Use of CYP51 inhibitor in preparation of drug for preventing and / or treating ophthalmic diseases

Abstract

The use of a CYP51 (cytochrome P450 family 51) inhibitor in the preparation of a drug for preventing and / or treating eye diseases.

Description

Use of CYP51 inhibitor in preparation of drug for preventing and / or treating ophthalmic diseases TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical medicine, and particularly relates to use of CYP51 inhibitor in preparation of drug for preventing and / or treating myopia. BACKGROUND

[0002] Lanosterol 14alpha-demethylase (CYP51) is a kind of exogenous terminal oxygenase containing ferriheme and thiol, which was first discovered by Yoshida et al. in 1984 in yeast, is the only one appearing in some bacteria such as Mycobacterium tuberculosis, and is also a cytochrome P450 superfamily protein widely existing in fungi, lower eukaryotes, higher plants and animals, and other biological kingdoms, and participates in the process of steroid hormone synthesis in vivo. CYP51 is a lanosterol demethylase, which is a key enzyme in the cholesterol synthesis pathway. It catalyzes the conversion of lanosterol to cholestanol, which is a key step in the synthesis of cholesterol. CYP51 has three subtypes: CYP51A1, CYP51A2 and CYP51B1. CYP51A1 is the subtype with the highest expression in human body, and mainly exists in tissues such as liver, kidney and intestinal tract. CYP51A2 mainly exists in gonadal tissues such as testis and ovary. CYP51B1 mainly exists in tissues such as skin and hair follicle.

[0003] At present, the most commonly used CYP51 inhibitor in clinical application is azole antifungal drug, such as fluconazole, itraconazole, voriconazole and the like. They are coordinated with the heme-based Fe atom of the target enzyme through the nitrogen atom on the azole ring, so that the heme loses the opportunity to combine with oxygen atom, blocks the hydroxylation reaction of the substrate, and as a result, the synthesis of ergosterol in the fungus is blocked, the membrane chemical composition is changed, the membrane permeability and the activity of many enzymes on the membrane are changed, thereby inhibiting and killing the fungus. At present, CYP51 enzyme inhibitors as target proteins of antibacterial drugs and compounds have attracted great attention of workers in the pharmaceutical chemical industry, and various novel compounds have also been synthesized as CYP51 enzyme inhibitors for the treatment of microbial infections. SUMMARY

[0004] The inventors of the present application accidentally found that CYP51 inhibitors can be used for the prevention or treatment of eye diseases, and thus the present application is proposed.

[0005] In a first aspect, the present application provides use of a CYP51 (cytochrome P450 family 51) inhibitor in preparation of a drug for preventing and / or treating an eye disease, wherein the CYP51 inhibitor is a CYP51A1 inhibitor.

[0006] In a second aspect, the present application provides a method for preventing and / or treating an eye disease, comprising administering to a subject a CYP51 (cytochrome P450 family 51) inhibitor.

[0007] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the eye disease is one or more of cataract, refractive error, or an eye disease associated with neovascularization.

[0008] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the cataract is age-related cataract, congenital cataract, traumatic cataract, or complicated cataract; the refractive error is myopia, presbyopia, astigmatism, or visual fatigue; and the eye disease associated with neovascularization is diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, epidemic keratoconjunctivitis, neovascular glaucoma, heterochromatic corneal dystrophy, limbal keratopathy, pterygium keratopathy, dry eye keratopathy, macular edema, macular degeneration, vitritis, or chronic uveitis.

[0009] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the CYP51A1 inhibitor is a small molecule chemical compound, an antibody, or a nucleic acid molecule.

[0010] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the small molecule chemical compound is one or more of fluconazole, itraconazole, voriconazole, albaconazole, opelconazole (PC945), VT-1598, praconazole, PC-1244, posaconazole, esabconazole, fenticonazole, omocozole, ketoconazole, letrozole, miconazole, clotrimazole, bifonazole, sertaconazole, oterconazole, or pentazoc.

[0011] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the nucleic acid molecule is an antisense nucleic acid molecule (ASO), a small interfering RNA molecule (siRNA), or a short hairpin RNA molecule (shRNA).

