2H),1.06(s,2H),1.05(s,2H),1.04(s,3H),1.00(s,2H),0.99(s,1 H),0.96(s,2H),0.94(s,3H),0.93(s,2H),0.91–0.89(m,18H),0.70(s,3H),0.10–0.08(m,6H)ppm.

[0331] Step 4: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-2-(((((S)-1-hydroxyprop-2-yl)oxy)carbonyl)oxy)benzoate (12d)

[0332] 8 g of compound 12c was dissolved in 50 mL of tetrahydrofuran, and 4.0 mL of pyridine hydrofluoride solution was added. The system was stirred at room temperature for 4 h. After the reaction was complete, the system was quenched by adding 20 mL of water and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed sequentially with saturated brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain 5.9 g of compound 12d as a white solid.

[0333] LCMS (ESI), m / z, [M+Na] + =729;

[0334] 1H NMR(500MHz, CDCl3)δ8.01(d,1H),7.57(t,1H),7.33(t,1H),7.22–7.20(m,1H),5.10(t,1H),5.04–4.98(m, 1H),4.75–4.70(m,1H),3.82(d,1H),3.70(dd,1H),2.97(s,1H),2.05–2.02(m,5H),1.79–1.74(m,3H),1.72– 1.68(m,6H),1.61(s,3H),1.59–1.46(m,4H),1.44–1.40(m,2H),1.37(d,3H),1.33–1.26(m,2H),1.24–1.16( m,3H),1.08–1.05(m,1H),1.04(s,3H),1.01(s,3H),0.94(s,3H),0.92(d,3H),0.89(s,3H),0.70(s,3H)ppm.

[0335] Step 5: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-2-(((((S)-1-(phosphonooxy)prop-2-yl)oxy)carbonyl)oxy)benzoate (12)

[0336] 2 g of compound 12d was dissolved in 30 mL of tetrahydrofuran. Under nitrogen, pyrophosphoryl chloride (1.28 mL) was slowly added dropwise at -50°C and stirred for 1.5 h. 10 mL of water was added, and the system was stirred at room temperature for 0.5 h. After the reaction was complete, the system was quenched by adding 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was slurried in acetonitrile to obtain 121.9 g of compound 12d as a white solid.

[0337] LCMS (ESI), m / z, [M+H] + =729.

[0338] Example 13

[0339] Step 1: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl-2-(((((2S)-1-((hydroxy(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)propan-2-yl)oxy)carbonyl)oxy)benzoate (13)

[0340] Compound 12 (0.5 g) was dissolved in 20 mL of dichloromethane, and 0.13 g of L-alanine isopropyl ester, 0.28 g of DCC, and 0.17 g of DMAP were added sequentially. The system was stirred at room temperature for 5 h. After the reaction was complete, the system was quenched by adding 10 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with saturated brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was slurried in acetonitrile to obtain 0.1 g of compound 13 as a white solid.

[0341] LCMS (ESI), m / z, [M+H] + =842.

[0342] Example 14

[0343] Step 1: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((ethoxy(((R)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)benzoic acid (Compound 14)

[0344] Phosphorus oxychloride (0.984 g, 6.42 mmol) was dissolved in 10 mL of dry dichloromethane and cooled to -78°C under nitrogen. A mixture of compound 1c (2.70 g, 4.94 mmol) and triethylamine (2.50 g, 24.69 mmol) in dichloromethane (20 mL) was slowly added dropwise. After the addition was complete, the reaction was stirred at this temperature for 30 minutes. A solution of L-alanine isopropyl ester (0.648 g, 4.94 mmol) in dichloromethane (5 mL) was then added. After the addition was complete, the temperature was raised to -50°C and stirring was continued for 1 hour. Anhydrous ethanol (1.44 mL, 24.69 mmol) was added and the temperature was naturally raised to room temperature, allowing the reaction to proceed overnight. 50 mL of dichloromethane and 20 mL of water were added, and the layers were separated. The organic layer was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained crude product was purified by silica gel column with 20% EA / PE as eluent to obtain 1.10 g of compound 14 as a white solid.

