Steroid compound and application thereof

Abstract

The invention relates to a steroid compound with a structure as shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite and a prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, and application of the steroid compound in preparation of medicines for treating ophthalmic diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a steroid compound, stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and application thereof in preparing medicine for treating ophthalmic diseases. Background Art

[0002] Cataract is an eye disease that occurs on the lens in the eyeball. The opacity of the lens is collectively called cataract. Aging, heredity, metabolic abnormalities, trauma, radiation, poisoning and local malnutrition can cause damage to the lens capsule, increase its permeability, lose its barrier function, or cause lens metabolism disorders, causing lens protein denaturation and turbidity. If the lens of the eyeball changes from transparent to opaque and affects the eye's ability to receive sunlight, it will affect the eye's vision. When the eyeball is less turbid, the impact on vision is less severe. As the degree of turbidity gradually deepens, vision will also increase. In severe cases, it will lead to blindness. Cataract is one of the most common blinding eye diseases and it is the main cause of blindness. Because the mechanism of cataract formation is still unclear, drug treatment has not made any breakthrough progress so far. Therefore, the only effective treatment method at present is surgical treatment.

[0003] Although the continuous progress of cataract surgery has provided great help for the treatment of cataracts, the cure rate of surgical treatment is still far lower than the incidence rate, and there is a possibility of serious complications; on the other hand, the cost of cataract surgery is very high. Even in developed countries, cataracts have brought a huge burden to the medical insurance system. Therefore, drug prevention and treatment plays a pivotal role. At present, the clinical treatment drugs for cataracts include: ① aldose reductase inhibitors, such as cataracts (cataract, kalinyou, Baineting), falcoline, benzyl lysine, etc.; ② antioxidant damage drugs, such as glutathione, taurine, aspirin, etc.; ③ nutritional metabolism drugs, such as vitamins, carotenoids, etc.; ④ Chinese medicine compound prescriptions include Shihu Yeguang Pills, Qiju Dihuang Pills, Shijueming Powder, etc. These drugs for the treatment of cataracts have been confirmed by long-term clinical trials to only delay the deterioration of cataracts, but cannot reverse the condition. At the same time, as my country begins to enter an aging society, the number of cataract patients is increasing, and the demand for cataract drugs will be more urgent. 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 have stable properties.

[0004] Lanosterol is an amphiphilic molecule that is enriched in the lens. It is synthesized by a key cyclization reaction of lanosterol synthase (LSS) in the cholesterol synthesis pathway. It can reduce the abnormal aggregation of lens proteins, rearrange them regularly, and restore the transparency of the lens. Studies have shown that lanosterol synthase can be detected in the lens. In addition, in the Shumiya cataract rat study, a specific combination of homozygous mutations of lanosterol synthase and farnesyl diphosphate farnesyltransferase 1 (FDFT1) can reduce the level of cholesterol in the lens and cause cataracts. At the same time, our recent studies have found that lanosterol can significantly reduce preformed lens protein aggregates at the in vitro and cellular levels. It has also been confirmed at the in vivo level that lanosterol can reverse the condition of cataracts and make the lens clear and transparent. This result has been recently published in Nature magazine, attracting widespread attention from all over the world. It is a new molecule for the prevention and treatment of cataracts. Summary of the invention

[0005] The object of the present invention is to provide a new steroid compound and its application in medicine, especially ophthalmic medicine.

[0006] In one aspect, the present invention provides a steroidal compound having a structure represented by formula (I) or formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, prodrug, pharmaceutically acceptable salt or ester of the structure represented by formula (I) or formula (II),

[0007]

[0008] Among them, X 1 O, S, -NR 5 -or-CR 6 R 7 -;

[0009] Y is -(CR 8 R 9 ) m -;

[0010] Z is CH or N;

[0011] R 1 and R 2 are each independently H, D (deuterium), alkyl, cycloalkyl, alkyl-C(═O)- or aryl-C(═O)-; or R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered monocyclic or bicyclic ring;

[0012] R 3 is H, D, halogen, alkyl or cycloalkyl;

[0013] A is -C(=O)-, -C(=S)-, -OC(=O)- or -NR 10 C(=O)-;

[0014] X 2 is aminoalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl-OC(=O)-CR 11 R 12 -, alkyl-C(=O)O-CR 11 R 12 -, arylalkyl, hydroxyalkyl, mercaptoalkyl, amino-C(=O)-alkyl;

[0015] Q is H, D, hydroxyl, amino, arylamino, halogen, alkyl, carboxyl, aryl, heteroaryl, monosaccharide, polysaccharide, cycloalkyl, cycloalkylalkyl, aryl-C(=O)-,