[0012] According to some embodiments of the use or method of the first aspect and the second aspect of the present application, the CYP51A1 inhibitor has a structure represented by Formula (I), or a stereoisomer, a tautomer, a nitroso, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound represented by Formula (I),

[0013] n is 2 or 3;

[0014] p is 0, 1, 2, 3, 4, or 5;

[0015] q is 0, 1, 2, 3, or 4;

[0016] X is O or S(=O) t , t is 0, 1 or 2;

[0017] each R 1 is independently halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;

[0018] each R 2 is independently halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;

[0019] R 3 is selected from nitro, -NR 5 R 6 , the is optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxy, halogenated C 1-4 alkyl;

[0020] R 5 is selected from hydrogen or C 1-4 alkyl;

[0021] R 6 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl or -C(=Y)R 7 , wherein Y is O or S;

[0022] R 7 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy or -NR 8 R 9 ;

[0023] R 8 is selected from hydrogen or C 1-4 alkyl;

[0024] R 9 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, R 11 -C(=O)O- or R 11 -C(=O)-;

[0025] R 10 is selected from hydrogen or -C(=O)R 11 ;

[0026] R 11 selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy or amino;

[0027] R 4 selected from hydrogen, C 1-4 alkyl or halogenated C 1-4 alkyl.

[0028] According to some embodiments of the use or method according to the first and second aspects of the application, in formula (I), C 1-4 alkyl is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.

[0029] According to some embodiments of the use or method according to the first and second aspects of the application, in formula (I), the halogen is selected from fluorine, chlorine, bromine and iodine, further preferred are fluorine and chlorine.

[0030] According to some embodiments of the use or method according to the first and second aspects of the application, in formula (I), the halogenated C 1-4 alkyl is trifluoromethyl.

[0031] According to some embodiments of the use or method according to the first and second aspects of the application, the CYP51A1 inhibitor is selected from the following compounds or optical isomers thereof:

[0032] According to some embodiments of the use or method according to the first and second aspects of the application, the CYP51A1 inhibitor is selected from the following compounds:

[0033] The CYP51 inhibitors provided herein can be used in therapy as the chemical agents as such, or as active ingredients of pharmaceutical compositions.

[0034] In a third aspect, the present application provides a use of a composition in the manufacture of a medicament for the prevention and / or treatment of an ophthalmic disease, said composition comprising a CYP51 inhibitor according to the first aspect, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

[0035] In a fourth aspect, the present application provides a method for the prevention and / or treatment of an ophthalmic disease, comprising administering to a subject a composition as defined in the use according to the third aspect.

[0036] Substances which can serve as pharmaceutically-acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, cetostearyl wax, cetyl alcohol, collagen, dextrin, dextran, glycerol, hydrogenated vegetable oil, kaolin, kitosan, light mineral oil, magnesium stearate, mucilage of silicagel, oily esters lentil, paraffin, polyethylene alcohol, polyaerylate, pyrogen-free water, sodium fatty acid, sodium benzoate, sodium pyruvate, sodium chloride, wax, talc, gelatin, sodium chloride, electrolytes (such as zinc), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; 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; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, preservatives and antioxidants.

[0037] In some embodiments of the use or method according to the third and fourth aspects of the application, the dosage form of the composition is selected from the group consisting of a tablet, an eye drop, a pill, a capsule, a powder, a granule, an emulsion, a suspension, a dispersion, a solution, a syrup, an elixir, an ointment, a drop, a suppository, an inhalant, or a spray.

[0038] In some embodiments of the use or method according to the third and fourth aspects of the application, the administration of the drug is selected from the group consisting of oral administration, eye drop administration, sublingual administration, intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, nasal administration, transdermal administration, parenteral administration, inhalation administration, intratracheal administration, intrapulmonary administration, bronchial administration, or a combination thereof.

[0039] In some embodiments of the use or method according to the third and fourth aspects of the application, the single administration of the CYP51A1 inhibitor is at a dose of 1-1000 mg / kg, for example, 1 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 250 mg / kg, 400 mg / kg, 450 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, or 1000 mg / kg.

[0040] In some embodiments of the use or method according to the third and fourth aspects of the application, the medicament further comprises an effective amount of a drug for treating cataract, a drug for treating refractive error, a drug for treating glaucoma, a drug for treating retinal disease, or a drug for treating dry eye disease, or a combination thereof.

[0041] In some embodiments of the use or method according to the third and fourth aspects of the application, the cataract drug is caline.

