Steroid compound and medical use thereof

Abstract

The present invention relates to a steroid compound and a medical use thereof, wherein the steroid compound has a structure as represented by formula (I'), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, pharmaceutically acceptable salts or a prodrug having a structure represented by formula (I'). The steroid compound provided by the present invention can be used for preparing a drug for preventing, handling, treating or mitigating eye diseases of patients.

Description

Steroid compound and medical use thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a steroid compound and medical use thereof. BACKGROUND

[0002] Cataract belongs to eye diseases, and occurs on the lens in the eyeball. The turbidity of the lens is collectively referred to as cataract. Aging, heredity, metabolic abnormalities, trauma, radiation, poisoning and local malnutrition can cause damage to the lens capsule, increase the permeability of the lens capsule, lose the barrier function, or cause metabolic disorders of the lens, so that the lens protein is denatured to form turbidity. If the lens of the eyeball changes from transparent to opaque and affects the eye to receive sunlight, the eyesight of the eye will be affected. When the turbidity of the eyeball is light, the effect on the eyesight is light, and as the degree of turbidity gradually deepens, the eyesight will also increase, and the severe case will lead to blindness. Cataract is one of the most common blinding eye diseases, and it is the main factor leading to blindness. Since the mechanism of cataract formation is not clear, no breakthrough has been made in drug treatment so far.

[0003] The treatment drugs for cataract in clinic include: ① aldehyde sugar reductase inhibitors, such as cathalin (cathalin, calin, and baijingsheng), falcogen, and benzyl daidzein; ② antioxidant damage drugs, such as glutathione, taurine, and aspirin; ③ nutritional metabolism drugs, such as vitamins and carotenoids; and ④ traditional Chinese medicine compounds, including shihujiaoyuan pill, qijujiang pill, and shijueming powder. However, long-term clinical trials have proved that these drugs for treating cataract can only delay the deterioration of cataract, and cannot reverse the disease.

[0004] Therefore, more safe, effective, strong intraocular penetration, and stable property new ophthalmic external anti-cataract drugs are needed in clinic. SUMMARY

[0005] To solve one of the above technical problems in the prior art, the present application provides a new steroid compound and medical use thereof.

[0006] In a first aspect, the present application provides a steroid compound having a structure as shown in formula (I'), or a stereoisomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure shown in formula (I'),

[0007] wherein R 2 is

[0008] R 3 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, -OR6 or -NR 5 R 6

[0009] R 4 R 7 (O-R 8 ) n

[0010] R 5 R 6 each independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=0)-alkyl, monophospho, or diphospho;

[0011] R 7 hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclyl;

[0012] R 8 alkylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene, or heteroarylene;

[0013] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;

[0014] wherein the alkylene, alkenylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene, heteroarylene, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, or phosphorus-containing heterocyclyl in R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkyloxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl, and heteroaryl;

[0015] R 10 is selected from

[0016] R a , R b , R c , R d , R e , R f , R g , R h , R i and R​​j each independently alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkylthio, halo- or hydroxy-substituted alkylthio, alkylamino, halo- or hydroxy-substituted alkylthio, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, or alkynyl;

[0017] R x halogen, hydroxyl, amino, alkyl, carboxyl, phosphato, sulfato, or alkoxy;

[0018] the hydrogen atoms on ring A, ring B, ring C, and ring D are unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

[0019] In some embodiments, the steroid compound has a structure according to Formula (I’-1) or Formula (I’-2), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (I’-1) or Formula (I’-2),

[0020] In Formula (I’-1) and Formula (I’-2), R 2 , R a , R b , R c , R d , R e , R f , and ring A, ring B, ring C, and ring D are as defined in Formula (I’).

[0021] In some embodiments, the steroid compound has a structure according to Formula (I-1), Formula (I-2), Formula (II-1), or Formula (II-2), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (I-1), Formula (I-2), Formula (II-1), or Formula (II-2),

[0022] In Formula (I-1), Formula (I-2), Formula (II-1), and Formula (II-2), R 1 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclyl; R2 The definition is the same as that in the aforementioned equation (I').

[0023] In some implementations, in equations (I-1), (I-2), (II-1), and (II-2), R 1 It can be hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or C 1-9 Heterocyclic group.

[0024] In some implementations, in equations (I-1), (I-2), (II-1), and (II-2), R 1 Hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl.

[0025] In other embodiments, in equations (I-1), (I-2), (II-1), and (II-2), R 1 It is hydrogen.

[0026] In other embodiments, in equations (I-1), (I-2), (II-1), and (II-2), R 1 C groups substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or fluorine. 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, or thiaalkyl.

[0027] In some embodiments, R in the steroidal compound 3 For hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, -OR 6 or -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 1-6 alkylene-OC(=O)-C 1-6 alkyl, monophosphate or diphosphate.

[0028] In some embodiments, the steroid compound is one in which R 3 is hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-butoxy, isopropoxy, methoxymethyl, fluorosubstituted C 1-3 alkyl, chlorosubstituted C 1-3 alkyl, -OR 6 or -NR 5 R 6 ;

[0029] R 5 and R 6 are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-butoxy, isopropoxy, methoxymethyl fluorosubstituted C 1-3 alkyl, chlorosubstituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 alkylene-OC(=O)-C 1-3 alkyl, monophosphate or diphosphate.

[0030] In some embodiments, the steroid compound is one in which R 3 is -OR 6 or -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C3-10 cycloalkyl, C 1-6 alkylene-OC(=O)-C 1-6 alkyl, monophosphate or diphosphate.

[0031] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0032] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0033] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 is hydrogen, R 6 is C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0034] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-3 alkylene-OC(=O)-C 1-3 alkyl.

[0035] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 and R 6 are each independently hydrogen, C 1-3 alkylene-OC(=O)-C 1-3 alkyl.

[0036] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R5 is hydrogen, R 6 is C 1-3 alkylene-OC(=0)-C 1-3 alkyl.