[0016] G is O or S;

[0017] R 5 and R 10 Each is independently H, D, alkyl or cycloalkyl;

[0018] R 4 , R 6 , R 7 , R 8 , R 9 , R 11 and R 12 each independently is H, D, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0019] m is 1, 2, 3 or 4;

[0020] n is 0, 1, 2, 3 or 4;

[0021] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X 2 and the alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkyl-C(=O)-, aryl-C(=O)-, alkoxy, heterocyclic, aryl, heteroaryl, monocyclic, bicyclic, The group is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl or heteroaryl;

[0022] The hydrogen atoms on ring a, ring b, ring c and ring d are unsubstituted or at least one hydrogen atom is substituted by deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy;

[0023] In some embodiments, R 1 and R 2 Each independently is H, D, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C(=O)- or C 6-10 Aryl-C(═O)-;

[0024] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclic group;

[0025] Among them C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 3-10 membered cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 deuterated, hydroxyl, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 1-6Alkylamino, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

[0026] In some embodiments, R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0027] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups:

[0028]

[0029]

[0030] R 13 and R 14 are independently H, D, oxo, hydroxyl, halogen, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 heteroaryl;

[0031] or R 13 and R 14 and the carbon atom to which it is attached to form a C 3-8 Cycloalkyl or C 2-9 Heterocyclic group, wherein C 3-8 Cycloalkyl and C 2-9The heterocyclic groups are each independently optionally substituted with 1, 2 or 3 D, hydroxy, halogen, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 substituted with heteroaryl;

[0032] Q 1 , Q 2 and Q 3 are each independently CH or N;

[0033] Q 4 is CH2, NH, O or S.

[0034] In some embodiments, R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0035] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups:

[0036]

[0037]

[0038] In some embodiments, X 2 C 1-6 Aminoalkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 1-6Alkyl-OC(=O)-CR 11 R 12 -、C 1-6 Alkyl-C(=O)O-CR 11 R 12 -、C 6-10 Aryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, aminoC(=O)-C 1-6 Alkyl or C 2-9 Heteroaryl C 1-9 alkyl.

[0039] In other embodiments, wherein X 2 is aminomethyl, aminoethyl, imidazolylmethyl, imidazolylethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thiophene, phenyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, Isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, methyl-OC(=O)-CR 11 R 12 -, ethyl-OC(=O)-CR 11 R 12 -, tert-butyl-OC(=O)-CR 11 R 12 -, methyl-C(=O)O-CR 11 R 12 -, ethyl-C(=O)O-CR 11 R12 -, tert-butyl-C(=O)O-CR 11 R 12 -, phenylmethyl, phenylethyl, phenylpropyl, phenyl tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl, mercaptoethyl, mercaptopropyl, amino C (= O) -methyl, amino C (= O) -ethyl, amino C (= O) -propyl, indolylmethyl or isoxazolylmethyl.

[0040] In some embodiments, wherein Q is H, hydroxyl, amino, C 6-10 Arylamino, halogen, C 1-6 Alkyl, carboxyl, phosphate, C 6-10 Aryl, C 2-9 Heteroaryl, monosaccharide, polysaccharide, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl-C(=O)-, Or not present; wherein, the G is O or S.

[0041] In other embodiments, wherein Q is hydrogen, hydroxyl, amino, phenylamino, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carboxyl, phosphate, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, isoxazolyl, monosaccharide, polysaccharide, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylpropyl, phenyl-C(=O)-, naphthyl-C(=O)-, or not present; said G is O or S.

[0042] In some embodiments, R 3 H, D, F, Cl, Br, C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0043] In some embodiments, R 5 and R 10 Each independently is H, D, C 1-6 Alkyl or C 3-8 Cycloalkyl.

[0044] In some embodiments, R 4 , R 6 , R 7 , R 8 , R 9 , R11 or R 12 are independently F, Cl, Br, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0045] In some embodiments, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted with 1, 2, 3 or 4 deuterated, hydroxyl, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

[0046] In some embodiments, R 3 is H, D, F, Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0047] In some embodiments, R 5 and R 10 Each is independently H, D, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0048] In some embodiments, R 4 , R 6 , R 7 , R8 , R 9 , R 11 or R 12 each independently represents F, Cl, Br, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl , pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl , benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0049] In some embodiments, the steroidal compound has one of the following structures:

[0050]

[0051]

[0052]

[0053] In another aspect, the present invention also provides a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0054] In yet another aspect, the present invention provides a 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.

[0055] In some embodiments, the eye disease is cataracts or floaters.

[0056] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.

