Steroid compound and application thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of Chinese patent application No. 202311282343.7 filed on September 28, 2023, with invention name “Steroid compounds and their applications”. The entire contents of the above patent application are incorporated into this application as a whole. Technical Field

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

[0004] 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.

[0005] 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.

[0006] 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

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

[0008]

[0009] Wherein A is a bond, an alkylene group, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-;

[0010] L is amino, heterocyclic, carbocyclic, aryl, heteroaryl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or X is -C(=O)-, -C(=O)NCHR 3 -, alkylene, hydroxyalkylene, alkenylene, alkyleneoxy or heterocyclylene;

[0011] Y is a bond, an alkylene group, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cycloalkylene or heterocyclylene;

[0012] R 4 is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, mercaptoalkyl, arylalkyl, alkoxy, aryl, heteroaryl, heterocyclic, carbocyclic, R 7C(=O)NR 8 -、R 9 R 10 N-alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0013] R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy or hydroxy-substituted alkoxy;

[0014] R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl;

[0015] R 7 is hydroxy, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0016] R 11 is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0017] R 12 and R 13 are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0018] L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13Optionally substituted with 1, 2, 3, 4, 5, 6 identical or different substituents selected from deuterium, halogen, hydroxy, amino, cyano, mercapto, carboxy, oxo, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0019] In some embodiments, A is a bond, C 1-6 Alkylene, -C(=O)-, -OC(=O)-, -R 2 NC(=O)- or -S(=O)2-;

[0020] R 1 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy;

[0021] A and R 1 Optionally, 1, 2, 3, 4 or 5 identical or different deuterium, halogen, C 1-6 Alkyl, hydroxyl, amino, thiol, nitro, carboxyl, cyano, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 substituted with heteroaryl.

[0022] In some embodiments, A is a bond, C 1-3 Alkylene, -C(=O)-, -R2 NC(=O)- or -S(=O)2-;

[0023] R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl or ethoxymethyl;

[0024] A and R 1 Optionally substituted with 1, 2, 3, 4 or 5 identical or different deuterium, F, Cl, Br, hydroxy, amino, mercapto, nitro, carboxyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl or tetrahydrofuranyl.

[0025] In some embodiments, L is amino, C 3-10 Carbon ring, C 2-9 Heterocyclic, C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or

[0026] X is -C(=O)-, -C(=O)NCHR 3 -、C 1-6 Alkylene, C 2-6 Alkenylene, C 1-6 Hydroxyalkylene, C 1-6 Alkyleneoxy, C 2-9 Heterocyclylene;

[0027] Y is a bond, C 1-6 Alkylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(=O)-、C 3-10 Cycloalkylene or C 2-9 Heterocyclylene;

[0028] R 4 is hydrogen, hydroxyl, amino, thiol, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C1-6 Alkoxy C 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-10 Aryl C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 2-9 Heteroaryl, C 2-9 Heterocyclic group, C 3-10 Carbocyclic group, R 7 C(=O)NR 8 -、R 9 R 10 NC 1-6 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0029] R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl or C 2-9 Heterocyclic group;

[0030] R 7 Hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl;

[0031] R 11 For hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C2-9 Heterocyclic group, C 6-10 aryl or heteroaryl;

[0032] R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl;

[0033] L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Optionally, 1, 2, 3, 4, 5, 6 identical or different groups selected from deuterium, halogen, hydroxyl, amino, cyano, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 The group is substituted with a heteroaryl substituent.

[0034] In some embodiments, L is amino, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiooxanyl, thiox ... alkyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or

[0035] X is -C(=O)-, -C(=O)NCHR 3 -, methylene, ethylene, propylene, methylmethylene, methyleneoxy, ethyleneoxy, propyleneoxy, methylmethyleneoxy, hydroxymethylene, hydroxyethylene, vinylene, propenylene, 1,3-dioxolanylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothiophenylene, dihydrothiophenylene, 1,3-dioxolanylene, dithiocyclopentylene, tetrahydropyranylene, dihydropyranylene, 2H-pyranylene, 4H-pyranylene, tetrahydrothiopyranylene, piperidinylene, morpholinylene, thiomorpholinylene, piperazinylene, dioxanylene, dithianylene, thioxanylene, homopiperazinylene, homopiperidinylene, oxepanylene or thiepanylene;

[0036] Y is a bond, methylene, ethylene, propylene, methylmethylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, 1,3-dioxacyclopentylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothienylene, dihydrothienylene, 1,3-dioxacyclopentylene, dithiocyclopentylene, tetrahydropyranylene, or dihydropyranylene;

[0037] R 4is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxymethoxymethyl, methoxymethoxyethyl, methoxyethoxymethyl, methoxyethoxyethyl, mercaptomethyl, mercaptoethyl, phenylmethyl, phenylethyl, methoxy, ethoxy, isopropoxy, tert-butoxy , phenyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, 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[4,3-b] 1,5-a]pyridinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, R 7 C(=O)NR 8 -、R 9 R 10 NC 1-3 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0038] R 2 , R 3 , R 5 , R 6 , R 8 , R9 and R 10 each is independently hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl or thiepanyl;

[0039] R 7 is hydroxy, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, or isothiazolyl;

[0040] R 11 , R 12 and R 13each independently represents hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, imidazolylmethyl or imidazoethyl;

[0041] L, X, Y, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12The present invention is optionally replaced by 1, 2, 3, 4, 5, or 6 identical or different radicals selected from deuterium, F, Cl, Br, hydroxyl, amino, cyano, mercapto, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, tris-difluoromethyl, methoxymethyl, methoxyethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3- -dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazole oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, The 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 substituents are substituted.