[0042] In some embodiments of the use or method according to the third and fourth aspects of the application, the drug for treating refractive error is atropine eye drops, NVK-002, OT-101, SYD-101, STN-1012701, Microline, R-19034, CBT-009, STN-1013400, pilocarpine hydrochloride eye drops, phentolamine mesylate, CSF-1, LZN-100, LZN-101, VT-101, ARNV-003, PRX-100, STN-1013600, GLK-302, AGN-242428, NVK-029, netarsudil, rilzabtag, latanoprost, bimatoprost, latanoprost, tafluprost, travoprost, isopropyl unoprostone, latanoprost + timolol, latanoprost + carteolol, tafluprost + timolol, bimatoprost + timolol, brimonidine, brinzolamide, brimonidine + brinzolamide, timolol, betaxolol, latanoprost + netarsudil, omidenepag isopropyl, brimonidine + brinzolamide, dorzolamide + timolol, brinzolamide + timolol, pilocarpine nitrate, brinzolamide, dorzolamide, mitomycin C, cyclosporine, lifitegrast, dexamethasone, loteprednol etabonate, sodium hyaluronate, Vizomitin, rebamipide, dequalium sodium, difluprednate, aflibercept, conbercept, avacincaptad pegol (ARC-1905), ranibizumab, adalimumab, pegcetacoplan (APL-2), TR-09, faricimab, bevacizumab, ocriplasmin, tecfidera, brolucizumab, lanadelumab, ecallantide, seneglinide, infliximab, sucikinumab, eculizumab, belatacept, conatumumab, rituximab, Retinalamin, kinoptin, iptacopan (LNP-023), vorolanib, methotrexate, valerenicline, lidocaine. DETAILED DESCRIPTION

[0043] Definitions and general terms

[0044] Unless otherwise indicated, the terms used in the present application in the specification and claims are intended to have the same meaning as those defined in the following.

[0045] Certain embodiments of the application are now described in detail by referring to the following illustrative figures and their accompanying descriptions. The application is intended to cover all alternatives, modifications and equivalents thereof encompassed by the following claims. Those skilled in the art will recognize that many methods and materials equivalent to those described herein can be used in the practice of the application. Nothing in the present application should be interpreted as a limitation on the scope or spirit of the application. In the event of any inconsistent usages between this document and

[0046] It is further noted that certain features of the application, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable

[0047] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0048] Unless defined otherwise, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The term "consisting" is intended to mean "consisting of," that is, closed, excluding any element not specified. The term "comprising" is intended to mean "comprising of," that is, open, including one or more elements not specified. The term "consisting essentially of" means that the composition, method or process can include additional steps, elements, compounds, compositions of matter, artificial or natural entities etc. that do not materially affect the basic and novel characteristics of the composition, method or process. The use of the negative term "consisting essentially of" does not mean that the positive term "consisting of" is necessarily excluded. The term "consisting of" means that the composition, method or process includes only the elements specified.

[0049] Unless otherwise indicated, the terms "a," "an," and "the" are intended to encompass both singular and plural referents. The terms "a" (or "an"), as well as the terms "one or more" and "at least one" used herein mean "one or more than one," that is, "one or more." For example, "a member" means one or more members, that is, there can be more than one member in the implementation of the described embodiment.

[0050] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0051] The term "subject" as used herein refers to a mammal or other animal. In some embodiments, "subject" refers to a mammal. In some embodiments, "subject" refers to a human (including adults and children).

[0052] The term "comprising" is a open term, which means that it includes what is recited but also anything more.

[0053] "stereoisomers" refers to compounds which have the same chemical constitution but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0054] "diastereomers" refers to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, e.g. HPLC.

[0055] The stereochemical definitions and rules as used herein generally follow S. P. 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.

[0056] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. One specific stereoisomer is the enantiomeric form, and mixtures of such isomers are called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such a racemic mixture has no optical activity.

[0057] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in racemic or enantiomeric excess forms, for example, in the (R)-, (S)-, or (R,S)-configurational forms. In certain embodiments, each asymmetric atom has at least a 50% enantiomeric excess in the (R)- or (S)- configuration, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least an 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0058] Depending on the choice of starting materials and methods, the compounds of the present application can be present in the form of one or more of possible isomers, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms), in the form of geometric isomers, in the form of tautomers, or as mixtures of isomers, such as tautomers. The optically active forms of (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can be in the cis- or trans-configuration.

[0059] Any mixture of stereoisomers can be separated into their individual stereoisomers using standard techniques, such as preparative chromatography.