[0057] Definitions and general terms

[0058] Unless otherwise stated, the terms used in the specification and claims of the present invention have the following definitions.

[0059] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention 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 differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0060] It should be further appreciated that certain features of the invention, 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 invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0061] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0062] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0063] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0064] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0065] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0066] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0067] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0068] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0069] The 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.

[0070] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0071] 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.

[0072] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0073] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0074] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0075] The term "prodrug" used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention 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 the present invention 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, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0076] Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0077] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0078] The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, thiocarboxylates, and the like, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, pamoates, salicylates, galactarate, glucoheptanoates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalates, or by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium and N + (C 1-4 The present invention 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.

[0079] 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.

[0080] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0081] 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.

[0082] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the 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, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0083] The term "protecting group" or "PG" refers to a substituent that is used to block or protect a specific functionality when reacting with another functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the 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 of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group. 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.

[0084] "Pharmaceutical composition" means a mixture of one or more salts of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs 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.

[0085] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing 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.

[0086] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. 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 introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0087] In another aspect, the compounds of the invention 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 1 3C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) and (II) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparation processes of the present invention.

[0088] In addition, the substitution of heavier isotopes, especially deuterium (i.e., 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0089] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as specifically exemplified in the examples, subclasses, and classes of compounds encompassed by the present invention. 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 specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent substituted 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 specific group, the substituents may be substituted the same or differently at each position. The substituents may be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, 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, carboxyalkoxy and the like.

[0090] The term "alkyl" as used herein 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 (-CH2CH2CH2C H2CH3), 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

[0091] (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl

[0092] (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl

[0093] (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl

[0094] (-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, such examples include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0095] The term "alkoxy" used in the present invention refers to an alkyl group, as defined in the present invention, connected to the main carbon chain through an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0096] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described herein, including groups having "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0097] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is an 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.

[0098] The term "cycloalkyl" 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 carbocyclic rings of 7-12 atoms may be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocyclic rings 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. 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.

[0099] The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring are independently and optionally replaced by heteroatoms, the heteroatoms having the meanings as described herein, the ring may be fully saturated or contain one or more unsaturations, but are never aromatic, and have only one point of attachment to other molecules. One or more hydrogen atoms in the ring are independently and optionally replaced by one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain 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 substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2).

[0100] Heterocyclic groups can be carbonyl or heteroatom groups. "Heterocyclic groups" also include groups formed by the combination of heterocyclic groups with saturated or partially unsaturated rings or heterocyclic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepine Base, diazepine Base, thiazolin 1-yl, pyrrolin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazine-1(4H)-yl)ethanone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl)ethanon-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl, 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms in the ring are replaced by oxygen atoms. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O) 2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O) 2, carboxyalkoxy and the like.

[0101] The term "aryl" may be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", for example, aromatic rings may 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.

[0102] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein heteroatoms have the meanings as described herein, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic compound". And the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, 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.

[0103] In other embodiments, heteroaryl includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following di- ring, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0104] 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).

[0105] The term "halogen" refers to F, Cl, Br or I.

[0106] The term "halogenated" used in the present invention means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

[0107] The term "hydroxy substituted" used in the present invention means that the group following it is substituted with a hydroxy group, and the number of the substitutions may be one or more.

[0108] When "substituted" in the present invention 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.

[0109] When multiple groups of the present invention are used in combination, they are in a substitution relationship from left to right, such as "arylalkyl" means an alkyl substituted with an aryl group, and "alkoxyalkoxy" means an alkoxy substituted with an alkoxy group.

[0110] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0111] Description of the compounds of the present invention

[0112] In one aspect, the present invention provides a steroidal compound having a structure as shown in formula (I) or formula (II). The present invention also provides stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or esters of the structure as shown in formula (I) or formula (II).

[0113]

[0114] Among them, X 1 O, S, -NR 5 -or-CR 6 R 7 -;

[0115] Y is -(CR 8 R 9 ) m -;

[0116] Z is CH or N;

[0117] R 1 and R 2 are each independently H, D, alkyl, cycloalkyl, alkyl-C(═O)- or aryl-C(═O)-; or R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered monocyclic or bicyclic ring;

[0118] R 3 is H, D, halogen, alkyl or cycloalkyl;

[0119] A is -C(=O)-, -C(=S)-, -OC(=O)- or -NR 10 C(=O)-;

[0120] X 2 is aminoalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl-OC(=O)-CR 11 R 12 -, alkyl-C(=O)O-CR 11 R 12 -, arylalkyl, hydroxyalkyl, mercaptoalkyl, amino-C(=O)-alkyl;