[0042] In some embodiments, For the following structure fragment

[0043]

[0044] On the other hand, the present application also provides a pharmaceutical composition, which comprises the compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0045] In yet another aspect, the present application provides a use of the compound or pharmaceutical composition described herein in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

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

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

[0048] Definitions and general terms

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

[0050] Some embodiments of the present application are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The present application is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present application as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present application. The present application is by no means limited to the methods and materials described herein. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0051] It should be further recognized that certain features of the present application, for clarity, are described in multiple independent embodiments, but can also be provided in combination in a single embodiment. Conversely, various features of the present application, for brevity, are described in a single embodiment, but can also be provided separately or in any suitable sub-combination.

[0052] Unless otherwise specified, all technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application belongs. All patents and publications involved in this application are incorporated herein by reference in their entirety.

[0053] Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of this application, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0054] 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.

[0055] The term "subject" as used herein refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

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

[0058] "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.

[0059] "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.

[0060] The stereochemical definitions and conventions used in this application generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0061] 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.

[0062] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0063] Depending on the choice of starting materials and process, the compounds of the present application may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0064] 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.

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

[0066] The term "prodrug" as used herein refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present application may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present application contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0067] 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).

[0068] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0069] The salts mentioned in the present application are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates, 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 application also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0070] Pharmaceutically acceptable salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

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

[0072] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

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

[0074] 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.

[0075] "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.

[0076] As used herein, the term "treating" any disease or condition refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or at least one clinical symptom thereof) in some embodiments. In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or deterioration of a disease or condition.

[0077] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. An isotopically enriched compound has a structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0078] In another aspect, the compounds described herein include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparations in this application.

[0079] In addition, heavier isotopes, especially deuterium (i.e. 2The substitution of H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present application is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present application refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present application include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0080] As described in the present application, the compounds of the present application may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples in the embodiments, subclasses, and a class of compounds contained in the present application. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not it is located before the term "substituted", indicates that one or more hydrogen atoms in the given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituted group can have a substituent substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner. The substituents may be, but are not limited to, deuterium, 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.

[0081] The term "alkyl" as used herein refers to a saturated linear or branched monovalent hydrocarbon group of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3 ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The term "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms, such examples include, but are not limited to, methylene, ethylene, isopropylidene, and the like.

[0082] The term "alkoxy" as used in this application refers to an alkyl group, as defined in this application, connected to the main carbon chain through an oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group can be substituted or unsubstituted, wherein the substituent can be, but are not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, etc.

[0083] 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.

[0084] 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 by one or more substituents described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

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

[0086] The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring 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 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).

[0087] 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.

[0088] The term "aryl" or "aromatic ring" 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.

[0089] The term "heteroaryl" or "heteroaromatic ring" 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 the heteroatoms have the meanings as described herein, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". And the heteroaryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy and the like.

[0090] In other embodiments, heteroaryl includes 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.

[0091] The term "heteroatom" means one or more O, S, N, P and Si atoms, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrolyl), NH (e.g., NH in pyrrolidinyl) or NR (e.g., NR in N-substituted pyrrolidinyl).

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

[0093] The term "halogen" as used herein means that the group following it is substituted with halogen, and the number of the substituted groups may be one or more.

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

[0095] When the term “substituted” is used between two groups, it is preceded by a substituent, such as “aryl-substituted alkyl” means an alkyl group having an aryl substituent, and “alkoxycarbonyl-substituted alkyl” means an alkyl group having an alkoxycarbonyl substituent.

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

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

[0098] Description of the compounds of the present application

[0099] On the one hand, the present application provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in formula (I),

[0100]

[0101] Wherein A is a bond, an alkylene group, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-;

[0102] L is amino, heterocyclic, carbocyclic, aryl, heteroaryl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or X is -C(=O)-, -C(=O)NCHR 3 -, alkylene, hydroxyalkylene, alkenylene, alkyleneoxy or heterocyclylene;

[0103] Y is a bond, an alkylene group, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cycloalkylene or heterocyclylene;

[0104] R 4 is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, mercaptoalkyl, arylalkyl, alkoxy, aryl, heteroaryl, heterocyclic, carbocyclic, R 7 C(=O)NR 8 -、R 9 R 10 N-alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0105] R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy or hydroxy-substituted alkoxy;

[0106] R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl;

[0107] R 7 is hydroxy, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0108] R 11 is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0109] R 12 and R 13 are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0110] L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Optionally substituted with 1, 2, 3, 4, 5, 6 identical or different substituents selected from deuterium, halogen, hydroxy, amino, cyano, mercapto, carboxy, oxo, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0111] In some embodiments, A is a bond, C 1-6 Alkylene, -C(=O)-, -R 2NC(=O)- or -S(=O)2-;

[0112] R 1 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy;

[0113] A and R 1 Optionally, 1, 2, 3, 4 or 5 identical or different deuterium, halogen, C 1-6 Alkyl, hydroxyl, amino, thiol, nitro, carboxyl, cyano, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 substituted with heteroaryl.