[0037] In some embodiments, the steroid compound is one in which R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or C 1-9 heterocyclyl; R 8 is C 1-6 alkylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0038] In some embodiments, the steroid compound is one in which R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen, C 1-6 alkyl; R 8 is C 1-6 alkylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0039] In some embodiments, the steroid compound is one in which R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen, deuterium, C 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl), vinyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkyl, or C 3-8 cycloalkyl; R 8 is C 1-3 alkylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0040] In other embodiments, the steroid compound has the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), 4 R 7 (O-R 8 ) n -; R 7 is hydrogen, C 1-4 alkyl; R 8 is C 1-3 alkylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0041] In other embodiments, the steroid compound has the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), 4 R 7 (O-R 8 ) n -; R 7 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or t-butyl; R 8 is C 1-3 alkylene; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0042] In other embodiments, the steroid compound has the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII),

[0043] wherein R 4 is R 7 (O-C 1-6 alkylene) n -;

[0044] R 5 and R 6 are each independently hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 1-6 alkylene-OC(=O)-C 1-6 alkyl, monophosphate, or diphosphate; R 7 is hydrogen, deuterium, C1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or C 1-9 heterocyclyl; n is 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0045] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen or C 1-6 alkyl; R 8 is C 1-6 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0046] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen or C 1-4 alkyl, R 8 is C 1-3 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4 is R 7 (O-R 8 ) n -; R 7 is hydrogen or C 1-4 alkyl, R 8 is C 1-3 alkylene; n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0047] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6alkyl. In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 5 is hydrogen, R 6 is C 1-6 alkylene-OC(=0)-C 1-6 alkyl.

[0048] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 5 and R 6 are each independently hydrogen, C 1-3 alkylene-OC(=0)-C 1-3 alkyl. In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 5 is hydrogen, R 6 is C 1-3 alkylene-OC(=0)-C 1-3 alkyl.

[0049] In other embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4 is R 7 (O-C 1-3 alkylene) n -; R 5 and R 6 are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-butoxy, isopropoxy, methoxymethylfluoro-substituted C 1-3 alkyl, chloro-substituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 alkylene-OC(=0)-C 1-3 alkyl, monophosphate, or diphosphate; R 7 is hydrogen, deuterium, C 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl), vinyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkyl, or C 3-8 cycloalkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0050] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII), R 4 is R 7 (O-R 8 ) n -; R 5 is hydrogen, R 6 is C 1-6 alkylene-OC(=O)-C 1-6 alkyl; R 7 is hydrogen or C 1-6 alkyl; R 8 is C 1-6 alkylene, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0051] In some embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII) and formula (VIII), R 4 is R 7 (O-R 8 ) n -; R 5 is hydrogen, R 6 is C 1-3 alkylene-OC(=O)-C 1-3 alkyl, R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or t-butyl, R 8 is methylene, ethylene or propylene, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0052] In some embodiments, the steroid compound has one of the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0053] In a second aspect, the present application provides a pharmaceutical composition comprising the steroid compound described above, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.

[0054] In a third aspect, the present application provides use of the steroid compound or the pharmaceutical composition described above in the manufacture of a medicament for preventing, managing, treating or alleviating an ocular disease in a patient.

[0055] In some embodiments, the ocular disease comprises at least one of cataract, floaters, myopia and presbyopia.

[0056] The foregoing summary only illustrates certain aspects of the application and is not intended to define an application scope in any way. The only application scope is defined by the claims below. DETAILED DESCRIPTION

[0057] Certain embodiments of the application are now described in detail by referring to the following illustrative figures and examples. Examples of the application are illustrated by the structural formulas and chemical schemes set forth below. The application is intended to encompass all alternatives, modifications and equivalents, which can be included within the scope of the application as defined by the claims. One skilled in the art will recognize many methods and materials as being suitable for use in practicing the application. No method or material is intended to be disclaimed apart from what is defined by the claims. In the event that one or more

[0058] It should be further recognized that certain of the application's features are described in separate embodiments for clarity but can also be provided in combination in a single embodiment. Conversely, the various features of the application are described in a single embodiment for brevity but can also be provided separately or in any suitable subcombination.

[0059] Definitions and General Terminology

[0060] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Unless otherwise indicated, all patents and publications referred to are incorporated by reference.

[0061] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Unless otherwise indicated, all patents and publications referred to are incorporated by reference.

[0062] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Unless otherwise indicated, all patents and publications referred to are incorporated by reference.

[0063] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "one or more") of the grammatical object of the article. By way of example, "an element" means one or more elements, and thus, possibly, more than one element is contemplated and can be employed.

[0064] 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.

[0065] The term "comprising" is a open term, i.e., it includes what the claims recite but not excluding other items.

[0066] "stereoisomers" refers to compounds which have a different spatial arrangement of atoms but possess the same chemical composition. A stereoisomer includes enantiomeric, diastereomeric, conformational (rotameric), geometric (syn / anti), atropisomeric, and the like.

[0067] "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.

[0068] The stereochemical definitions and conventions 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.

[0069] 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 one or more chiral centers. The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound, which is dextrorotatory, has the prefix (+) or d. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which occurs when there has been no stereocontrol in a chemical reaction or process.

[0070] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in a racemic or enantiomeric enriched form, e.g., in the (R)-, (S)-, or (R,S)-configurational form. 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.

[0071] Depending on the choice of starting materials and methods, the compounds of the present application can be synthesized as one of the possible isomers or a mixture of them, such as, for example, in the form of racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms (in case of a racemate, two asymmetric carbon atoms; in case of a diastereomeric mixture, more than two asymmetric carbon atoms). The optically active (R)- or (S)-isomers can be obtained by optical resolution of the racemates using conventional techniques, or by synthesis using chiral synthons or chiral reagents. If a compound contains a double bond, the substituents can be in the E or Z configuration; if a compound contains a disubstituted cycloalkyl, the substituents on the cycloalkyl can be in the cis or trans configuration.

[0072] Any mixture of stereoisomers of the compounds can be separated into their individual components by conventional techniques, such as HPLC or fractional crystallization.

[0073] Unless otherwise stated, the formulae described herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational isomers): e.g., R, S configurations about asymmetric carbon atoms, (Z), (E) isomers about double bonds, and (Z), (E) conformational isomers. Accordingly, the present application includes a single stereochemical isomer of a steroid compound of the present application or a mixture of its enantiomeric, diastereomeric, or geometric (or conformational) isomers.

[0074] 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.

[0075] Any resulting racemate of an end product or intermediate can be resolved into the separate optical antipodes by known methods, e.g., by separation of the racemate into its diastereomeric salts by means of a salt-forming reagent, e.g., an optically active chiral acid, and separating the diastereomeric salts thus formed into their respective constituent parts by a suitable means such as partitioning in a partitioning system. The racemate can also be resolved by chromatographic means using chiral sorbents. In particular, the 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, 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).

[0076] 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.