[0121] Q is H, D, hydroxyl, amino, arylamino, halogen, alkyl, carboxyl, aryl, heteroaryl, monosaccharide, polysaccharide, cycloalkyl, cycloalkylalkyl, aryl-C(=O)-,

[0122] G is O or S;

[0123] R 5 and R 10 Each is independently H, D, alkyl or cycloalkyl;

[0124] R 4 , R 6 , R 7 , R 8 , R 9 , R 11 and R 12 each independently is H, D, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0125] m is 1, 2, 3 or 4;

[0126] n is 0, 1, 2, 3 or 4;

[0127] Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X 2 and the alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkyl-C(=O)-, aryl-C(=O)-, alkoxy, heterocyclic, aryl, heteroaryl, monocyclic, bicyclic, The group is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl or heteroaryl;

[0128] The hydrogen atoms on ring a, ring b, ring c and ring d are unsubstituted or at least one hydrogen atom is substituted by deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halogenated or hydroxy-substituted alkoxyalkyl, alkoxy, halo-substituted or hydroxy-substituted alkoxy, alkoxyalkoxy, halo-substituted or hydroxy-substituted alkoxyalkoxy, alkylamino, halo-substituted or hydroxy-substituted alkylamino, alkylthio, halo-substituted or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy.

[0129] In some embodiments, R 1 and R 2 Each independently is H, D, C 1-6 Alkyl or C 3-8 Cycloalkyl;

[0130] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclic group;

[0131] Among them C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

[0132] In some embodiments, R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0133] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups:

[0134]

[0135] R 13 and R 14 are independently H, D, oxo, hydroxyl, halogen, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 heteroaryl;

[0136] or R 13 and R 14 and the carbon atom to which it is attached to form a C 3-8 Cycloalkyl or C 2-9 Heterocyclic group, wherein C 3-8 Cycloalkyl and C 2-9 The heterocyclic groups are each independently optionally substituted with 1, 2 or 3 D, hydroxy, halogen, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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, C3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 substituted with heteroaryl;

[0137] Q 1 , Q 2 and Q 3 are each independently CH or N;

[0138] Q 4 is CH2, NH, O or S.

[0139] In some embodiments, R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0140] or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups:

[0141]

[0142]

[0143] In some embodiments, X 2 C 1-6 Aminoalkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 1-6 Alkyl-OC(=O)-CR 11 R 12 -、C 1-6 Alkyl-C(=O)O-CR 11 R 12 -、C 6-10 Aryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, aminoC(=O)-C 1-6 Alkyl or C 2-9 Heteroaryl C 1-9 alkyl.

[0144] In other embodiments, wherein X 2is aminomethyl, aminoethyl, imidazolylmethyl, imidazolylethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thiophene, phenyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, Isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, methyl-OC(=O)-CR 11 R 12 -, ethyl-OC(=O)-CR 11 R 12 -, tert-butyl-OC(=O)-CR 11 R 12 -, methyl-C(=O)O-CR 11 R 12 -, ethyl-C(=O)O-CR 11 R 12 -, tert-butyl-C(=O)O-CR 11 R 12 -, phenylmethyl, phenylethyl, phenylpropyl, phenyl tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl, mercaptoethyl, mercaptopropyl, amino C (= O) -methyl, amino C (= O) -ethyl, amino C (= O) -propyl, indolylmethyl or isoxazolylmethyl.

[0145] In some embodiments, wherein Q is H, hydroxyl, amino, C 6-10 Arylamino, halogen, C 1-6 Alkyl, carboxyl, phosphate, C 6-10 Aryl, C 2-9Heteroaryl, monosaccharide, polysaccharide, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl-C(=O)-, Or not present; wherein, the G is O or S.

[0146] In other embodiments, wherein Q is hydrogen, hydroxyl, amino, phenylamino, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carboxyl, phosphate, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, isoxazolyl, monosaccharide, polysaccharide, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylpropyl, phenyl-C(=O)-, naphthyl-C(=O)-, or not present; said G is O or S.

[0147] In some embodiments, R 3 H, D, F, Cl, Br, C 1-6 Alkyl or C 3-8 In some embodiments, R 3 is H, D, F, Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0148] In some embodiments, wherein R 5 and R 10 Each independently is H, D, C 1-6 Alkyl or C 3-8 Cycloalkyl; and / or R 4 , R 6 , R 7 , R 8 , R 9 , R 11 or R 12 are independently F, Cl, Br, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 1-9 Heteroaryl.