[0114] In some embodiments, A is a bond, C 1-3 Alkylene, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-;

[0115] R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl or ethoxymethyl;

[0116] A and R1 Optionally substituted with 1, 2, 3, 4 or 5 identical or different deuterium, F, Cl, Br, hydroxy, amino, mercapto, nitro, carboxyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl or tetrahydrofuranyl.

[0117] In some embodiments, L is amino, C 3-10 Carbon ring, C 2-9 Heterocyclic, C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or

[0118] X is -C(=O)-, -C(=O)NCHR 3 -、C 1-6 Alkylene, C 2-6 Alkenylene, C 1-6 Hydroxyalkylene, C 1-6 Alkyleneoxy, C 2-9 Heterocyclylene;

[0119] Y is a bond, C 1-6 Alkylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(=O)-、C 3-10 Cycloalkylene or C 2-9 Heterocyclylene;

[0120] R 4 is hydrogen, hydroxyl, amino, thiol, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-10 Aryl C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 2-9 Heteroaryl, C 2-9 Heterocyclic group, C 3-10 Carbocyclic group, R7 C(=O)NR 8 -、R 9 R 10 NC 1-6 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0121] R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 Independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl or C 2-9 Heterocyclic group;

[0122] R 7 Hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl;

[0123] R 11 For hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 aryl or heteroaryl;

[0124] R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 6-10 Aryl C1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl;

[0125] L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Optionally, 1, 2, 3, 4, 5, 6 identical or different groups selected from deuterium, halogen, hydroxyl, amino, cyano, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 The group is substituted with a heteroaryl substituent.

[0126] In some embodiments, L is amino, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiooxanyl, thiox ... alkyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or

[0127] X is -C(=O)-, -C(=O)NCHR 3 -, methylene, ethylene, propylene, methylmethylene, methyleneoxy, ethyleneoxy, propyleneoxy, methylmethyleneoxy, hydroxymethylene, hydroxyethylene, vinylene, propenylene, 1,3-dioxolanylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothiophenylene, dihydrothiophenylene, 1,3-dioxolanylene, dithiocyclopentylene, tetrahydropyranylene, dihydropyranylene, 2H-pyranylene, 4H-pyranylene, tetrahydrothiopyranylene, piperidinylene, morpholinylene, thiomorpholinylene, piperazinylene, dioxanylene, dithianylene, thioxanylene, homopiperazinylene, homopiperidinylene, oxepanylene or thiepanylene;

[0128] Y is a bond, methylene, ethylene, propylene, methylmethylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, 1,3-dioxacyclopentylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothienylene, dihydrothienylene, 1,3-dioxacyclopentylene, dithiocyclopentylene, tetrahydropyranylene, or dihydropyranylene;

[0129] R 4is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxymethoxymethyl, methoxymethoxyethyl, methoxyethoxymethyl, methoxyethoxyethyl, mercaptomethyl, mercaptoethyl, phenylmethyl, phenylethyl, methoxy, ethoxy, isopropoxy, tert-butoxy , phenyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, 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[4,3-b] 1,5-a]pyridinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, R 7 C(=O)NR 8 -、R 9 R 10 NC 1-3 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or

[0130] R 2 , R 3 , R 5 , R 6 , R 8 , R9 and R 10 each is independently hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl or thiepanyl;

[0131] R 7 is hydroxy, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, or isothiazolyl;

[0132] R 11 , R 12 and R 13each independently represents hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, imidazolylmethyl or imidazoethyl;

[0133] L, X, Y, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12The present invention is optionally replaced by 1, 2, 3, 4, 5, or 6 identical or different radicals selected from deuterium, F, Cl, Br, hydroxyl, amino, cyano, mercapto, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, tris-difluoromethyl, methoxymethyl, methoxyethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3- -dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazole oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, The 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 substituents are substituted.

[0134] In some embodiments, For the following structure fragment

[0135]

[0136] In some embodiments, the compound has the structure shown in formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0137]

[0138] Among them, R 1 , X, Y, and R 4 Has the definitions given herein.

[0139] In some embodiments, R 1 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C1-6 Alkyl or C 1-6 In some embodiments, R 1 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl or chloroethyl. 1 For hydrogen.

[0140] In some embodiments, X is C 1-6 Alkylene, C 3-6 Azoheterocyclyl; Y is a bond, C 1-6 Alkylene, R 4 is hydrogen, hydroxyl, amino, thiol, cyano, nitro, carboxyl, C 1-6 In some embodiments, X is methylene, ethylene, propylene, piperidinylene; Y is a bond, methylene, ethylene, propylene; R 4 It is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl.