[0077] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are those that are well 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 acid salts such as carboxylic acid salts, sulfonic acid salts, sulfinic acid salts, sulfamic acid salts, and the like, specifically, but not limited to, methanesulfonic acid salts, ethanesulfonic acid salts, formic acid salts, acetic acid salts, succinic acid salts, benzoic acid salts, succinic acid salts, pamoic acid salts, salicylic acid salts, galactaric acid salts, glucoheptanoic acid salts, mandelic acid salts, 1,2-ethanedisulfonic acid salts, 2-naphthalenesulfonic acid salts, carbonic acid salts, trifluoroacetic acid salts, glycolic acid salts, glycolylethylsulfonic acid salts, oxalic acid salts, maleic acid salts, tartaric acid salts, citric acid salts, malonic acid salts, benzenesulfonic acid salts, p-toluenesulfonic acid salts, malic acid salts, fumaric acid salts, lactic acid salts, lactobionic acid salts, or oxalic acids, or by other methods such as ion exchange procedures as art-known. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, bromoate, 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 salts, and the like. Furthermore, 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.

[0078] Pharmaceutically acceptable salts can be formed with inorganic acids and organic acids, for example acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlorobenzoate, citrate, ethandisulfonate, 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, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0079] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0080] 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.

[0081] "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 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 the complex where the solvent molecule is water.

[0082] The term "protecting group" or "PG" refers to a substituent that is commonly employed to block or protect the functionality of a particular group while undergoing a reaction elsewhere in the molecule. For example, "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the functionality of the amino group while other transformations are carried out elsewhere on the molecule. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the functionality of the hydroxy group while other transformations are carried out elsewhere on the molecule. Suitable protecting groups for hydroxyl include acetyl and silyl. "Carboxy-protecting group" refers to a substituent of a carboxylic acid group that blocks or protects the functionality of the carboxylic acid group while other transformations are carried out elsewhere on the molecule. Typical carboxy-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, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0083] "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.

[0084] The term "treat," "treating" or "treatment" of any disease or disorder, as used herein in some embodiments, means to ameliorate the disease or disorder (i.e., to slow or arrest or reduce the development of the disease or at least one of the clinical symptoms thereof). In other embodiments, "treat," "treating" or "treatment" means to alleviate or ameliorate at least one physical parameter including those not discernible by the patient. In other embodiments, "treat," "treating" or "treatment" means to mediate or modulate a disease or disorder either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treat," "treating" or "treatment" means to prevent or delay the onset or development of a disease or disorder.

[0085] Any formula given herein is also intended to represent unlabelled forms as well as isotopically enriched forms of the compounds. Isotopically enriched compounds have the same structure as those depicted by the formulas given herein, but contain one or more isotopically enriched atoms. Exemplary isotopes which can be 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.

[0086] In another aspect, the compounds according to the application include isotopically enriched compounds as defined by the 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 therapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically-enriched compounds of Formula (I'), (I'-1), (I'-2), (I-1), (I-2), (II-1), (II-2), (III), (IV), (V), (VI), (VII), (VIII) can be prepared by conventional techniques known to those skilled in the art or by the

[0087] In addition, the heavier isotope, particularly deuterium (i.e., 2Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is believed that deuterium in the present application is regarded as a substituent of a compound of formula (I). 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 of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor at each indicated deuterium atom of at least 3500 (52.5% deuterium incorporation at each indicated 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) for each specified deuterium atom. Pharmaceutically acceptable solvates of the present application include those in which the solvent can be isotopically substituted, e.g., D2O, acetone-d6, DMSO-d6.

[0088] As described herein, the compounds of the present application can be optionally substituted with one or more substituents, as in the general formula above, or as in the specific examples, subgeneric classes, and generic classes of compounds embraced by the present application. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" whether applied to a term used in, before, or after the term "substituted" means that one or more hydrogen atoms of the named moiety are replaced by a particular substituent. Unless otherwise indicated, a single optional substituent group can have a substituent at each substitutable position of the group. Where more than one position in the given structure can be substituted with one or more substituents selected from a specified group, the substituents can be the same or different at each position. The substituents described herein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, heteroaryloxy, oxo (=0), carboxyl, hydroxyl-substituted alkoxy, hydroxyl-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxyl-substituted alkyl-S(=0), hydroxyl-substituted alkyl-S(=0)2, carboxylalkoxy, and the like.

[0089] The term "alkyl" as used herein denotes a saturated straight or branched chain monovalent hydrocarbon radical of from 1 to 20 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms, or from 1 to 3 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 denotes 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. In the present application, reference to an alkylene group means a divalent group formed by the removal of one hydrogen atom from an alkyl group.

[0090] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the parent chain through an oxygen atom. Examples include, but are not limited to, 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, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, thiol, nitro, and the like. In this application, the term "alkyleneoxy" refers to an alkoxy group further losing one hydrogen atom to form a divalent radical.

[0091] The term "alkenyl" denotes a straight-chain or branched-chain monovalent hydrocarbon group having from 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including the positioning of the group as "trans", "cis", or "E", "Z". Specific examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. In this application, the term "alkenylene" refers to an alkenyl group further losing one hydrogen atom to form a divalent radical.

[0092] The term "alkynyl" denotes a straight-chain or branched-chain monovalent hydrocarbon group having from 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one C-C is an sp3 triple bond, wherein the alkynyl group can be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and the like.

[0093] The term "cycloalkyl" or "carbocyclic" refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including monocyclic rings having 3 to 12 carbon atoms or bicyclic rings having 7 to 12 carbon atoms. Bicyclic carbocyclic rings having 7 to 12 atoms can be bicyclo[4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocyclic rings having 9 or 10 atoms can be bicyclo[5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of cyclic aliphatic groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1- enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Also, the "cyclic aliphatic" or "carbocyclic", "carbocyclyl", "cycloalkyl" groups can be substituted or unsubstituted, where the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy and the like. In the present application, reference to cycloalkenyl refers to a divalent group formed by the further loss of a hydrogen atom from a cycloalkyl group.