[0149] In the present invention, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6Alkoxy, C 2-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted with 1, 2, 3 or 4 deuterated, hydroxyl, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 Haloalkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

[0150] In other embodiments, R 5 and R 10 Each is independently H, D, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0151] In other embodiments, R 4 , R 6 , R 7 , R 8 , R 9 , R 11 or R 12each independently represents F, Cl, Br, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl , pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl , benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0152] In some embodiments, the steroidal compound has one of the following structures:

[0153]

[0154]

[0155]

[0156] Compositions, formulations and administration of compounds of the invention

[0157] The pharmaceutical composition comprises any one of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0158] The pharmaceutical composition can be used to treat eye diseases, and in particular, has a good therapeutic effect on cataracts or floaters.

[0159] Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum 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, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl 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.

[0160] When it can be used for treatment, the therapeutically effective amount of the compound of the present invention can be given as a raw chemical drug, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" used herein refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction). When a separate active ingredient is used for separate administration, the term refers only to the ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, sequential or simultaneous administration. In terms of compatibility with other ingredients of the preparation and harmlessness to its recipient, the carrier, diluent or excipient must be acceptable. According to another aspect of the present invention, a method for preparing a pharmaceutical preparation is also provided, which includes mixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effectively used for the intended purpose.

[0161] 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.

[0162] Uses of the compounds and compositions of the present invention

[0163] Use of the compound or pharmaceutical composition of the present invention in preparing a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

[0164] Particularly, the eye disease is cataract or floaters.

[0165] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or alleviating the severity of one or more of the conditions mentioned herein. According to the methods of the present invention, the compounds and compositions thereof may 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 according to the patient's condition, depending on age, the patient's general condition, the severity of the infection, special factors, mode of administration, and the like. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

[0166] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0167] General synthesis process

[0168] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are provided to further illustrate the present invention.

[0169] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention 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 recognized to be applicable to the preparation of other compounds of the invention.

[0170] In the examples described below, all temperatures are set in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0171] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0172] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0173] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The NMR spectra were performed with CDCl3, d6-DMSO, CD3OD or d6-acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0174] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was 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.

[0175] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was 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.

[0176] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0177] Table 1

[0178] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0179] The process conditions for HPLC preparation are:

[0180] (1) Take an appropriate amount of a mixture of diastereoisomers containing compound (II) and dissolve it in a mobile phase;

[0181] (2) Set the flow rate of the mobile phase, detection wavelength and column temperature;

[0182] (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;

[0183] Chromatographic column: a normal phase chiral chromatographic column with silica gel containing polysaccharide derivatives as the stationary phase; more specifically, the chromatographic column used is Daicel AD-H (10*250nm, 5um) or Daicel AD (20*250nm, 5um).

[0184] Mobile phase: 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 sum of the 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 sum of the components in the mobile phase is 100%.

[0185] Detection wavelength: 250nm~320nm;

[0186] Flow rate: 0.5-10 mL / min; more specifically 2-5 mL / min;

[0187] Column temperature: 10~35℃.

[0188] The following abbreviations are used throughout this invention:

[0189] AcOH: acetic acid

[0190] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0191] Boc: tert-butyloxycarbonyl

[0192] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0193] CH3CN: Acetonitrile

[0194] DCM: dichloromethane

[0195] DIPEA: N,N-diisopropylethylamine

[0196] EA: Ethyl acetate

[0197] HCl: Hydrogen chloride

[0198] HCl / EA: Hydrogen chloride in ethyl acetate

[0199] H2O: water

[0200] NaOH: Sodium hydroxide

[0201] NaI: Sodium iodide

[0202] K2CO3: Potassium carbonate

[0203] rt, rt: room temperature

[0204] TABF: Tetrabutylammonium fluoride Example

[0205] Example 1, Synthesis of Compound 1

[0206]

[0207] Compound 1 was obtained according to the above route and the conventional operation of those skilled in the art to obtain 50 mg.

[0208] Step 1:

[0209] At 15°C, imidazole (87.75 g, 1.29 mol) and TMSCl (95.47 g, 879 mmol) were added to a solution of lanosterol raw material (250 g, purity of lanosterol about 60%) in N,N-dimethylformamide (2500 mL), and stirred at 70°C for 5 hours. After the reaction, the reaction solution was cooled to 15°C, extracted with petroleum ether (2500×2 mL), and the petroleum ether phase was washed with saturated NaCl solution (2000 mL) and water (2000 mL), respectively, to obtain 287 g of intermediate compound 1-2.