[0345] 1 H NMR(500MHz, CDCl3)δ7.83(t,1H),7.55(t,1H),7.47(dd,1H),7.28(t,1H),5.10(t,1H),4.98– 4.90(m,1H),4.73(dd,1H),4.26–4.19(m,1H),4.19–4.12(m,1H),4.01–3.91(m,1H),2.17–2.0 1(m,5H),2.00–1.93(m,1H),1.93–1.71(m,8H),1.71–1.61(m,4H),1.60(s,3H),1.57–1.50(m, 1H),1.50–1.16(m,20H),1.09(s,3H),1.03(d,3H),0.99(d,3H),0.95(d,6H),0.75(s,3H)ppm;

[0346] 31 P NMR (202MHz, CDCl3) δ7.18, 7.10ppm.

[0347] Example 15

[0348] first step:

[0349] Compound 1c (10.9 g, 20.0 mmol) was dissolved in 110 mL of dry tetrahydrofuran. Compound 15a (12.9 g, 50.0 mmol), sodium iodide (0.150 g, 1.00 mmol), and sodium hydroxide (1.60 g, 40.0 mmol) were added under nitrogen. The mixture was reacted at 35°C for 48 hours. Ethyl acetate (100 mL) and water (50 mL) were added, and the layers were separated. The organic layer was washed once with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified on a silica gel column using 10% EA / PE as the eluent to obtain 15.0 g of Compound 15b as a white solid.

[0350] LCMS (APCI), m / z, [2M+Na] + =1561;

[0351] 1 H NMR(500MHz, CDCl3)δ7.81(dd,1H),7.50–7.42(m,1H),7.32(d,1H),7.10(t, 1H),5.65(d,2H),5.11(t,1H),4.75(dd,1H),2.11–1.98(m,5H),1.98–1.70(m ,8H),1.69(s,3H),1.61(s,3H),1.61–1.46(m,2H),1.46(s,18H),1.46–1.15 (m,8H),1.03(s,3H),0.99(s,6H),0.92(d,3H),0.89(s,3H),0.70(s,3H)ppm;

[0352] 31 P NMR (202MHz, CDCl3) δ-12.27ppm.

[0353] Step 2:

[0354] Compound 15b (10.0 g, 13.0 mmol) was dissolved in 50 mL of dichloromethane, and silica gel (200-300 mesh, 20 g) was added. After complete addition, the mixture was stirred at room temperature for 3 hours. Filtered, the residue was washed with 200 mL of 20% MeOH / DCM, and the filtrate was collected and concentrated under reduced pressure. The crude product was slurried with acetonitrile for 20 minutes, filtered, and the filter cake was dried to obtain 5.10 g of Compound 15c as a white solid.

[0355] LCMS (APCI), m / z, [M+H] + =657.

[0356] Step 3: (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-2-(((hydroxy(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)oxy)methoxy)benzoate (Synthesis of Compound 15)

[0357] Compound 15c (0.656 g, 1.00 mmol) was dissolved in 10 mL of dry dichloromethane. 600 mg of powdered 4A molecular sieves, L-alanine isopropyl ester (0.262 g, 2.00 mmol), DMAP (12 mg, 0.1 mmol), and DCC (0.412 g, 2.00 mmol) were added. After complete addition, the mixture was stirred at room temperature under nitrogen overnight. Insoluble matter was removed by filtration through celite, and the filter residue was washed with 20 mL of dichloromethane. The combined filtrates were concentrated, and the crude product was purified on a silica gel column using DCM-10% MeOH / DCM as the eluent to afford 0.110 g of Compound 15 as a white solid.

[0358] LCMS (APCI), m / z, [M+Na] + =792;

[0359] 1 H NMR(500MHz, CDCl3)δ7.74(d,1H),7.36(s,2H),6.95–6.89(m,1H),5.59(d,2H),5.10(t,1H),4.83–4 .75(m,1H),4.62–4.52(m,1H),3.85–3.72(m,1H),2.10–2.00(m,3H),1.99–1.70(m,7H),1.68(s,3H), 1.68–1.55(m,6H),1.52–1.20(m,9H),1.20–1.12(m,5H),1.12–1.02(m,7 H),0.98(s,3H),0.94(s,3H),0.92(d,3H),0.88(s,6H),0.68(s,3H)ppm;

[0360] 31 P NMR (202MHz, CDCl3) δ6.39ppm.