[0094] The terms "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" are used interchangeably herein and refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms independently and optionally are replaced by heteroatoms having the meaning as described herein, the ring can be fully saturated or contain one or more degrees of unsaturation, but is not aromatic, and there is only one point of attachment to the rest of the molecule. One or more rings can independently and optionally be substituted with one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" group is a 3-7 membered monocyclic ring (having 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P are optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, when the ring is a three membered ring, wherein only one of the heteroatoms is present) 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 are optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0095] Heterocyclic groups can be carbonyl or heteroatomyl. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, aziridine, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, aziridineheptyl, oxacycloheptyl, thiohexacycloheptyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxacyclobutyl... 2-diaza Base, sulfur nitrogen 1-pyrrololin-1-yl, 2-pyrrololin-3-pyrrololin-1-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl) acetone-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]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridin-5-yl, 3H-indolyl-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinide groups. The heterocyclic group can be substituted or unsubstituted, and the substituents can be, but are not limited to, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O)2, carboxyalkoxy, etc. In this application, the subheterocyclic group refers to a divalent group formed by further losing a hydrogen atom from a heterocyclic group.

[0096] The term "aryl" or "aromatic ring" can be used alone or as part of "aralkyl", "aralkoxy" or "aryloxyalkyl" and refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing in total 6 to 14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" as an aromatic ring can include phenyl, naphthyl and anthryl groups. Also, the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, 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.

[0097] The term "heteroaryl" or "heteroaromatic ring" refers to monocyclic, bicyclic, and tricyclic ring systems containing in total 5 to 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 meaning as described herein, wherein each ring system contains 3 to 7 ring members, and only one attachment point to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". Also, the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like. In the present application, reference to aryl groups also refers to aryl groups further loosing one hydrogen atom to form a divalent radical.

[0098] In other embodiments, the heteroaryl group includes, but is not limited to, the following 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 (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl. Also included are the following bicyclic rings, but are not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), benzo[d]thiazol-2-yl, imidazo[l,5-a]pyridin-6-yl. In the present application, reference to a heteroaryl group is intended to refer to the divalent radical formed by the removal of one hydrogen atom from a heteroaromatic ring.

[0099] The term "heteroatom" means one or more O, S, N, P and Si atoms, including forms of N, S and P in any oxidation state; primary, secondary, tertiary, and quaternary amines and amine salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced by a substituent, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[0100] The term "halogen" means F, Cl, Br or I.

[0101] The term "halo" as used herein means one or more of the halogens F, Cl, Br or I.

[0102] The term "hydroxy" as used herein means one or more hydroxyl groups.

[0103] The term "substituted" when used in the context of two groups, is preceded by the substituent, e.g., "aryl substituted alkyl" means an alkyl group having an aryl substituent, "alkoxycarbonyl substituted alkyl" means an alkyl group having an alkoxycarbonyl substituent.

[0104] When multiple groups of the present application are used in conjunction, the substituent relationships proceed from left to right, e.g., "arylalkyl" indicates an aryl group substituted on an alkyl group, "alkoxyalkoxy" indicates an alkoxy group substituted on an alkoxy group.

[0105] The term "unsaturated" as used herein refers to a structural moiety containing one or more degrees of unsaturation.

[0106] Description of the compounds of the present application

[0107] The present application provides a steroid compound having a structure as shown in formula (I'), or a stereoisomer, a tautomer, a nitroso, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure shown in formula (I'),

[0108] wherein R 2 is

[0109] R 3 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=O)-alkyl, monophosphate or diphosphate; 6 or -NR 5 R 6 ;

[0110] R 4 is R 7 (O-R 8 ) n -;

[0111] R 5 and R 6 are each independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=O)-alkyl, monophosphate or diphosphate;

[0112] R 7 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or heterocyclyl;

[0113] R 8 is alkylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene or heteroarylene;

[0114] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0115] wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R8 the alkylene, alkenylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene, heteroarylene, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, or phosphorus-containing heterocyclyl group in ring A, ring B, ring C, and ring D is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloaryl, aryl, and heteroaryl;

[0116] R 10 is selected from

[0117] R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkylthio, halo- or hydroxy-substituted alkylthio, alkylamino, halo- or hydroxy-substituted alkylthio, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl, or alkynyl;

[0118] R x is halogen, hydroxyl, amino, alkyl, carboxyl, phosphato, sulfato, or alkoxy;

[0119] the hydrogen atoms on ring A, ring B, ring C, and ring D are unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

[0120] In some embodiments, the steroid compound has a structure according to Formula (I’-1) or Formula (I’-2), or is a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a structure according to Formula (I’-1) or Formula (I’-2),

[0121] In formula (I'-1) and formula (I'-2), R 2 , R a , R b , R c , R d , R e , R f , ring A, ring B, ring C and ring D have the same definitions as those in formula (I') described above.

[0122] In some embodiments, the steroid compound has a structure as shown in formula (I-1), formula (I-2), formula (II-1) or formula (II-2), or is a stereoisomer, a tautomer, a nitroso compound, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the structure shown in formula (I-1), formula (I-2), formula (II-1) or formula (II-2),

[0123] In formula (I-1), formula (I-2), formula (II-1) and formula (II-2), R 1 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or heterocyclyl;

[0124] R 2 has the same definition as that in formula (I') described above.

[0125] In some embodiments, in formula (I-1), formula (I-2), formula (II-1) and formula (II-2), R 1 is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or C 1-9 heterocyclyl.

[0126] In some other embodiments, in formula (I-1), formula (I-2), formula (II-1) and formula (II-2), R 1 is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethenyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, C 1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, or thiaalkyl.

[0127] In some specific embodiments, in the steroidal compound, R 3 For hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 6 or -NR 5 R 6 ;R 5 and R 6 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, monophosphate, or diphosphate.

[0128] In some other specific embodiments, in the steroidal compound, R 3 C substituted with hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, methoxymethyl, or fluorine. 1-3 Alkyl, chlorinated C 1-3 Alkyl, -OR 6 or -NR 5 R 6 ;R 5 and R 6 Each of the following C atoms is independently substituted with hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, or methoxymethyl fluorine. 1-3 Alkyl, chlorinated C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 Alkylene-OC(=O)-C 1-3 Alkyl, monophosphate, or diphosphate.

[0129] In some embodiments, the steroid compound is one in which R 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0130] In some embodiments, the steroid compound is one in which R 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6 alkyl. In some embodiments, the steroid compound is one in which R 5 is hydrogen and R 6 is C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0131] In some embodiments, the steroid compound is one in which R 4 is R 7 (O-C 1-6 alkylene) n ; and R 7 is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, or C 1-9 heterocyclyl.

[0132] In some embodiments, the steroid compound is one in which R 7 is hydrogen or C 1-6 alkyl.

[0133] In some embodiments, the steroid compound is one in which R 4 is R 7 (O-C 1-3 alkylene) n ; and R 7 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethenyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkyl, or C 3-8 cycloalkyl.