[0210] Step 2:

[0211] Weigh compound 1-2 (5.00 g, 10 mmol) in a reaction flask, stir and dissolve with 200 ml tetrahydrofuran and 50 ml water, and then cool and stir at -15 °C. Add NBS (2.14 g, 12 mmol) in batches, and stir and react at -15 °C for 1 hour. Sample TLC detection shows that the raw material is completely consumed. Add saturated sodium sulfite aqueous solution at room temperature to quench the reaction, extract the aqueous phase with ethyl acetate, and wash the organic phase with saturated sodium bicarbonate and brine, respectively, and dry over anhydrous sodium sulfate. Purify by silica gel column chromatography to obtain 4.75 g of white solid compound 1-3.

[0212] Step 3:

[0213] Weigh compound 1-3 (4.75 g, 8 mmol) into a reaction bottle, cool to 0°C, add 200 mL of THF to the reaction bottle, and then slowly heat to reflux for 4 h. After cooling, quenching, extraction with dichloromethane, and purification by silica gel column chromatography, 2.00 g of white solid compound 1-4 was obtained.

[0214] Step 4:

[0215] Compound 1-4 (2.00 g, 3.9 mmol) and 2-chloroethyldimethylamine hydrochloride (670 mg, 4.68 mmol) were placed in a reaction bottle containing 50 mL of DMF, K2CO3 (645 mg, 4.68 mmol) was added, and the mixture was heated to 60°C for 2 h, cooled to room temperature, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 1.38 g of compound 1-5.

[0216] Step 5:

[0217] Compound 1-5 (1.38 g, 2.34 mmol) was added to a reaction bottle containing 50 mL of THF, and TBAF was added.

[0218] (732 mg, 2.81 mmol), heated to reflux for 5 h, cooled to room temperature, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 602 mg of compound 1.

[0219] Biological Testing

[0220] Example 2: Effect of Compound 1 of the Invention on the Intracellular Aggregation of Crystallin Mutants

[0221] The lens is the only biconvex transparent body in the body that is rich in high concentrations of proteins and has elastic properties that can change its focusing ability. Crystallins are present in high concentrations in the lens fibers. The crystallin superfamily includes α-, β- and γ-crystallins, which are some of the most highly concentrated intracellular proteins in the human body. Several factors, including crystallin mutations, can lead to protein aggregation - one of the most important causes of cataract formation.

[0222] This example is directed to the crystallin αB-R120G mutant, αA-Y118D mutant, βB2-V187E mutant, γC-G129C mutant and γD-W43R mutant, and the following method is used to detect the effect of the compounds provided by the present invention on the intracellular aggregation of the above crystallin mutants:

[0223] The HeLa cells in good condition are inoculated into a 12-well plate on which a cell slide has been pre-plated, with a cell density of 40% to 50%; after culturing for about 24 hours, the cell density is about 80%, and the expression vector of the above-mentioned crystallin mutant can be transfected into the cells, and the specific operation is carried out according to the scheme recommended by the transfection reagent LipofectamineTM 2000; after transfection, the culture medium is replaced with fresh DMEM culture medium and culture is continued. At this time, the crystallin mutant has been expressed in large quantities in the cells and a certain proportion of aggregates is formed; the cell culture medium is replaced with opti-MEM, and the compound of the present invention is added to a final concentration of 4uM; after culturing for 4 hours, the culture medium is replaced with fresh DMEM culture medium and cultured for another 4 hours; the preparation of immunofluorescence labels includes the following steps: PBS washing, 4% paraformaldehyde fixation, PBS washing, 0.4% Triton The slides were incubated with X-100 at room temperature, washed with PBS, blocked at room temperature, washed with PBS, incubated with primary antibody, washed with PBS, incubated with fluorescent secondary antibody of corresponding source at room temperature, washed with PBS, sealed with DAPI-Fluoromount-G fluorescent sealing agent, and placed in the dark at room temperature for about 1 hour; observed under a microscope, and the aggregation in the cells was counted in a single-blind manner to analyze the efficacy of the compound of the present invention.

[0224] The above method was used to statistically analyze the aggregation of various crystallin mutants in HeLa cells by compound 1 of the present invention. The experimental results show that the compound provided by the present invention has good activity in inhibiting protein aggregation caused by crystallin mutations in cells, and its activity is better than lanosterol.

[0225] Example 3: Cytotoxicity assay of compounds

[0226] This example uses the following method to detect the cytotoxicity of the compounds of the present invention:

[0227] 1. The cytotoxicity of the compound was detected by the MTT (3-(4,5-dimethyl-2-thiazole)-2,5-dimethylbenzene tetrazolium bromide) method. The method is to expose cells in the exponential growth phase to the compound, remove the compound, and then allow the cells to proliferate for 2 to 3 population doubling times, so that the proliferating surviving cells can be distinguished from the non-proliferating surviving cells, and then the number of surviving cells is determined by the MTT dye reduction reaction. The MTT-formazan product is dissolved in an appropriate solvent and quantified by spectrophotometry.