[0361] Example 16

[0362] Step 1: Synthesis of 2-((tert-butyldimethylsilyl)oxy)ethyl(4-nitrophenyl)carbonate (Compound 16b)

[0363] Dissolve 4-nitrophenyl chloride (30 g, 148 mmol) in dry DCM (100 mL) under nitrogen protection. Add compound 16a (17.5 g, 99 mmol) in dry DCM (50 mL) under an ice bath. Finally, add triethylamine (20.6 mL, 149 mmol). Allow to react at room temperature for 4 hours. Quench with water (60 mL) and extract with DCM (60 mL x 3). The combined organic phases are washed with saturated brine and water, respectively, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and purify on a silica gel column (PE / EA = 1%) to yield 29 g of a light yellow oil.

[0364] LCMS (ESI), m / z, [M+H] + =472

[0365] Step 2: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((2-((tert-butyldimethylsilyl)oxy)ethoxy)carbonyl)oxy)benzoate (Compound 16c)

[0366] Compound 1c A 29g, 53mmol) solution was dissolved in anhydrous THF (80mL), and potassium tert-butoxide (7.4g, 66mmol) was added under nitrogen. The mixture was stirred at room temperature for 10 minutes. Compound 16b (15g, 44mmol) was dissolved in dry THF (20mL) and added to the system under ice-cooling. The reaction was allowed to proceed at this temperature for 10 hours. After the reaction was complete, the mixture was quenched with water (60mL) and extracted with ethyl acetate (60mL x 3). The combined organic phases were washed with saturated brine and water, respectively, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified on a silica gel column (PE / EA = 1%) to yield 16.5g of a white solid.

[0367] Step 3: Synthesis of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((2-hydroxyethoxy)carbonyl)oxy)benzoate (Compound 16d)

[0368] Compound 16c (22 g, 30 mmol) was dissolved in THF (120 mL), and 70% pyridine hydrofluoric acid solution (7.7 mL, 60 mmol) was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was quenched with water (60 mL) and extracted with DCM (60 mL x 3). The combined organic phases were washed with saturated brine and water, respectively, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified on a silica gel column (PE / EA = 20%) to yield 13 g of a white solid.

[0369] Step 4: Preparation of (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(((2-((hydroxy(phenoxy))phosphoryl)oxy)ethoxy)carbonyl)oxy)benzoate (Compound 16)

[0370] Under nitrogen, phenyl dichlorophosphate (1.3 g, 6.2 mmol) was added dropwise to dichloromethane (10 mL) at -40°C. Compound 16d (2.0 g, 3.2 mmol) and pyridine (0.55 g, 6.9 mmol) in dichloromethane (10 mL) were then added dropwise. The mixture was stirred and allowed to react for 2 hours. A solution of sodium bicarbonate (2.7 g, 21.1 mmol) in water (30 mL) was added dropwise, and the mixture was allowed to return to room temperature and stirred for 6 hours. Completion of the reaction was monitored by TLC. The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high-pressure preparative separation to yield 0.83 g of compound 16 as a white solid.

[0371] LC-MS m / z (ESI) = 789.4 [M+H] + ;

[0372] 1 HNMR(500MHz, CDCl3)δ7.88(dd,1H),7.36(t,1H),7.23–7.17(m,3H),7.08(t, 2H),7.00(d,1H),6.89(t,1H),5.11(t,1H),4.64(dd,1H),4.11(d,4H),2.03( s,3H),1.99–1.84(m,4H),1.75–1.57(m,13H),1.52–1.36(m,4H),1.33–1.11( m,5H),1.03(dd,1H),0.97(s,3H),0.91(d,6H),0.86(s,6H),0.68(s,3H)ppm;

[0373] 31 PNMR(202MHz, CDCl3)δ-3.92(s)ppm.

[0374] Comparative Example 1: Synthesis of control compound

[0375] Referring to the synthesis method of Example 8 in WO2018137683, a reference compound was synthesized, and its structural formula is as follows:

[0376] Biological testing

[0377] Test Example 1: Drug Content Detection in Rabbit Aqueous Humor

[0378] This method detects the drug content in the aqueous humor of New Zealand rabbits to determine the ability of the test compound to penetrate the cornea and be hydrolyzed.

[0379] Twelve male New Zealand rabbits (3-5 months old) were acclimated in the animal room for 3 days before use. A certain amount of compound was weighed and added to the solvent (1.2% HP-β-CD, 20.5% poloxamer (P407), 1.6% poloxamer (P188)). Ultrasonication was performed until complete dissolution or a stable suspension was formed. The final compound concentration was 5 mM.