[0060] Unless otherwise stated, the formulae described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational isomers): for example, R, S configurations about asymmetric carbon, (Z), (E) isomers about double bonds, and (Z), (E) conformational isomers. Thus, individual stereochemical isomers or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers), where possible, of the compounds of the present application are within the scope of the application.

[0061] The term "prodrug" as used herein refers to a compound which 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 enzymatic conversion in the blood or tissue to the parent structure. The prodrug class of compounds of the present invention can be esters, and among the esters that can serve as prodrugs in the present invention are benzoic acid esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A complete discussion of prodrugs is found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium 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 S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0062] Any resulting racemate of an end product or intermediate can be resolved into the individual optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, which are obtained by treatment with the customary resolving agents. The racemates can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, the enantiomers can be prepared by asymmetric synthesis, e.g., 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, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. 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).

[0063] The term "tautomer" or "tautomerism" refers to structural isomers that have different energies and can interconvert by a low energy barrier. If tautomerism is possible (as in solution), a chemical equilibrium of the tautomers can be reached. For example, protontautomer (also known as prototropic tautomer) includes interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversions by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the application are within the scope of the application.

[0064] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are those that are known in the art, as described in Berge et al., J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, and organic acids such as carboxylic acids, sulfonic acids, sulfinic acids, sulfamic acids, and the like, specifically, but not limited to, methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, succinic acid, benzoic acid, succinic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptanoic acid, mandelic acid, 1,2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, carbonic acid, trifluoroacetic acid, glycolic acid, glycollyl sulfonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, malonic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, lactobionic acid, or oxalic acid, or by other methods such as ion exchange procedures, as described in the literature. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, brofenacinate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, 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 can include salts of acidic groups that are formed by appropriate bases, such as alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl)4 salts. The present application also contemplates the quaternary ammonium salts of any group containing N. Water 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, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a basic group, such as halogen, carboxy, sulfate, phosphate, nitrate, C 1-8 sulfonate, and aromatic sulfonate.

[0065] Pharmaceutically acceptable salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlorate, citrate, edisylate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, and trifluoroacetate.

[0066] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0067] 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, subsalicylic acid, and the like.

[0068] "Solvate" of the present application refers to an association or complex of one or more solvent molecules with a compound of the present application. Solvents which form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to the complex where the solvent molecule is water.

[0069] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0070] The term "treat," as used herein with respect to any disease or condition, means, in some embodiments, to ameliorate the disease or condition (i.e., to slow or arrest or reduce the development of the disease or at least one of its clinical symptoms). In other embodiments, "treat" means to alleviate or ameliorate at least one physical parameter, including perhaps not observable by the patient. In other embodiments, "treat" means to mediate a disease or condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treat" means to prevent or delay the onset, occurrence or worsening of a disease or condition.

[0071] Any formula given herein is also intended to represent corresponding structural isomers. For example, if a given formula contains an -CH2- group, it also encompasses the -CH2- group as a +CH2- group. All tautomers are intended to be encompassed by any formula given herein, for example, pyridine, pyridazine, pyrazine, and pyrimidine each represent any tautomer of the foregoing. The present application is intended in all respects to be illustrative and not restrictive. Numerous alternative to the embodiments illustrated herein will be apparent to those skilled in the art in view of the foregoing description. Any and all such alternatives are intended to be encompassed by the present application. Accordingly, the scope of the application is to be limited only by the following claims. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

[0072] In another aspect, the compounds of the present application include isotopically enriched compounds as defined by the present application, for example, those in which a radioisotope is present, such as 3 H, 14 C, and 18 F, or in which a non-radioactive isotope is present, such as 2 H, and 13 C. Such isotopically enriched compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H, or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for patient treatment where isotopic enrichment is medically beneficial. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically-enriched compounds of the application can be prepared by conventional techniques known to those skilled in the art or by the procedures described in the examples and preparations described herein using appropriate isotopically-enriched reagents in place of the non-enriched reagents previously employed.

[0073] Also, the heavier isotopes, particularly deuterium (i.e., 2Substitution of H or D) can provide certain therapeutic advantages that result from, for example, increased metabolic stability, or decreased dosage requirements, or improved therapeutic index. It will be appreciated that deuterium is regarded as a substituent in the compounds of the application. The concentration of such heavier isotopes, particularly deuterium, can be defined in terms of an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of the specified isotope and the natural abundance. If a substituent in a compound of the application is specified to be deuterium, the compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium incorporation at each specified 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) at each specified deuterium atom. The pharmaceutically acceptable solvates of the present application include those in which the solvent can be isotopically substituted, e.g., D2O, acetone-d6, DMSO-d6.