[0228] The specific steps include: suspending human lens epithelial cells and adding samples to a 96-well plate for culture, diluting the compound in multiples by at least 5 concentration gradients with culture medium, adding the compound when the cells enter the exponential growth phase, and setting up a control group without the addition of the compound; after adding the compound, continue to culture the cells until the end of the growth phase, add fresh culture medium and MTT to each well, wrap the culture plate with aluminum foil and culture for 4h to 8h, add DMSO to each well to dissolve the residual MTT-formazan crystals, and then add glycine buffer to each well containing DMSO, and record the absorbance at 570nm.

[0229] A curve was drawn with drug concentration as the horizontal axis (X axis) and absorbance value as the vertical axis (Y axis) to obtain the percentage inhibition curve.

[0230] 2. Inoculate HLE-B3 cells in good condition into 12-well plates with a cell density of 40-50%; culture for about 24 hours, and when the cell density reaches about 80%, cell transfection can be performed, and crystallin αA-Y118D, αB-R120G, βB2-V187E, γC-G129C and γD-W43R mutants, as well as an empty control group, are transfected. The specific operation was carried out according to the protocol recommended by the transfection reagent LipofectamineTM 2000; after 4 hours of transfection, the culture medium was replaced with fresh DMEM and cultured for 16 hours, at which time the crystallin mutant was already expressed in large quantities in the cells; after being digested and dispersed with 0.25% trypsin (EDTA), the cells were inoculated into a 96-well plate with 2000 cells per well and cultured for 12 hours; the cell culture medium was replaced with opti-MEM, and the compound of the present invention was added, two concentration gradients were set, the final concentration was 5uM or 50nM, and the cells were incubated for 12 hours; 10μL CKK-8 was added, incubated for 1 hour, and the absorbance was measured at 450nm.

[0231] Statistical analysis by the above method showed that compound 1 provided by the present invention had no cytotoxicity to normal lens epithelial cells and cell lines transfected with various lens protein mutants, but instead improved cell viability to a certain extent.

[0232] It can be seen from the experimental results that the compound provided by the present invention has no toxic side effects on lens cells and has good safety.

[0233] The compound of the present invention has good activity in inhibiting protein aggregation caused by intracellular crystallin mutation, has no toxic side effects on lens cells, has good water solubility, is easily absorbed by the body, and has good clinical application prospects.

[0234] 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 contemplated that the embodiments are to be considered in all respects as illustrative and non-restrictive, and reference should be made to the appended claims rather than to the foregoing embodiments, and all changes within the meaning and range of equivalents of the appended claims are therefore intended to be included herein.

Claims

1. A steroidal compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, prodrug, or a pharmaceutically acceptable salt or ester thereof, in, X 1 O, S, -NR 5 -or-CR 6 R 7 -; Y is -(CR 8 R 9 ) m -; Z is CH or N; R 1 and R 2 are each independently H, D, alkyl, cycloalkyl, alkyl-C(═O)- or aryl-C(═O)-; or R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered monocyclic or bicyclic ring; R 3 is H, D, halogen, alkyl or cycloalkyl; A is -C(=O)-, -C(=S)-, -OC(=O)- or -NR 10 C(=O)-; X 2 is aminoalkyl, heteroarylalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl-OC(=O)-CR 11 R 12 -, alkyl-C(=O)O-CR 11 R 12 -, arylalkyl, hydroxyalkyl, mercaptoalkyl, amino-C(=O)-alkyl; Q is H, D, hydroxyl, amino, arylamino, halogen, alkyl, carboxyl, aryl, heteroaryl, monosaccharide, polysaccharide, cycloalkyl, cycloalkylalkyl, aryl-C(=O)-, G is O or S; R 5 and R 10 Each is independently H, D, alkyl or cycloalkyl; R 4 , R 6 , R 7 , R 8 , R 9 , R 11 and R 12 each independently is H, D, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; m is 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , X 2 and the alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, alkyl-C(=O)-, aryl-C(=O)-, alkoxy, heterocyclic, aryl, heteroaryl, monocyclic, bicyclic, The group is optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, alkyl, haloalkyl, deuterated alkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl or heteroaryl; The hydrogen atoms on ring a, ring b, ring c and ring d are unsubstituted or at least one hydrogen atom is substituted by deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halogenated or hydroxy-substituted alkoxyalkyl, alkoxy, halo-substituted or hydroxy-substituted alkoxy, alkoxyalkoxy, halo-substituted or hydroxy-substituted alkoxyalkoxy, alkylamino, halo-substituted or hydroxy-substituted alkylamino, alkylthio, halo-substituted or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy.