[0380] Pull down the rabbit's lower eyelid and precisely drip 50 μL of compound solution or suspension into both eyes using a pipette. Observe for leakage of the drug solution after administration. Draw aqueous humor from three rabbits at 0, 0.5, 2, and 4 hours after administration (50 μL / eye / rabbit, both eyes simultaneously) for analysis of drug content using LC-MS / MS.

[0381] The results showed that the compounds of this application were able to penetrate the aqueous humor through the cornea or other pathways; they were also converted to lanosterol during the penetration process, resulting in higher lanosterol concentrations and exposure in the aqueous humor. Six hours after eye drop administration of the compounds of this application, the concentration of lanosterol in the aqueous humor of rabbits was higher than that of the reference compound lanosterol salicylate at the same dose.

[0382] Test Example 2: Oral Pharmacokinetics Test in Rats

[0383] Purpose of the experiment: This experiment administered the test substance to SD rats by single-dose gavage, determined the concentration of the test substance in rat plasma, and evaluated the pharmacokinetic characteristics of the test substance in rats.

[0384] Experimental animals: Male SD rats, larger than 180 g, 6-8 weeks old, 3 rats per compound, purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0385] Test method:

[0386] 1. Blank solvent preparation: Take an appropriate amount of MC, add the theoretical amount of ultrapure water, and stir thoroughly to obtain 0.5% MC liquid.

[0387] 2. Preparation of dosing preparation: Weigh an appropriate amount of test substance (calculated for purity and salt coefficient), add the prescribed amount of 0.5% MC solvent, and vortex to mix to obtain a preparation with the specified theoretical concentration. Prepare immediately before use.

[0388] 3. Animal Dosing: On the day of the experiment, SD rats were randomly divided into groups according to body weight, with three SD rats assigned to each compound. The rats were fasted overnight before dosing, but not water, and resumed eating 4 hours after dosing.

[0389] 4. Sampling: At each time point (0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing), approximately 300 μL of blood was collected into tubes containing EDTA-K2 anticoagulant and centrifuged within 60 min to obtain plasma. Whole blood samples were placed on ice before centrifugation. All collected plasma samples were stored on dry ice or in a freezer until analysis.

[0390] 5. Detection: For each test, prepare at least one set of standard curves and QC samples using blank plasma to quantify the samples to be tested. The accuracy of at least 3 / 4 of the standard curve samples should be within the range of 80%-120% of the true concentration (the accuracy of the LLOQ should be within the range of 75%-125%).

[0391] 6. The results are shown in Table 1

[0392] Table 1

[0393] Conclusion: At the same dose, compounds 4 and 5 of the present application, as prodrugs of the control compound, significantly increased the amount of the control compound released in plasma, indicating that the compounds of the present application have good oral absorption properties.

[0394] Test Example 3: Solubility Test

[0395] 1. Instruments and Materials

[0396] Instruments: Shimadzu LC-20ADXR; shaker; glassware; pipette.

[0397] Materials: pH = 7.2 PBS buffer, pure water, HPLC ethanol, HPLC methanol, HPLC tetrahydrofuran

[0398] 2. Experimental Procedure

[0399] 2.1 Preparation of Standards for Relevant Compounds Take a sample of the relevant compound and place it in a centrifuge tube. Add 1 mL of tetrahydrofuran at room temperature to completely dissolve the sample and calculate the concentration of the mother solution.

[0400] 2.2 Preparation of Saturated Sample Solutions of the Compounds: Place the sample of the compound in a centrifuge tube and add 1 mL of pure water at room temperature. Place the sample in a shaker and shake at room temperature for 1 hour. Remove the sample and place it in a refrigerated centrifuge at 4000 rpm, 25°C, and centrifuge for 10 minutes. Remove the sample and aspirate the upper layer of saturated clear solution. Filter through a 0.22 μm filter membrane.

[0401] 2.3 Prepare the standard curve solution. Take the mother solution and dilute it in a gradient with tetrahydrofuran. Vortex the solution to mix well.

[0402] 2.4 Determination of sample solubility

[0403] Specific solubility was determined using an HPLC method.