[0141] In some embodiments, Has the following structure:

[0142]

[0143] In some embodiments, the compound has one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

[0144]

[0145]

[0146]

[0147] Compositions, formulations and administration of the compounds of the present application

[0148] The pharmaceutical composition comprises any one of the compounds of the present application. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0149] The pharmaceutical composition can be used to treat eye diseases, and in particular, has a good therapeutic effect on cataracts, floaters or presbyopia.

[0150] 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.

[0151] When it can be used for treatment, the therapeutically effective amount of the compound of the present application can be given as a raw chemical drug, and can also be provided as an active ingredient of a pharmaceutical composition. Therefore, the present application also provides a pharmaceutical composition, which includes a therapeutically effective amount of the compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" used herein refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction). When a separate active ingredient is administered alone, the term refers only to the ingredient. When used in combination, the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, sequential or simultaneous administration. In terms of compatibility with other ingredients of the preparation and harmlessness to its recipient, the carrier, diluent or excipient must be acceptable. According to another aspect of the present application, a method for preparing a pharmaceutical preparation is also provided, which includes mixing the compound of the present application with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to the compounds, raw materials, compositions and / or dosage forms of the present invention, which are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effectively used for the intended purpose.

[0152] 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.

[0153] Uses of the compounds and compositions of the present invention

[0154] The use of the compound or pharmaceutical composition of the present application in the preparation of a drug for preventing, treating, curing or alleviating an eye disease in a patient.

[0155] Particularly, the eye disease is cataract, floaters or presbyopia.

[0156] The "effective amount" or "effective dose" of the compound or pharmaceutically acceptable composition of the present application refers to an effective amount for treating or alleviating the severity of one or more of the conditions mentioned in the present application. According to the methods of the present application, the compound and its composition can be effectively used to treat or alleviate the severity of the disease in any dosage and any route of administration. The exact amount required will vary according to the patient's condition, which depends on the age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc. The compound or composition of the present application can be co-administered with one or more other therapeutic agents, as discussed in the present application.

[0157] In order to enable those skilled in the art to better understand the technical solution of the present application, some non-limiting embodiments are further disclosed below to further explain the present application in detail.

[0158] General synthesis process

[0159] Generally, the compounds of the present application can be prepared by the methods described in the present application. The following reaction schemes and examples are used to further illustrate the content of the present application.

[0160] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present application, and other methods for preparing the compounds of the present application are considered to be within the scope of the present application. For example, the synthesis of the non-exemplified compounds according to the present application can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described in the present application, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed in the present application or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present application.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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 CDC13, 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).

[0165] 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.

[0166] 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.

[0167] 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:

[0168] Table 1

[0169] 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

[0170] The process conditions for HPLC preparation are:

[0171] (1) Take an appropriate amount of a mixture of diastereoisomers containing a compound and dissolve it in a mobile phase;

[0172] (2) Set the flow rate of the mobile phase, detection wavelength and column temperature;

[0173] (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;

[0174] 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).

[0175] 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%.

[0176] Detection wavelength: 250nm~320nm;

[0177] Flow rate: 0.5-10 mL / min; more specifically 2-5 mL / min;

[0178] Column temperature: 10~35℃.

[0179] The following abbreviations are used throughout this application:

[0180] AcOH: acetic acid

[0181] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0182] Boc: tert-butyloxycarbonyl

[0183] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0184] CH3CN: Acetonitrile

[0185] DCM: dichloromethane

[0186] DIPEA: N,N-diisopropylethylamine

[0187] EA: Ethyl acetate

[0188] HCl: Hydrogen chloride

[0189] HCl / EA: Hydrogen chloride in ethyl acetate

[0190] H2O: water

[0191] NaOH: Sodium hydroxide

[0192] NaI: Sodium iodide

[0193] K2CO3: Potassium carbonate

[0194] rt, rt: room temperature

[0195] PE: Petroleum ether

[0196] DCC: dicyclohexylcarbodiimide

[0197] DMAP: 4-dimethylaminopyridine

[0198] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0199] MC: Methylcellulose

[0200] DMSO: dimethyl sulfoxide

[0201] HP-β-CD: Hydroxypropyl-β-cyclodextrin

[0202] Example

[0203] Example 1

[0204] (3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-ylsulfamate (Compound 1)

[0205]

[0206] first step:

[0207] Under nitrogen protection, formic acid (0.7 g, 15.1 mmol) was added dropwise to a solution of sulfamoyl chloride (0.27 g, 2.3 mmol) in acetonitrile (5 mL) at 0°C. The resulting mixture was stirred at room temperature for 6 hours. The temperature was lowered to 0°C, and a solution of lanosterol 1a (1.0 g, 2.3 mmol) in acetonitrile (5 mL) was added dropwise to the above reaction solution, and the mixture was stirred at room temperature for 12 hours after the solution was added. The reaction was monitored to be complete by TLC; the mixture was concentrated under reduced pressure, ethyl acetate (50 mL) was added to dissolve the residue, the residue was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by high pressure preparation to obtain compound 1 (0.53 g, yield 45%).

[0208] LC-MS m / z(ESI)[M+H] + =506.6.