2. The compound according to claim 1, wherein the compound has a structure as shown in formula (II):

3. The compound according to claim 1 or 2, wherein R 1 and R 2 Each independently is H, D, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyl-C(=O)- or C 6-10 Aryl-C(═O)-; or, R 1 and R 2 Together with the atoms to which it is attached, it forms a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclic group; Among them C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 3-10 membered cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 deuterated, hydroxyl, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

4. The compound according to claim 1 or 2, wherein R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups: R 13 and R 14 are independently H, D, oxo, hydroxyl, halogen, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 heteroaryl; or R 13 and R 14 and the carbon atom to which it is attached to form a C 3-8 Cycloalkyl or C 2-9 Heterocyclic group, wherein C 3-8 Cycloalkyl and C 2-9 The heterocyclic groups are each independently optionally substituted with 1, 2 or 3 D, hydroxy, halogen, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 substituted with heteroaryl; Q 1 , Q 2 and Q 3 are each independently CH or N; Q 4 is CH2, NH, O or S.

5. The compound according to claim 1 or 2, wherein R 1 and R 2 each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following heterocyclic groups:

6. The compound according to any one of claims 1 to 5, wherein X 2 C 1-6 Aminoalkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 6-10 Aryl, C 2-9 Heteroaryl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 1-6 Alkyl-OC(=O)-CR 11 R 12 -、C 1-6 Alkyl-C(=O)O-CR 11 R 12 -、C 6-10 Aryl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Mercaptoalkyl, aminoC(=O)-C 1-6 Alkyl or C 2-9 Heteroaryl C 1-9 alkyl.

7. The compound according to any one of claims 1 to 6, wherein X 2 is aminomethyl, aminoethyl, imidazolylmethyl, imidazolylethyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thiophene, phenyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl, purinyl, quinolyl, Isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, methyl-OC(=O)-CR 11 R 12 -, ethyl-OC(=O)-CR 11 R 12 -, tert-butyl-OC(=O)-CR 11 R 12 -, methyl-C(=O)O-CR 11 R 12 -, ethyl-C(=O)O-CR 11 R 12 -, tert-butyl-C(=O)O-CR 11 R 12 -, phenylmethyl, phenylethyl, phenylpropyl, phenyl tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl, mercaptoethyl, mercaptopropyl, amino C (= O) -methyl, amino C (= O) -ethyl, amino C (= O) -propyl, indolylmethyl or isoxazolylmethyl.

8. The compound according to any one of claims 1 to 7, wherein Q is H, hydroxyl, amino, C 6-10 Arylamino, halogen, C 1-6 Alkyl, carboxyl, phosphate, C 6-10 Aryl, C 2-9 Heteroaryl, monosaccharide, polysaccharide, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, C 6-10 Aryl-C(=O)-, Or not present; wherein, the G is O or S.

9. The compound according to any one of claims 1 to 8, wherein Q is hydrogen, hydroxy, amino, phenylamino, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carboxyl, phosphate, phenyl, naphthyl, furanyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, indolyl, isoxazolyl, monosaccharide, polysaccharide, cyclopropylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylpropyl, phenyl-C(=O)-, naphthyl-C(=O)-, or not present; said G is O or S.

10. The compound according to any one of claims 1 to 9, wherein R 3 H, D, F, Cl, Br, C 1-6 Alkyl or C 3-8 Cycloalkyl; and / or R 5 and R 10 Each independently is H, D, C 1-6 Alkyl or C 3-8 Cycloalkyl; and / or R 4 , R 6 , R 7 , R 8 , R 9 , R 11 or R 12 are independently F, Cl, Br, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 1-9 heteroaryl; Among them C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-9 Heterocyclic group, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted with 1, 2, 3 or 4 deuterated, hydroxyl, amino, halogen, cyano, oxo, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated 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 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl or C 1-9 The heteroaryl group is substituted with a substituent.

11. The compound according to any one of claims 1 to 10, wherein R 3 is H, D, F, Cl, Br, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or R 5 and R 10 each independently is H, D, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or R 4 , R 6 , R 7 , R 8 , R 9 , R 11 or R 12 each independently represents F, Cl, Br, hydroxy, amino, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl , pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl , benzothiophenyl, indolyl, purinyl, quinolyl, isoquinolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

12. The compound according to claim 1, having one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, 13. A pharmaceutical composition comprising the steroid compound according to any one of claims 1 to 12 or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts or esters, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

14. Use of the steroidal compound or its stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, prodrug, or pharmaceutically acceptable salt or ester according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

15. The use according to claim 14, wherein the eye disease is cataract or floaters.

Images