[0404] 2.5 Determine the standard curve. Pipette 200 μL of the standard curve solution into the inner insert tube, start injecting from the low concentration, inject 1 μL each time, and record the chromatographic peak area.

[0405] 2.6 Inject 1 μL of the saturated solution and record the chromatographic peak area.

[0406] 3. Comparison of clarity after centrifugation

[0407] Place pure water in a centrifuge tube. Compare the upper clear solution from step 2.2 to the pure water. The clear solution should be free of granular, flocculent, or suspended solid particles. Its clarity is similar to that of pure water.

[0408] 4. Calculation

[0409] 4.1 Calculation: Fit the curve between concentration and chromatographic peak area to obtain the standard curve regression equation.

[0410] 4.2 The peak area measured for the saturated sample was used to calculate the concentration using the regression equation.

[0411] 4.3 The solubility values ​​(unit: mg / mL) were obtained. The results are shown in Table 2.

[0412] 5.HPLC method conditions

[0413] Chromatographic column: YMC-Triart C8 5μm 4.6x50 mm;

[0414] Method: Mobile phase: 0.1% trifluoroacetic acid in methanol and ethanol; Mobile phase gradient: 100% methanol as phase A, 100% ethanol as phase B, 10% B to 90% B, 3 mins; Post-equilibration with 10% ethanol, 0.5 min; Detection wavelength: Full wavelength scan

[0415] Detection temperature: 40℃

[0416] Table 2 Solubility test results

[0417] Conclusion: From the results in Table 2, it can be seen that the solubility of the compound of the present application in aqueous solution is significantly improved compared with the control compound, and it is suitable for preparation into solution-type eye drops.

[0418] Test Example 4: Detection of drug content in rabbit eye tissue

[0419] The distribution of the test compound in the eye tissues was detected by detecting the drug content in different eye tissues of cyanotic rabbits.

[0420] Twelve male, 3-5 month old, chinchilla rabbits were used for each compound and acclimated in the animal room for 3 days before use. A predetermined amount of compound was weighed and added to the solvent (which varies depending on the compound, ensuring that the osmotic pressure and pH values ​​are within the required range). Ultrasonication was performed until completely dissolved or a stable suspension was formed. The final compound concentration was 0.5-2%.

[0421] The rabbit lower eyelids were lowered, and 50 μL of compound solution or suspension was precisely pipetted into both eyes. The drug was administered simultaneously to both eyes and observed for leakage. Three rabbits were euthanized at 0.5, 3, 6, and 10 hours after administration. The eyeballs were enucleated and various ocular tissue structures were dissected (from both eyes). LC-MS / MS was used to analyze the levels of unchanged drug and metabolites in the conjunctiva, cornea, sclera, and aqueous humor. The results are shown in Tables 3-5.

[0422] Table 3 Concentrations of drugs and control compounds in the conjunctiva of blue rabbits after eye drops of different concentrations of compounds (ng / mL)

[0423] Table 4 Concentrations of drug and control compounds in the cornea of ​​blue rabbits after eye drops of different concentrations of compounds (ng / mL)

[0424] BQL: Below the quantitative limit

[0425] Table 5 Concentrations of drugs and control compounds in the sclera of blue rabbits after eye drops of different concentrations of compounds (ng / mL)

[0426] BQL: Below the quantitative limit

[0427] It can be seen from the data in Tables 3 to 5 that Compound 4 and Compound 5 of the present application, as prodrugs of the control compounds, can be successfully converted into the control compounds in the eye drops of cyanotic rabbits, and the drugs stay in the eyes for a long time and have sustained-release characteristics.

[0428] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments and may be embodied in other specific forms without departing from its essential characteristics. It is therefore intended that the embodiments be considered in all respects as illustrative and non-restrictive, and that reference should be made to the appended claims rather than to the foregoing embodiments, and all changes that come within the meaning and range of equivalents of the appended claims are intended to be embraced herein.