[0074] As used herein, the term "alkyl" means a saturated straight chain or branched chain monovalent hydrocarbon radical of one to twenty carbon atoms, or one to ten carbon atoms, or one to eight carbon atoms, or one to six carbon atoms, or one to four carbon atoms, or one to three carbon atoms, wherein the alkyl group can be independently and optionally substituted with one or more substituents as 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), t-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-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-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 terms "alkyl" and its prefix "alk" as used herein encompass both straight chain and branched chain saturated carbon chains. The term "alkylene" as used herein means a saturated divalent hydrocarbon radical derived from a straight chain or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, examples of which include, but are not limited to, methylene, ethylene, isopropylene, and the like.

[0075] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Examples, without limitation, include methoxy, ethoxy, propyloxy, butyloxy and the like. The alkoxy group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, thiol, nitro and the like.

[0076] The term "halogen" refers to F, Cl, Br or I.

[0077] In order to make the skilled person better understand the technical solutions of the present application, some non-limiting examples are further disclosed below to further illustrate the present application in detail.

[0078] General synthetic procedures

[0079] In general, the compounds of the present application can be prepared by the methods described herein. The following reaction schemes and examples are intended to further illustrate the present application.

[0080] Those skilled in the art will appreciate that the chemical reactions described herein can be performed using conventional techniques, and that the reaction conditions employed in the methods described herein are not critical unless otherwise specified. Unless otherwise specified, the reactions described herein are performed in a solvent or mixture of solvents. The reaction conditions, including the reaction temperature and the reaction time, are not critical and can be readily determined by the skilled artisan. The reaction conditions can be adjusted according to the reactivity of the particular reactants used.

[0081] Unless otherwise indicated, all temperatures are in degrees Celsius. 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. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoguyu Chemicals Co. Ltd., Qingdao Tenglong Chemical Reagent Co. Ltd., and Qingdao Haoyang Chemical Factory.

[0082] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal by reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride by reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used after drying over anhydrous sodium sulfate.

[0083] The following reactions are generally run under a positive pressure of nitrogen or argon or under anhydrous conditions in a dry box (unless otherwise noted), reaction vessels are fitted with a suitable rubber septum and substrates are introduced via syringe. Glassware is oven- or flame-dried.

[0084] Chromatography columns are run using silica gel. Silica gel (300-400 mesh) is purchased from Qingdao Ocean Chemical Factory. NMR spectra are reported in ppm using CDC13, d6-DMSO, CD3OD or d6-acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiplets occur, 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).

[0085] The following abbreviations will be used throughout this application:

[0086] AcOH: acetic acid; Boc20, BOC anhydride: di-tert-butyl dicarbonate; Boc: tert- butyloxycarbonyl; Bu4NHS04: tetrabutylammonium hydrogen sulfate; CH3CN: acetonitrile; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; HC1: hydrogen chloride; HC1 / EA: hydrogen chloride in ethyl acetate; H20: water; NaOH: sodium hydroxide; Nal: sodium iodide; K2C03: potassium carbonate; rt, r.t.: room temperature; PE: petroleum ether; THF: tetrahydrofuran; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; TBAI: tetrabutylammonium iodide; DMF: dimethylformamide; p-TsOH: p-toluenesulfonic acid; TFA: trifluoroacetic acid; TBAF: tetrabutylammonium fluoride.

[0087] Example 1, synthesis of compound 1

[0088] 4-((((2S,4S)-2-((1H-imidazol-1-yl)methyl)-2-(4-chlorophenethyl)-1,3-dioxolan-4- yl)methyl)thio)aniline (compound 1)

[0089] First step, 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)butan-2-one

[0090] In a 500 mL round bottom flask, compound 1a (10.0 g, 39.88 mmol) was dissolved in DCM (200 mL), cooled to 0 °C, then added Dess-Martin Oxidizing Reagent (50.75 g, 119.65 mmol) in batches, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction was quenched by adding pure water, and the liquid was separated. The aqueous phase was extracted with dichloromethane (3 * 100 mL), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound 1b, a white solid (8.0 g). LC-MS m / z (ESI) = 249.07 [M+H] + .