[0209] Example 2

[0210] (3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl(E)-3-(3,4-dihydroxyphenyl)acrylate (Compound 2)

[0211]

[0212] first step:

[0213] Under nitrogen protection, thionyl chloride (0.18 g, 1.52 mmol) was added dropwise to a solution of caffeic acid (0.21 g, 1.17 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was heated to reflux and stirred for 1 hour. The temperature was lowered to 0°C, and a solution of lanosterol 1a (0.5 g, 1.17 mmol) in dioxane (5 mL) was added dropwise to the above reaction solution, and the mixture was returned to room temperature and stirred for 10 hours. TLC monitored the reaction to be complete; the crude product was concentrated under reduced pressure, and compound 2 (0.17 g, yield 25%) was obtained by direct high pressure preparative separation.

[0214] LC-MS m / z(ESI)[M+H] + =589.5.

[0215] Example 3

[0216] 4-Oxo-4-(((3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)butanoic acid (Compound 3)

[0217]

[0218] first step:

[0219] Under nitrogen protection, a toluene (20 mL) solution of lanosterol 1a (1.0 g, 2.34 mmol), succinic anhydride (0.28 g, 2.81 mol) and 4-(dimethylamino)pyridine (28.0 mg, 0.23 mmol) was heated to 110°C and stirred for 18 hours, then cooled to room temperature. TLC monitored the reaction to be complete; the crude product was concentrated under reduced pressure and directly separated by high pressure preparation to obtain compound 3 (0.37 g, yield 30%).

[0220] LC-MS m / z(ESI)[M+H] + =527.8.

[0221] Example 4

[0222] (3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl(E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (Compound 4)

[0223]

[0224] first step:

[0225] Lanosterol 1a (412.9 mg, 1.0 mmol), ferulic acid (194.2 mg, 1.0 mmol), DCC (250.1 mg, 1.2 mmol) and DMAP (146.7 mg, 1.2 mmol) were added to a 25 mL single-mouth bottle, and DCM (10 mL) was added and refluxed at 40°C for 24 h. The reaction solution was cooled to room temperature and concentrated, and separated and purified by silica gel column chromatography (PE:EA = 10:1 to PE:EA = 3:1 gradient elution) to obtain white powder solid compound 4 (400.3 mg, 0.68 mmol).

[0226] LC-MS m / z(ESI)[M+H] + =603.8;

[0227] 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.68(d,J=15.9Hz,1H),7.09(dd,J=8.2,1.6Hz,1H),7.05(d,J=1.5Hz,1H), 6.93(d,J=8.2Hz,1H),6.29(d,J=15.9Hz,1H),5.09(t,J=7.0Hz,1H),4.62(dd,J=11.2,4.8Hz,1H),3.93(s,3H) ,1.94–1.87(m,2H),1.78–1.73(m,2H),1.68(s,3H),1.60(s,3H),1.57–1.45(m,4H),1.41(m,5H),1.35–1.21(m ,5H),1.16(dt,J=12.8,6.3Hz,3H),1.09–1.02(m,2H),1.01(s,3H),0.91(m,9H),0.87(s,3H),0.68(s,3H)ppm.

[0228] Example 5

[0229] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl dimethylaminosulfonate (Compound 5)

[0230]

[0231] first step:

[0232] Lanosterol 1a (412.9 mg, 1.0 mmol), compound 5-1 (143.9 mg, 1.0 mmol), DMAP (22.4 mg, 0.2 mmol) were added to a 25 mL single-necked bottle, and DCM (10 mL) and DIPEA (0.35 mL, 2.0 mmol) were added and refluxed at 40 ° C for 24 h. The reaction solution was cooled to room temperature and concentrated, and purified by silica gel column chromatography (PE: EA = 10: 1 to PE: EA = 1: 1 gradient elution) to obtain a white powder solid compound 5 (421.1 mg, 0.81 mmol).

[0233] LC-MS m / z(ESI)[M+H]+=534.8.

[0234] Example 6

[0235] 2-((((3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)carbonyl)amino)1-ethanesulfonic acid (Compound 6)

[0236]

[0237] first step:

[0238] Lanosterol 1a (4128.7 mg, 10.0 mmol), compound 6-1 (1186.9 mg, 4.0 mmol), DMAP (224.9 mg, 2.0 mmol) were added to a 250 mL single-necked bottle, and DCM (100 mL) and DIPEA (3.5 mL, 20.0 mmol) were added and reacted at room temperature for 24 h. The reaction solution was concentrated and recrystallized with PE:DCM = 10:1 (110 mL) to obtain a white powder solid compound 6-2 (3421.9 mg, 7.2 mmol).

[0239] Step 2:

[0240] Compound 6-2 (475.9 mg, 1.0 mmol), compound 6-3 (125.9 mg, 1.0 mmol), DMAP (22.4 mg, 0.2 mmol) were added to a 25 mL single-necked bottle, DCM (10 mL) and DIPEA (0.35 mL, 2.0 mmol) were added and reacted at room temperature for 24 h. The reaction solution was concentrated and purified by column chromatography (PE:EA=10:1 to PE:EA=1:1 to EA gradient elution) to obtain white powder solid compound 6 (445.8 mg, 0.79 mmol).

[0241] LC-MS m / z(ESI)[M+H] + =578.7.