Claims

1. A steroidal 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; X is a bond, alkylene, -Oalkylene-, -alkyleneOC(=O)O-, -OalkyleneOC(=O)O-, -alkyleneOC(=O)-, or -OalkyleneOC(=O)-; R 1 is hydroxyl, hydroxyalkyl, alkoxyalkyl, halogenated alkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ; R 2 is hydroxyl, hydroxyalkyl, alkoxyalkyl, halogenated alkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ; Optionally, R 1 and R 2 Together with the attached phosphorus atom, it forms a phosphorus-containing heterocyclic group; R 3 is H, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy or hydroxy-substituted alkoxy; R 4 , R 5 and R 6 are each independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, R 11 C(=O)O-alkyl, R 12 C(=O)S-alkyl, monophosphate or diphosphate; R 7 , R 8 , R 9 and R 10 are each independently H, deuterium, alkyl, cycloalkyl, aryl, heteroaryl or -R 13 OC(=O)-alkyl; optionally, R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle; R 11 , R 12 and R 13 are each independently alkyl, cycloalkyl, aryl, heteroaryl or arylalkyl; R 14 is deuterium, alkyl, alkylOC(=O)-; Where R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 11 , R 12 , R 13 or R 14 The alkyl, aryl, cycloalkyl, heteroaryl, phosphorus-containing heterocyclic group, heterocycle or heterocyclic group described in the above-mentioned group is optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic group, haloaryl, aryl and heteroaryl.

2. The steroid compound according to claim 1, wherein A ring is C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, C 3-10 Carbon ring or C 2-9 Heterocyclic ring; X is a key, C 1-6 Alkylene, -C 1-6 Alkylene OC(=O)O-, -OC 1-6 Alkylene OC(=O)O-, -C 1-6 Alkylene OC(=O)- or -OC 1-6 Alkylene OC(═O)—; R 3 H, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy.

3. The steroid compound according to claim 1, wherein Ring A is a benzene ring, a thiazole ring, a thiophene ring, a furan ring, a pyrrole ring, a pyridine ring or a pyrimidine ring; X is a bond or methylene, ethylene, propylene, or methylmethylene; R 3 is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

4. The steroid compound according to claim 1, wherein R 1 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ; R 2 C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ; R 4 , R 5 and R 6 Each independently is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, R 11 C(=O)OC 1-6 Alkyl, -R 12 C(=O)SC 1-6 Alkyl, monophosphate or diphosphate; R 7 , R 8 , R 9 and R 10 Each independently is H, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 Heteroaryl or R 13 C(=O)OC 1-6 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 substituted 5-6 membered heterocycle; R 11 , R 12 and R 13 Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, C 2-9 heteroaryl or benzyl; R 14 Deuterium, C 1-6 Alkyl, C 1-6 Alkyl OC(═O)—.

5. The steroid compound according to claim 1, wherein R 1 is hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 5 or -NR 7 R 8 ; R 2 is hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, trifluoromethyl, chloroethyl, R 4 OC(=O)-、-OR 6 or -NR 9 R 10 ; R 4 , R 5 and R 6 each independently represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, R 11 C(=O)OC 1-3 Alkyl, R 12 C(=O)SC 1-3 Alkyl, monophosphate or diphosphate; R 7 , R 8 , R 9 and R 10 are each independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl or R 13 C(=O)OC 1-3 Alkyl; optionally R 9 and R 10 and the atoms to which they are attached form independently optionally R 14 Substituted 5-6 membered nitrogen heterocycle; R 11 , R 12 and R 13 each independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridinyl, pyrimidinyl or benzyl; R 14 is deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1-4 Alkyl OC(═O)—.

6. The steroid compound according to any one of claims 1 to 5, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 11 , R 12 , R 13 and R 14 C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Cycloalkyl, C 2-9 Heteroaryl, C 2-9 Phosphorus-containing heterocyclic group or C 2-9 The heterocyclic group is optionally substituted by 1, 2, 3 or 4 groups selected from hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 6-10 Aryl halide and C 2-9 The heteroaryl group is substituted with a substituent.

7. The steroid compound according to claim 6, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 11 , R 12 , R 13 and R 14 The methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl described in the above-mentioned group is optionally substituted by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

8. The steroidal compound according to any one of claims 1 to 7, which has a structure as shown in formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (II), 9. The steroid compound according to any one of claims 1 to 8, wherein The steroidal compound has one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, 10. A pharmaceutical composition comprising the steroid compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

11. Use of the steroid compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

12. The use according to claim 11, wherein the eye disease is cataract, floaters or presbyopia.

13. A method for preventing, managing, treating or alleviating an eye disease in a patient, comprising administering to the patient an effective amount of the steroid compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10.

14. The method according to claim 13, characterized in that The eye disease is cataract, floaters or presbyopia.

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