[0091] Second step: ((4S)-2-((1H-imidazol-1-yl)methyl)-2-(4-chlorophenethyl)-1,3-dioxolan-4- yl)methyl-4-methylbenzenesulfonate

[0092] In a 250 mL round bottom flask, compound 1b (8.0 g, 32.17 mmol) was dissolved in toluene (80 mL), followed by the addition of compound 1c (9.21 g, 32.17 mmol) and methane sulfonic acid (927 mg, 9.65 mmol), and the resulting solution was directly heated to reflux for 16 hours. After the reaction was completed, the reaction liquid was directly concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1d, a white solid (8.0 g). LC-MS m / z (ESI) = 477.12 [M+H] + .

[0093] Third step: 4-((((4S)-2-((1H-imidazol-1-yl)methyl)-2-(4-chlorophenethyl)-1,3-dioxolan-4- yl)methyl)thio)aniline

[0094] In a 250 mL round bottom flask, compound 1d (8.0 g, 16.77 mmol) was dissolved in anhydrous acetone (160 mL), followed by the sequential addition of compound 1e (4.2 g, 33.54 mmol) and potassium carbonate (4.64 g, 33.54 mmol), and the reaction liquid was directly heated to reflux overnight. After the reaction was completed, the reaction liquid was directly concentrated to dryness to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1f, a white solid (6.0 g). LC-MS m / z (ESI) = 430.13 [M+H] + .

[0095] Fourth step: 4-((((2S,4S)-2-((1H-imidazol-1-yl)methyl)-2-(4-chlorophenethyl)-1,3-dioxolan-4- yl)methyl)thio)aniline (compound 1)

[0096] Compound 1f (6.0 g) was subjected to high performance liquid preparation separation to obtain compound 1, white solid (1.5 g). LC-MS m / z (ESI) = 430.13 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.33 (d, 2H), 7.21 (d, 2H), 7.12 (d, 2H), 7.08 (s, 1H), 6.88 (s, 1H), 6.53 (d, 2H), 5.32 (s, 2H), 4.17 (d, 2H), 4.12 - 4.04 (m, 2H), 3.53 - 3.39 (m, 1H), 3.13 (t, 1H), 2.77 (dd, 1H), 2.61 (t, 2H), 1.77 (dd, 2H) ppm.

[0097] Examples 2-111 were synthesized according to the procedure of Example 1, wherein compound 1a and compound 1e were replaced with the corresponding other alcohol and other substituted phenol (thiol).

[0098] Examples 112 & 113, synthesis of compound 112 and compound 113

[0099] In a 250 mL round-bottom flask, compound 1 (3.0 g, 6.98 mmol) was dissolved in a mixture of water and methanol (60 mL, v / v = 1:1), followed by the addition of potassium monopersulfate (7.25 g, 20.93 mmol) in batches, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was directly diluted with 100 mL of water, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and then dried and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 112, white solid (0.8 g, LC-MS m / z (ESI) = 446.12 [M+H] + ); and compound 113, white solid (1.5 g, LC-MS m / z (ESI) = 462.12 [M+H] + ).

[0100] Examples 114-129 were synthesized following the procedure of Examples 112 & 113 to synthesize the corresponding sulfone and sulfoxide.

[0101] Example 130, synthesis of compound 130

[0102] In a 50 mL round bottom flask, compound 1 (1.0 g, 2.33 mmol) was dissolved in ethanol (20 mL), followed by dropwise addition of hydrochloric acid solution (5 mL, 1 M), and the reaction was refluxed for 1 hour. The reaction was allowed to cool to room temperature, and a solid precipitated, which was directly filtered. The filter cake was washed with a small amount of ethanol, and the solid was collected and dried under vacuum to give compound 130 as a white solid (1.0 g).

[0103] Examples 131-160 were synthesized following the procedure of Example 130 to synthesize the corresponding salts. In these examples, hydrochloric acid was replaced by the corresponding acid.

[0104] Biological Example 1: Oral bioavailability of the drug

[0105] This method was used to evaluate the pharmacokinetic characteristics of the compounds in vivo by detecting the drug content at different time points after administration to mice. Six C57 / 6j mice (male, 4-6 weeks old) were placed in the animal room for 3 days of acclimation before use.