[0134] In some specific embodiments, n in the steroidal compound is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0135] In some specific embodiments, n in the steroidal compound is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0136] In some specific embodiments, n in the steroidal compound is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0137] In other embodiments, the steroidal compound has a structure represented by formula (III), (IV), (V), (VI), (VII), or (VIII), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure represented by formula (III), (IV), (V), (VI), (VII), or (VIII).

[0138] In equations (III), (IV), (V), (VI), (VII), and (VIII), R 4 For R 7 (OC 1-6 Alkylene) n -;

[0139] R 5 and R 6 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, monophosphate, or diphosphate; R 7 For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl or C 1-9 Heterocyclic group; n is 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0140] In some embodiments, R 4 is R 7 (O-C 1-3 alkylene) n ; R 5 and R 6 are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-butoxy, isopropoxy, methoxymethyl-fluorine substituted C 1-3 alkyl, chloro-substituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 alkylene-OC(=O)-C 1-3 alkyl, monophosphate or diphosphate; R 7 is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, vinyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkyl or C 3-8 cycloalkyl; n is 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0141] In some embodiments, the steroid compound has one of the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0142] Compositions, formulations and administration of the compounds of the present application

[0143] The pharmaceutical composition comprises any one of the steroid compounds of the present application. The pharmaceutical composition can further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0144] The pharmaceutical composition can be used for treating ocular diseases, in particular, cataract, floaters, myopia or presbyopia.

[0145] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, 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 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 and polyethylene 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.

[0146] When used in therapy, therapeutically effective amounts of the compounds of the application can be administered as the neat chemical, or as the active ingredient in a pharmaceutical composition. Accordingly, the present application also provides pharmaceutical compositions which include a therapeutically effective amount of a compound of the application, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein means the total amount of each active component that is sufficient to yield a meaningful patient benefit (e.g., reduction in viral load) when administered alone or in combination. When applied in conjunction with the administration of separate active ingredients, the term refers to the combined amounts of the active components that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. Carriers, diluents, or excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject in need thereof. In accordance with another aspect of the present application, there is also provided a process for preparing a pharmaceutical formulation including admixing a compound of the application with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and / or dosage forms of the present application are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0147] It will be appreciated that, in addition to ingredients particularly mentioned herein, the formulations can include other agents conventional in the art, for example, those suitable for oral administration can include flavoring agents.

[0148] Use of the compounds and compositions of the present application

[0149] Use of the compounds or pharmaceutical compositions of the present application in the manufacture of a medicament for preventing, managing, treating or lessening ocular disease in a patient.

[0150] In some embodiments, the ocular disease is cataract, floaters, myopia or presbyopia.

[0151] An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present application means an amount effective at treating or lessening the severity of one or more of the disorders contemplated by the present application. The compounds and compositions thereof according to the method of the present application can be used to treat or lessen the severity of the disease in any amount and by any route of administration effective for that purpose. The precise amount required can vary depending on the subject's condition, depending on the ethnic, age, general condition of the patient, the severity of the infection, special factors, the mode of administration, and the like. The compounds or compositions of the present application can be administered in combination with one or more other therapeutic agents, as discussed herein.

[0152] In order that those skilled in the art can better understand the technical solutions of the present application, some non-limiting embodiments are further disclosed below to further illustrate the present application in detail.

[0153] General synthetic procedures

[0154] 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.

[0155] Those skilled in the art will appreciate that the chemical reactions described herein can be used to prepare many of the other compounds of the present application and that other methods for their preparation can be employed as art known. For example, the synthesis of those non-exemplified compounds according to the present application can be successfully performed by modifications apparent to those skilled in the art, by analogy with the procedures described herein or with other known procedures. Also, as art known, the reaction conditions can be varied as appropriate, to affect the desired result.

[0156] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma, Aldrich, Merck, Bide, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Factory, Guangzhou Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haian Chemical Factory.

[0157] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal. Anhydrous dichloromethane and chloroform were dried over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used after drying over anhydrous sodium sulfate.

[0158] The following reactions were generally carried out under an atmosphere of nitrogen or argon, or under an atmosphere of dry solvent in a dry box, unless otherwise indicated. Reaction vessels were fitted with a septum and substrates were introduced via syringe. Glassware was oven- or flame-dried.

[0159] Chromatography was performed using silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Haian Chemical Factory. NMR spectra were recorded in CDC13, d6-DMSO, CD3OD or d6-acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as internal standard. When multiplets were observed, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are reported in Hertz (Hz).

[0160] Low resolution mass spectrometry (MS) data were determined by LC-MS spectrometer of Shimadzu LCMS-2020 series or LCMS-2050 series equipped with LC-20ADXR quaternary pump and CTO-20A (column temperature was kept at 40 °C), SIL-20ACXR autosampler and SPD-M40 PDA detector were applied for analysis, ESI source was applied for LC-MS spectrometer.

[0161] The following abbreviations are used throughout the application:

[0162] AcOH: acetic acid; Boc20, BOC anhydride: di-tert-butyl dicarbonate; Boc: tert- butyloxycarbonyl; Bu4NHS04: tetra-butylammonium hydrogen sulfate; CH3CN: acetonitrile; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; HC1: hydrogen chloride; HC1 / EA: ethyl acetate solution of hydrogen chloride; 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: tetra-butylammonium iodide; DMF: dimethylformamide; p-TsOH: p-toluenesulfonic acid; TAF: trifluoroacetic acid; TBAF: tetra-butylammonium fluoride.