[0242] Example 7

[0243] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 1-methylpiperidin-4-carboxylate (Compound 7)

[0244]

[0245] first step:

[0246] Add 1-methylpiperidine-4-carboxylic acid (860 mg, 6 mmol), 4-dimethylaminopyridine (110 mg, 0.9 mmol) and lanosterol 1a (1.3 g, 3 mmol) in dichloromethane (30 mL) to the reaction flask, add EDCI (1.73 g, 9 mmol) in batches under stirring, and stir at room temperature until all the raw materials are completely converted. After the reaction is completed, add 30 mL of water to the reaction mixture, stir for 5 minutes, stand and separate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain a solid separated by column chromatography (ethyl acetate / petroleum ether = 60%) to obtain the target compound 7.

[0247] LC-MS m / z(ESI)[M+H] + =552.9.

[0248] Example 8

[0249] (3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl(3-acetylaminopropionyl)-L-histidine (Compound 8)

[0250]

[0251] first step:

[0252] Lanosterol 1a (412.3 mg, 1.0 mmol), compound 8-1 (269.1 mg, 1.0 mmol), DCC (250.1 mg, 1.2 mmol) and DMAP (146.7 mg, 1.2 mmol) were added to a 25 mL single-mouth bottle, and DCM (10 mL) was added and refluxed at 40°C for 24 h. The reaction solution was cooled to room temperature and concentrated, and separated and purified by silica gel column chromatography (PE:EA = 10:1 to PE:EA = 1:1 gradient elution) to obtain white powder solid compound 8 (271.8 mg, 0.41 mmol).

[0253] LC-MS m / z(ESI)[M+H] + =677.9.

[0254] Example 9

[0255] (E)-4-oxo-4-(((3S,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en)-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)2-butenoic acid (Compound 9)

[0256]

[0257] first step:

[0258] Under nitrogen protection, lanosterol 1a (1.0 g, 2.3 mmol), maleic anhydride (0.23 g, 2.3 mmol) and N,N-dimethylformamide (10 mL) were added to a 50 mL single-necked bottle and heated to 100 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was separated by high pressure preparation to obtain the target compound 9 (0.26 g, yield 21%).

[0259] LC-MS m / z(ESI)[M+H] + =525.5.

[0260] Example 10

[0261] (3S,5R,10S,13R,14R,17R)-4,4,10,13,14-pentamethyl-17-((R)-6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yltetrahydro-2H-pyran-4-carboxylate (Compound 10)

[0262]

[0263] first step:

[0264] Lanosterol 1a (1.0 g, 2.3 mmol) and dichloromethane (10 mL) were added to the reaction flask, and the temperature was lowered to 0°C under nitrogen protection. Tetrahydropyran-4-carbonyl chloride (0.34 g, 2.3 mmol) and triethylamine (0.23 g, 2.3 mmol) were added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction was complete after TLC monitoring; the residue was concentrated under reduced pressure, and the residue was separated by high pressure preparation to obtain compound 10 (0.74 g, yield 60%).

[0265] LC-MS m / z(ESI)[M+H] + =539.6.

[0266] Biological Testing

[0267] Test Example 1: Detection of drug content in rabbit aqueous humor

[0268] This method detects the drug content in the aqueous humor of New Zealand rabbits to detect the ability of the test compound to pass through the cornea and hydrolyze.

[0269] Twelve New Zealand rabbits (male, 3-5 months old) were placed in an animal room for acclimatization for 3 days before use. A certain amount of compound was weighed, added with solvent (1.2% HP-β-CD, 20.5% poloxamer (P407), 1.6% poloxamer (P188)), and ultrasonically vibrated until completely dissolved or a stable suspension was formed, and the final concentration of the compound was 5 mM.

[0270] Pull down the lower eyelid of the rabbit, use a pipette to accurately drop 50μL of compound solution or suspension, and administer the drug to both eyes at the same time. After administration, observe whether there is leakage of the drug solution. At 0h, 0.5h, 2h, and 4h after administration, extract the aqueous humor of 3 rabbits (50μL / eye / rabbit, both eyes are collected), and use LC-MS / MS to detect the drug content in the aqueous humor. Lanosterol was selected as the reference compound for this test.

[0271] The results show that the compounds of the invention can penetrate into the aqueous humor from the cornea or through other pathways; and the compounds of the present application can be converted into lanosterol during the penetration process and show higher lanosterol concentrations and exposure amounts in the aqueous humor.

[0272] The concentration of lanosterol in rabbit aqueous humor 6 hours after eye drop administration in Examples 3, 7 and 8 was higher than that of the reference compound lanosterol at the same dose. Test Example 2: Oral Bioavailability of Drugs

[0273] This method evaluates the pharmacokinetic characteristics of the compound in vivo by detecting the drug content at different time points after administration to mice.

[0274] Six ICR mice (male, 4-6 weeks old) were placed in the animal room for 3 days of adaptation before use. A certain amount of compound was weighed and the corresponding solvent (oral: 0.5% MC; intravenous: DMSO: 30% HP-β-CD = 10:90) was used to prepare the corresponding compound solution.

[0275] Three mice were orally administered 10 mg / kg of the compound, and micro-blood samples were collected at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0276] Three mice were injected with 1 mg / kg of the compound through the tail vein, and micro-blood samples were collected at 0 h, 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after administration.