[0106] A certain amount of compound was weighed, and a corresponding solvent (oral: 0.5% MC; intravenous: DMSO: 30% HP-β-CD = 10:90) was used to prepare a corresponding compound solution. Three mice were each orally administered 10 mg / kg of the compound, and micro blood samples were taken at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Three mice were each injected intravenously with 1 mg / kg of the compound, and micro blood samples were taken at 0 h, 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 6 h, and 24 h after administration. LC-MS / MS was used to detect the drug content in the plasma of each sample. Pharmacokinetic parameters and bioavailability were calculated using WinNonlin. The results are shown in Table 1 below.

[0107] Table 1

[0108] The results show that the compounds of the present application can be well absorbed by mice through oral administration.

[0109] Biological Example 2: Effect of the drug on the content of sterols

[0110] The method assesses the potential efficacy of the compound in vivo by detecting the change of the content of sterol compounds in the body of mice after continuous administration. Five C57 / 6j mice (male, 4-6 weeks old) are placed in the animal room for 3 days of adaptation and then reserved. A certain amount of compound is weighed and configured into a compound suspension solution using 0.5% MC. After 7 days of continuous oral administration (50 mpk, QD), 50 μL of blood is collected from the eye socket, and the plasma is separated; then the mice are euthanized, and the bilateral eyeballs are collected. The contents of lanosterol, dihydrolanosterol, dihydrocholesterol and cholesterol in the plasma and eyeballs are detected using LC-MS / MS. The results are shown in Table 2.

[0111] Table 2

[0112] The results show that the compound of the present application can significantly reduce the content of endogenous cholesterol in the plasma and eyeballs of mice, and at the same time increase the content of lanosterol, dihydrolanosterol and dihydrocholesterol in the plasma and eyeballs.

[0113] Biological Example 3: Cell lens protein aggregation test

[0114] This example aims to evaluate the inhibition of lens protein aggregation by the compound by detecting the aggregation level of lens protein cryAA in cells. HLE-B3 cells (purchased from ATCC) are inoculated into a 6-well plate (2 coverslips are placed in each well) at 1×104 cells per well. After 24 h of inoculation, the pcDNA3.1-Flag-cryAAY118D plasmid is transfected using lipofectamine 3000; 4 h after transfection, the transfection reagent is removed, and then 20 μM of the compound and 100 mM of hydrogen peroxide are added to each well for co-incubation for 48 h. The culture medium is discarded, and 1 mL of 4% paraformaldehyde is added for fixation, followed by incubation with rabbit anti-Flag primary antibody and goat anti-rabbit IgG Alexa Fluor 488 secondary antibody. The number of fluorescent cells and the number of protein aggregates in each well are analyzed by fluorescence microscopy. The number of aggregated cells in the well without the compound is taken as 100%, and the effect of each compound on the number of intracellular aggregates (inhibition rate, %) is calculated. The results are shown in Table 3.

[0115] Table 3

[0116] The results show that the compound of the present application can significantly reduce the aggregation degree of lens protein in cells, and has potential application in the treatment of cataract.

[0117] The method is used for evaluating the improvement effect of the compound on cataract by inducing the cataract model of rats with sodium selenite. 7-day-old (P7) SD rat pups are randomly divided into a dosing group and a model control group (5 rats / group), the model group is orally administered (25mpk, 0.5% MC solvent), and the control group is orally administered 0.5% MC; the administration is continuously performed for 4 weeks. After 3 days of administration (P10), a single subcutaneous injection of 20 μM / kg sodium selenite solution (dissolved in normal saline) is performed, and the blank control group is subcutaneously injected with 0.25 mL of normal saline. (1) Starting from P14, the cataract level is evaluated once a week by a slit lamp to evaluate the improvement level of the drug on cataract. The evaluation score standard is as follows: 0 points: no turbidity; 1 point: mild turbidity (initial stage); 2 points: the lens is basically turbid (immature stage); 3 points: the whole lens is completely turbid (mature stage). (2) On the last day of the experiment, the lenses of the rats in each group are dissected and separated, placed on a grid paper, photographed, and analyzed for lens transparency. (3) The lenses of the rats in each group are homogenized, and the glutathione peroxidase (GSH-PX) activity is analyzed and detected, and the lanosterol content in the lens is analyzed. The results are shown in Table 4

[0118] Table 4

[0119] The results show that the compound of the present application can significantly reduce the cataract score of rats in the sodium selenite-induced rat cataract model, and has the potential for treating cataract.

[0120] Although the present application has been described in detail above with general description, specific embodiments and experiments, some modifications or improvements can be made on the basis of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the present application, all belong to the scope of the present application claimed.