[0163] Example 1: Synthesis of Compound 1

[0164] Phosphorus oxychloride (1.7 g, 10.9 mmol) was added dropwise to dichloromethane (10 mL) at -78 °C under nitrogen protection, then a solution of compound 1-1 (3.0 g, 5.5 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 1 h after the dropwise addition was completed. A solution of L-alanine isopropyl ester (1.4 g, 10.8 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (10 mL) was added dropwise to the above reaction solution, and the reaction was stirred for 2 h after the dropwise addition was completed. A solution of heptaglycerol (7.0 g, 21.7 mmol) and triethylamine (2.3 g, 22.2 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 8 h after the temperature was returned to room temperature. The reaction was monitored by TLC. The reaction solution was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by medium pressure preparative chromatography to obtain compound 1 (1.0 g, colorless oil). LCMS (ESI), m / z, [M+1] + = 1048.6; 1HNMR (500 MHz, CDC13) δ 7.81 (dd, 1H), 7.46 (dd, 2H), 7.18 (t, 1H), 5.28 (s, 1H), 5.08 (t, 1H), 5.00 - 4.85 (m, 1H), 4.77 - 4.70 (m, 1H), 4.30 - 4.23 (m, 2H), 4.07 - 3.98 (m, 1H), 3.70 (t, 4H), 3.61 (m, 23H), 2.08 - 1.99 (m, 5H), 1.95 - 1.81 (m, 3H), 1.80 - 1.69 (m, 4H), 1.67 (s, 3H), 1.59 (s, 3H), 1.51 (m, 3H), 1.44 - 1.26 (m, 6H), 1.26 - 1.16 (m, 8H), 1.14 (t, 3H), 1.03 (d, 3H), 0.99 (s, 1H), 0.97 (d, 3H), 0.93 (d, 2H), 0.90 (d, 3H), 0.87 (s, 3H), 0.68 (s, 3H) ppm; 31 PNMR (202 MHz, CDC13) δ 2.96 (s), 2.86 (s) ppm.

[0165] Example 2: Synthesis of compound 2

[0166] Phosphorus oxychloride (1.7 g, 10.9 mmol) was added dropwise to dichloromethane (10 mL) at -78 °C under nitrogen protection, then a solution of compound 1-1 (3.0 g, 5.5 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 1 h after the dropwise addition was completed; a solution of L-alanine isopropyl ester (1.4 g, 10.8 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (10 mL) was added dropwise to the above reaction solution, and the reaction was stirred for 2 h after the dropwise addition was completed; a solution of dodecaethylene glycol monomethyl ether (12.1 g, 21.7 mmol) and triethylamine (2.3 g, 22.2 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 6 h after the temperature returned to room temperature; TLC monitoring showed that the reaction was complete. The reaction solution was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by medium pressure preparative chromatography to obtain compound 2 (1.1 g, colorless oil). LCMS (ESI), m / z, [M+1] + = 1282.9; 1HNMR (500 MHz, CDC13) δ 7.81 (dd, 1H), 7.51 - 7.44 (m, 2H), 7.19 (t, 1H), 5.09 (t, 1H), 5.02 - 4.87 (m, 1H), 4.77 - 4.69 (m, 1H), 4.30 - 4.23 (m, 2H), 4.03 (dd, 1H), 3.70 (t, 2H), 3.63 (d, 44H), 3.53 (dd, 2H), 3.36 (s, 3H), 2.09 - 1.96 (m, 6H), 1.92 (dd, 1H), 1.86 - 1.79 (m, 2H), 1.73 (dd, 3H), 1.67 (s, 4H), 1.59 (s, 3H), 1.55 - 1.44 (m, 2H), 1.43 - 1.26 (m, 6H), 1.24 - 1.18 (m, 7H), 1.14 (t, 3H), 1.03 (d, 3H), 0.99 (s, 1H), 0.97 (d, 3H), 0.94 (s, 2H), 0.90 (d, 3H), 0.88 (s, 3H), 0.68 (s, 3H) ppm; 31 PNMR (202 MHz, CDC13) δ 2.97 (s), 2.86 (s) ppm.

[0167] Example 3: Synthesis of compound 3

[0168] Phosphorus oxychloride (1.7 g, 10.9 mmol) was added dropwise to dichloromethane (10 mL) at -78 °C under nitrogen protection, then a solution of compound 1-1 (3.0 g, 5.5 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 1 h after the dropwise addition was completed; a solution of L-alanine isopropyl ester (1.4 g, 10.8 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (10 mL) was added dropwise to the above reaction solution, and the reaction was stirred for 2 h after the dropwise addition was completed; a solution of tetrapolyethylene glycol monomethyl ether (9.0 g, 43.2 mmol) and triethylamine (2.3 g, 22.2 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 3 h after the temperature returned to room temperature; TLC monitoring showed that the reaction was complete. The reaction solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by medium pressure preparative chromatography to obtain compound 3 (1.9 g, colorless oil). LCMS (ESI), m / z, [M+1] + = 931.2; 1HNMR (500 MHz, CDC13) δ 7.81 (dd, 1H), 7.46 (dd, 2H), 7.19 (t, 1H), 5.09 (t, 1H), 4.94 (m, 1H), 4.74 (d, 1H), 4.28 (dd, 2H), 4.03 (dd, 1H), 3.71 (t, 2H), 3.63 (d, 10H), 3.55 - 3.51 (m, 2H), 3.36 (s, 3H), 2.10 - 1.96 (m, 6H), 1.95 - 1.81 (m, 3H), 1.81 - 1.68 (m, 5H), 1.67 (s, 3H), 1.59 (s, 3H), 1.57 - 1.46 (m, 2H), 1.37 (dd, 5H), 1.31 (d, 1H), 1.19 (dd, 8H), 1.14 (t, 3H), 1.03 (s, 3H), 1.00 (s, 1H), 0.97 (d, 3H), 0.94 (s, 2H), 0.91 (d, 3H), 0.88 (s, 3H), 0.69 (s, 3H) ppm; 31 PNMR (202 MHz, CDC13) δ 2.96 (s), 2.87 (s) ppm.

[0169] Example 4: Synthesis of compound 4

[0170] Phosphorus oxychloride (1.7 g, 10.9 mmol) was added dropwise to dichloromethane (10 mL) at -78 °C under nitrogen protection, then a solution of compound 1-1 (3.0 g, 5.5 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 1 h after the dropwise addition was completed; a solution of L-alanine isopropyl ester (1.4 g, 10.8 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (10 mL) was added dropwise to the above reaction solution, and the reaction was stirred for 2 h after the dropwise addition was completed; a solution of dimeric ethylene glycol monomethyl ether (5.2 g, 43.8 mmol) and triethylamine (1.4 g, 13.7 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 3 h after the temperature returned to room temperature; TLC monitoring showed that the reaction was complete. The reaction solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by medium pressure preparative chromatography to obtain compound 4 (1.95 g, colorless oil). LCMS (ESI), m / z, [M+1] + = 843.0; 1HNMR (500 MHz, CDC13) δ 7.81 (dd, 1H), 7.48 (dt, 2H), 7.19 (t, 1H), 5.10 (t, 1H), 4.95 (m, 1H), 4.79 - 4.70 (m, 1H), 4.29 (m, 2H), 4.05 (dd, 1H), 3.72 (t, 2H), 3.65 - 3.60 (m, 2H), 3.54 - 3.49 (m, 2H), 3.36 (d, 3H), 2.09 - 1.98 (m, 5H), 1.97 - 1.82 (m, 3H), 1.82 - 1.69 (m, 6H), 1.68 (s, 3H), 1.63 - 1.51 (m, 5H), 1.51 - 1.46 (m, 1H), 1.45 - 1.27 (m, 6H), 1.20 (dd, 7H), 1.15 (t, 3H), 1.04 (d, 3H), 0.98 (dd, 6H), 0.93 - 0.87 (m, 6H), 0.69 (s, 3H) ppm; 31 PNMR (202 MHz, CDC13) δ 2.93 (s), 2.87 (s) ppm.