[0277] The drug content in plasma of each sample was detected by LC-MS / MS. Pharmacokinetic parameters and bioavailability were calculated by WinNonlin. Lanosterol was selected as the reference compound in this experiment.

[0278] The results showed that after oral administration, Examples 3, 7 and 8 had good absorption characteristics, lanosterol could be detected in the blood, and the bioavailability was better than that of the reference compound lanosterol.

[0279] Test Example 3: Solubility Test

[0280] 1. Instruments and Materials

[0281] Instruments: Shimadzu LC-20ADXR; shaker; glass instrument; pipette.

[0282] Materials: pH = 7.2 PBS buffer, pure water, HPLC ethanol, HPLC methanol, HPLC tetrahydrofuran

[0283] 2. Experimental Procedure

[0284] 2.1 Preparation of relevant compound sample standards Take relevant compound samples, place in centrifuge tubes, add 1 mL of tetrahydrofuran at room temperature to completely dissolve the samples, and obtain the concentration of the mother solution.

[0285] 2.2 Preparation of saturated sample solution of relevant compounds Take the sample of relevant compounds, place it in a centrifuge tube, and add 1mL of pure water at room temperature. Place it on a shaker and shake it at room temperature for 1 hour. Take out the sample and put it into a refrigerated centrifuge, set the centrifuge to 4000 rpm, 25℃, and centrifuge for 10 minutes. After taking it out, aspirate the upper saturated clear solution. Filter it using a 0.22μm filter membrane.

[0286] 2.3 Prepare the standard curve solution. Take the mother solution and dilute it with tetrahydrofuran in a gradient manner. Vortex and shake evenly.

[0287] 2.4 Determination of sample solubility

[0288] The specific solubility was determined using an HPLC method.

[0289] 2.5 Determine the standard curve. Pipette 200 μL of the standard curve solution into the inner insert tube. Start injecting from low concentration, inject 1 μL each time, and record the chromatographic peak area.

[0290] 2.6 Inject 1 μL of saturated solution and record the chromatographic peak area.

[0291] 3. Comparison of clarity after centrifugation

[0292] Take pure water and put it into a centrifuge tube. Compare the upper clear solution in step 2.2 with pure water. There are no granular, flocculent, or suspended solid particles in the clear solution. The clarity is similar to that of pure water.

[0293] 4. Calculation

[0294] 4.1 Calculate the concentration and chromatographic peak area to make a fitting curve and obtain the standard curve regression equation.

[0295] 4.2 The peak area measured for the saturated sample was used to calculate the concentration using the regression equation.

[0296] 4.3 Obtain the solubility value (in mg / mL).

[0297] 5.HPLC method conditions

[0298] Column: YMC-Triart C8 5μm 4.6x50 mm;

[0299] Method: Mobile phase: 0.1% trifluoroacetic acid in methanol and ethanol; Mobile phase gradient: 100% methanol as phase A, 100% ethanol as phase B, 10% B to 90% B, 3 mins; Post-equilibrium 10% ethanol, 0.5 mins; Detection wavelength: Full wavelength scan

[0300] Detection temperature: 40℃

[0301] The results showed that lanosterol was basically insoluble in water, and the solubility of compounds 1-10 of the present application in water was in the range of 0.1 mg / mL to 5 mg / mL, which was significantly higher than that of lanosterol and was suitable for preparation into solution-type eye drops.

[0302] It will be apparent to those skilled in the art that the present application 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 therefore all changes within the meaning and range of equivalents of the appended claims are 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, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I), in, A is a bond, an alkylene group, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-; L is amino, heterocyclic, carbocyclic, aryl, heteroaryl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or X is -C(=O)-, -C(=O)NCHR 3 -, alkylene, hydroxyalkylene, alkenylene, alkyleneoxy or heterocyclylene; Y is a bond, an alkylene group, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cycloalkylene or heterocyclylene; R 4 is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, alkyl, alkenyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxyalkoxyalkyl, mercaptoalkyl, arylalkyl, alkoxy, aryl, heteroaryl, heterocyclic, carbocyclic, R 7 C(=O)NR 8 -、R 9 R 10 N-alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy or hydroxy-substituted alkoxy; R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl; R 7 is hydroxy, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 11 is hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 12 and R 13 are each independently hydrogen, alkyl, hydroxyalkyl, haloalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Optionally substituted with 1, 2, 3, 4, 5, 6 identical or different substituents selected from deuterium, halogen, hydroxy, amino, cyano, mercapto, carboxy, oxo, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

2. The steroid compound according to claim 1, wherein A is a key, C 1-6 Alkylene, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-; R 1 is hydrogen, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl, C 2-9 Heteroaryl, C 6-10 Aryloxy, C 6-10 Arylamino, C 2-9 Heteroaryloxy or hydroxy substituted C 1-6 Alkoxy; A and R 1 Optionally, 1, 2, 3, 4 or 5 identical or different deuterium, halogen, C 1-6 Alkyl, hydroxyl, amino, thiol, nitro, carboxyl, cyano, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 substituted with heteroaryl.