Claims

1. Use of a CYP51 (Cytochrome P450 Family 51) inhibitor, which is a CYP51A1 inhibitor, in the manufacture of a medicament for preventing and / or treating an ocular disease.

2. A method for preventing and / or treating an ocular disease, comprising administering to a subject a CYP51 (Cytochrome P450 Family 51) inhibitor.

3. The use or method of claim 1 or 2, wherein, The ocular disease is one or more of cataract, refractive error or ocular disease associated with neovascularization.

4. The use or method of claim 3, wherein, The cataract is one or more of age-related cataract, congenital cataract, traumatic cataract or complicated cataract; the refractive error is one or more of myopia, presbyopia, astigmatism or visual fatigue; the ocular disease associated with neovascularization is one or more of diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, epidemic keratoconjunctivitis, neovascular glaucoma, heterochromatic corneal dystrophy, limbal keratopathy, pterygium keratopathy, dry eye keratopathy, macular edema, macular degeneration, vitreitis or chronic uveitis.

5. The use or method according to claim 1 or 2, wherein, The CYP51A1 inhibitor is a small chemical molecule, an antibody or a nucleic acid molecule; the small molecule is one or more of fluconazole, itraconazole, voriconazole, posaconazole, albaconazole, efmaconazole, opelconazole (PC945), VT-1598, praconazole, PC-1244, fenticonazole, omoconazole, ketoconazole, letrozole, miconazole, clotrimazole, bifonazole, sertaconazole, oterconazole or pentanoconazole; the nucleic acid molecule is an antisense oligonucleotide (ASO), a small interfering RNA molecule (siRNA) or a short hairpin RNA molecule (shRNA).

6. The use or method according to claim 1 or 2, wherein, The CYP51A1 inhibitor has a structure shown in Formula (I), or a stereoisomer, a tautomer, a nitroso, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound having a structure shown in Formula (I), n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3 or 4; X is O or S(=O) t t is 0, 1 or 2; Each R 1 Independent of halogen, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; Each R 2 Independent of halogen, C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; R 3 selected from nitro, -NR 5 R 6 、 The optionally substituted by one or more substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxy, haloC 1-4 alkyl; R 5 selected from hydrogen or C 1-4 alkyl; R 6 selected from hydrogen, C 1-4 alkyl, C 1-4 alkylsulfonyl or -C(=Y)R 7 wherein Y is O or S; R 7 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy or -NR 8 R 9 ; R 8 selected from hydrogen or C 1-4 alkyl; R 9 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, R 11 -C(=O)O- or R 11 -C(=O)-; R 10 selected from hydrogen or -C(=O)R 11 ; R 11 selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy or amino; R 4 selected from hydrogen, C 1-4 alkyl or haloC 1-4 alkyl; Preferably, the halogen is selected from fluorine, chlorine, bromine and iodine, further preferably fluorine and chlorine. Preferably, said halogenated C 1-4 alkyl is trifluoromethyl.

7. The use or method according to claim 1 or 2, wherein, The CYP51A1 inhibitor is selected from the following compounds or optical isomers thereof:

8. The use or method according to claim 1 or 2, wherein, The CYP51A1 inhibitor is selected from the following compounds:

9. Use of a composition in the manufacture of a medicament for preventing and / or treating an ocular disease, wherein the composition comprises a CYP51A1 inhibitor as defined in the use or method of any one of claims 1-8, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.

10. A method for preventing and / or treating an ocular disease, comprising administering to a subject a composition as defined in the use of claim 9.

11. Use or method according to claim 9 or 10, wherein, The dosage form of the composition is selected from a tablet, eye drops, a pill, a capsule, a powder, a granule, an emulsion, a suspension, a dispersion, a solution, a syrup, an elixir, an ointment, a drop, a suppository, an inhalant or a spray.

12. The use or method of any one of claims 1-11, wherein, The administration of the medicament is selected from oral administration, eye drop administration, sublingual administration, intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, nasal administration, transdermal administration, parenteral administration, inhalation administration, intratracheal administration, intrapulmonary administration, bronchial administration or a combination thereof; and / or, the dose of the CYP51A1 inhibitor administered in a single administration of the medicament is 1-1000 mg / kg.

13. The use or method according to any one of claims 1 to 12, further comprising an effective amount of a drug or combination thereof for treating an ocular disease such as cataract, refractive error, glaucoma, dry eye, retinal disease, or the like.

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