[0171] Example 5: Synthesis of compound 5

[0172] Phosphorus oxychloride (1.7 g, 10.9 mmol) was added dropwise to dichloromethane (10 mL) at -78 °C under nitrogen protection, then a solution of compound 1-1 (3.0 g, 5.5 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 1 h after the dropwise addition was completed; a solution of L-alanine isopropyl ester (1.4 g, 10.8 mmol) and triethylamine (1.2 g, 11.4 mmol) in dichloromethane (10 mL) was added dropwise to the above reaction solution, and the reaction was stirred for 2 h after the dropwise addition was completed; a solution of dimeric ethylene glycol monomethyl ether (5.2 g, 43.8 mmol) and triethylamine (1.4 g, 13.7 mmol) in dichloromethane (20 mL) was added dropwise, and the reaction was stirred for 3 h after the temperature returned to room temperature; TLC monitoring showed that the reaction was complete. The reaction solution was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by medium pressure preparative chromatography to obtain compound 5 (1.95 g, colorless oil). LCMS (ESI), m / z, [M+1] + = 887.1; 1HNMR (400 MHz, CDC13) δ 7.85 - 7.77 (m, 1H), 7.52 - 7.44 (m, 2H), 7.19 (t, 1H), 5.10 (t, 1H), 4.95 (dp, 1H), 4.74 (dd, J = 11.4, 4.0 Hz, 1H), 4.31 - 4.24 (m, 2H), 4.18 - 4.01 (m, 1H), 3.71 (t, 2H), 3.66 - 3.60 (m, 7H), 3.55 - 3.50 (m, 2H), 3.36 (s, 3H), 2.10 - 1.97 (m, 5H), 1.96 - 1.79 (m, 3H), 1.82 - 1.69 (m, 4H), 1.68 (s, 3H), 1.64 - 1.47 (m, 5H), 1.44 - 1.29 (m, 6H), 1.21 (t, 7H), 1.15 (dd, 3H), 1.04 (d, 3H), 1.02 - 0.97 (m, 6H), 0.95 (s, 2H), 0.93 - 0.87 (m, 6H), 0.69 (s, 3H) ppm; 31 PNMR (162 MHz, CDC13) δ 2.96 (s), 2.88 (s) ppm.

[0173] Example 6: Synthesis of compound 6

[0174] Dichloromethane (30 mL) was added into a 250 mL three-necked flask under nitrogen protection, cooled to -70 °C, phosphorus oxychloride (0.92 mL, 9.9 mmol) was added, a solution of compound 1-1 (3 g, 5.5 mmol.) and triethylamine (1.45 mL, 10.4 mmol) in dichloromethane (10 mL) was added dropwise, after the addition was completed, it was stirred for 30 minutes, TLC monitoring reaction was complete; a solution of L-alanine isopropyl ester (1.6 g, 11.9 mmol.) and triethylamine (1.66 mL, 11.9 mmol) in dichloromethane (30 mL) was added dropwise, after the addition was completed, it was stirred for 2 hours; a solution of hexaethylene glycol monomethyl ether (3.5 g, 10.8 mmol.) and triethylamine (1.88 mL, 13.5 mmol) in dichloromethane (10 mL) was added dropwise, after the addition was completed, it was stirred at room temperature for 3 hours. TLC monitoring reaction was complete, concentrated under reduced pressure to get the crude product, the crude product was separated by medium pressure preparative chromatography and high pressure preparative chromatography to obtain compound 6 (0.65 g, white solid). LCMS (ESI), m / z, [M+1] + = 1018.6; 1HNMR (400 MHz, CDC13) δ 7.87 - 7.78 (m, 1H), 7.53 - 7.46 (m, 2H), 7.20 (t, 1H), 5.10 (t, 1H), 5.03 - 4.87 (m, 1H), 4.75 (d, 1H), 4.27 (dd, 2H), 4.20 - 3.99 (m, 1H), 3.72 (t, 2H), 3.67 - 3.58 (m, 19H), 3.54 (dd, 2H), 3.37 (s, 3H), 2.05 (d, 5H), 1.84 (dd, 3H), 1.75 (dd, 3H), 1.68 (s, 3H), 1.65 (s, 4H), 1.61 (s, 4H), 1.47 - 1.30 (m, 6H), 1.26 - 1.20 (m, 7H), 1.15 (dd, 3H), 1.04 (s, 3H), 1.02 - 0.98 (m, 4H), 0.95 (s, 2H), 0.93 - 0.87 (m, 6H), 0.70 (s, 3H) ppm; 31 PNMR (202 MHz, CDC13) δ 2.92 (s), 2.86 (s) ppm.

[0175] Example 7: Synthesis of compound 7

[0176] First step: synthesis of compound 7-1

[0177] phenyl 4-nitrochloroformate (7.37 g, 36.6 mmol) was dissolved in dichloromethane (200 mL), compound 1-1 (10 g, 18.3 mmol) and pyridine (2.96 mL, 36.6 mmol) were added successively, the system was stirred at room temperature for 12 h. The reaction was complete, the system was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 20 / 1) to obtain compound 7-1 (11 g, white solid). 1 H NMR (400 MHz, CDC13) δ 7.87 - 7.78 (m, 1H), 7.53 - 7.46 (m, 2H), 7.20 (t, 1H), 5.10 (t, 1H), 5.03 - 4.87 (m, 1H), 4.75 (d, 1H), 4.27 (dd, 2H), 4.20 - 3.99 (m, 1H), 3.72 (t, 2H), 3.67 - 3.58 (m, 19H), 3.54 (dd, 2H), 3.37 (s, 3H), 2.05 (d, 5H), 1.84 (dd, 3H), 1.75 (dd, 3H), 1.68 (s, 3H), 1.65 (s, 4H), 1.61 (s, 4H), 1.47 - 1.30 (m, 6H), 1.26 - 1.20 (m, 7H), 1.15 (dd, 3H), 1.04 (s, 3H), 1.02 - 0.98 (m, 4H), 0.95 (s, 2H), 0.93 - 0.87 (m, 6H), 0.70 (s, 3H) ppm;