3. The steroid compound according to claim 1, wherein A is a key, C 1-3 Alkylene, -C(=O)-, -R 2 NC(=O)- or -S(=O)2-; R 1 is hydrogen, deuterium, hydroxy, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl or ethoxymethyl; A and R 1 Optionally substituted with 1, 2, 3, 4 or 5 identical or different deuterium, F, Cl, Br, hydroxy, amino, mercapto, nitro, carboxyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl or tetrahydrofuranyl.

4. The steroid compound according to claim 1, wherein L is amino, C 3-10 Carbon ring, C 2-9 Heterocyclic, C 6-10 Aromatic ring, C 2-9 Heteroaromatic ring, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or X is -C(=O)-, -C(=O)NCHR 3 -、C 1-6 Alkylene, C 2-6 Alkenylene, C 1-6 Hydroxyalkylene, C 1-6 Alkyleneoxy or C 2-9 Heterocyclylene; Y is a bond, C 1-6 Alkylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(=O)-、C 3-10 Cycloalkylene or C 2-9 Heterocyclylene; R 4 is hydrogen, hydroxyl, amino, thiol, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Mercaptoalkyl, C 6-10 Aryl C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 2-9 Heteroaryl, C 2-9 Heterocyclic group, C 3-10 Carbocyclic group, R 7 C(=O)NR 8 -、R 9 R 10 NC 1-6 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl or C 2-9 Heterocyclic group; R 7 Hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl; R 11 For hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 aryl or heteroaryl; R 12 and R 13 are independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 6-10 Aryl C 1-6 Alkyl, C 2-9 Heteroaryl C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 heteroaryl; L, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 Optionally, 1, 2, 3, 4, 5, 6 identical or different groups selected from deuterium, halogen, hydroxyl, amino, cyano, thiol, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 Cycloalkyl, C 2-9 Heterocyclic group, C 6-10 Aryl or C 2-9 The group is substituted with a substituent of a heteroaryl group.

5. The steroid compound according to claim 1, wherein L is amino, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homocyclopentyl, cyclohexan ... piperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, R 5 R 6 NCH(=N)NR 3 CH(=N)-、-S(=O)2NR 5 R 6 or X is -C(=O)-, -C(=O)NCHR 3 -, methylene, ethylene, propylene, methylmethylene, methyleneoxy, ethyleneoxy, propyleneoxy, methylmethyleneoxy, hydroxymethylene, hydroxyethylene, vinylene, propenylene, 1,3-dioxolanylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothiophenylene, dihydrothiophenylene, 1,3-dioxolanylene, dithiocyclopentylene, tetrahydropyranylene, dihydropyranylene, 2H-pyranylene, 4H-pyranylene, tetrahydrothiopyranylene, piperidinylene, morpholinylene, thiomorpholinylene, piperazinylene, dioxanylene, dithianylene, thioxanylene, homopiperazinylene, homopiperidinylene, oxepanylene or thiepanylene; Y is a bond, methylene, ethylene, propylene, methylmethylene, -OC(=O)O-, -OC(=O)-, -C(=O)O-, -NR 5 C(═O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, 1,3-dioxacyclopentylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothienylene, dihydrothienylene, 1,3-dioxacyclopentylene, dithiocyclopentylene, tetrahydropyranylene, or dihydropyranylene; R 4 is hydrogen, hydroxy, amino, mercapto, cyano, nitro, carboxyl, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxymethoxymethyl, methoxymethoxyethyl, methoxyethoxymethyl, methoxyethoxyethyl, mercaptomethyl, mercaptoethyl, phenylmethyl, phenylethyl, methoxy, ethoxy, isopropoxy, tert-butoxy , phenyl, indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, 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[4,3-b] 1,5-a]pyridinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, R 7 C(=O)NR 8 -、R 9 R 10 NC 1-3 Alkyl, R 11 OS(=O)2-、R 11 OC(=O)CR 12 R 13 -、R 9 R 10 NC(=O)-or R 2 , R 3 , R 5 , R 6 , R 8 , R 9 and R 10 each is independently hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl or thiepanyl; R 7 is hydroxy, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, or isothiazolyl; R 11 , R 12 and R 13 each independently represents hydrogen, methyl, ethyl, isopropyl, propyl, n-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, difluoromethyl, chloroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, phenyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, imidazolylmethyl or imidazoethyl; L, X, Y, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 The present invention is optionally replaced by 1, 2, 3, 4, 5, or 6 identical or different radicals selected from deuterium, F, Cl, Br, hydroxyl, amino, cyano, mercapto, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, trifluoromethyl, tris-difluoromethyl, methoxymethyl, methoxyethyl, ethoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3- -dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, furanyl, imidazolyl, 3-isoxazolyl, isoxazole oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, The 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 substituents are substituted.

6. The steroid compound according to any one of claims 1 to 5, wherein For the following structure fragment:

7. The steroid compound according to any one of claims 1 to 6, wherein The steroidal compound has one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, 8. A pharmaceutical composition comprising the steroid compound according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

9. Use of the steroid compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating, curing or alleviating an eye disease in a patient.

10. The use according to claim 9, wherein the eye disease is cataract, floaters or presbyopia.

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