[0178] Step 2: Synthesis of compound 7

[0179] Compound 7-1 (356 mg, 0.500 mmol) was dissolved in 5 mL dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and the prepared solution was added dropwise slowly. After the addition was completed, the reaction was continued at 0 °C for 30 minutes. 20 mL of ethyl acetate and 10 mL of water were added, and the mixture was separated. The organic layer was washed with 10 mL of saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column, eluent: 10% EA / PE-100% EA, to obtain compound 7 (80 mg, white solid). LCMS (ESI), m / z, [M+1] + = 921.4; 1 H NMR (500 MHz, CDCl3) δ 8.00 (dd, 1H), 7.58-7.55 (m, 1H), 7.34 (t, 1H), 7.22 (d, J = 8.1 Hz, 1H), 5.12 (t, 1H), 4.75 (dd, 1H), 4.44-4.39 (m, 2H), 3.85-3.79 (m, 2H), 3.76-3.63 (m, 22H), 3.63-3.58 (m, 2H), 2.22 (br s, 1H), 2.11-2.00 (m, 5H), 1.99-1.71 (m, 6H), 1.70 (s, 3H), 1.65-1.60 (m, 3H), 1.60-1.46 (m, 3H), 1.45-1.24 (m, 6H), 1.24-1.14 (m, 2H), 1.10-1.03 (m, 4H), 1.00 (s, 3H), 0.95 (s, 3H), 0.94 (d, 3H), 0.90 (s, 3H), 0.71 (s, 3H) ppm.

[0180] Example 8: Synthesis of compound 8

[0181] Dodecaethylene glycol monomethyl ether (560.6 mg, 1.00 mmol) was dissolved in 5 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and potassium tert-butoxide (112.2 mg, 1.000 mmol) was added. After the addition was completed, the mixture was stirred at 0 °C for another 30 min and used as prepared. Compound 7-1 (712 mg, 1.00 mmol) was dissolved in 5 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and the prepared solution was added dropwise slowly. After the addition was completed, the mixture was stirred at 0 °C for another 30 min. Ethyl acetate 20 mL and water 10 mL were added, and the mixture was separated. The organic layer was washed with saturated sodium chloride 10 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EA / PE-100% EA-3% MeOH / DCM as the eluent to give compound 9 (200 mg, white solid). 1 H NMR (500 MHz, CDC13) δ 8.01 (d, 1H), 7.58 - 7.55 (m, 1H), 7.34 (t, 1H), 7.21 (d, 1H), 5.12 (t, 1H), 4.75 (dd, 1H), 4.44 - 4.40 (m, 2H), 3.86 - 3.79 (m, 2H), 3.74 - 3.62 (m, 22H), 3.58 - 3.54 (m, 2H), 3.39 (s, 3H), 2.10 - 2.00 (m, 5H), 1.99 - 1.71 (m, 6H), 1.70 (s, 3H), 1.60 (s, 3H), 1.60 - 1.47 (m, 3H), 1.47 - 1.26 (m, 6H), 1.24 - 1.16 (m, 2H), 1.10 - 1.02 (m, 4H), 1.01 (s, 3H), 0.95 (s, 3H), 0.94 (d, 3H), 0.90 (s, 3H), 0.71 (s, 3H) ppm.

[0182] Example 9: Synthesis of compound 9

[0183] Dodecaethylene glycol monomethyl ether (560.6 mg, 1.00 mmol) was dissolved in 5 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and potassium tert-butoxide (112.2 mg, 1.000 mmol) was added. After the addition was completed, the mixture was stirred at 0 °C for another 30 min and used as prepared. Compound 7-1 (712 mg, 1.00 mmol) was dissolved in 5 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and the prepared solution was added dropwise slowly. After the addition was completed, the mixture was stirred at 0 °C for another 30 min. Ethyl acetate 20 mL and water 10 mL were added, and the mixture was separated. The organic layer was washed with saturated sodium chloride 10 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 10% EA / PE-100% EA-3% MeOH / DCM as the eluent to give compound 9 (200 mg, white solid). 1H NMR (500 MHz, CDC13) δ 8.00 (d, 1H), 7.56 (t, 1H), 7.34 (t, 1H), 7.21 (d, 1H), 5.11 (t, 1H), 4.74 (dd, 1H), 4.45 - 4.36 (m, 2H), 3.84 - 3.78 (m, 2H), 3.74 - 3.61 (m, 42H), 3.56 (t, 2H), 3.39 (s, 3H), 2.11 - 2.00 (m, 5H), 1.98 - 1.70 (m, 6H), 1.70 (s, 3H), 1.62 (s, 3H), 1.60 - 1.48 (m, 3H), 1.48 - 1.25 (m, 6H), 1.20 (m, 2H), 1.08 - 1.03 (m, 4H), 1.00 (s, 3H), 0.95 (s, 3H), 0.93 (d, 3H), 0.90 (s, 3H), 0.71 (s, 3H) ppm.

[0184] Example 10: Synthesis of compound 10

[0185] Decaethylene glycol (458.5 mg, 1.00 mmol) was dissolved in 6 mL dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, sodium hydride (40 mg, 60%, 1.00 mmol) was added, and the mixture was stirred at 0 °C for 30 min before use. Intermediate 7-1 (712 mg, 1.00 mmol) was dissolved in 10 mL dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and the solution was added dropwise slowly. The mixture was stirred at 0 °C for 30 min before use. Ethyl acetate 20 mL, water 10 mL were added, and the mixture was separated. The organic layer was washed with saturated sodium chloride 10 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 10% EA / PE-100% EA as eluent to give compound 10 (60 mg, white solid). LCMS (APCI), m / z, [M+1] = 1031. + Comparative Example 1: Synthesis of control compound 1

[0186] Control compound 1 was synthesized according to the synthesis method of Example 8 in WO2018137683, and its structural formula is as follows:

[0187] Test Example 1: Solubility test

[0188] 1. Instruments and materials

[0189] Instruments: Shimadzu LC-20ADXR; shaker; glass instruments; pipette.

[0190] Materials: pH = 7.2 PBS buffer, pure water, HPLC ethanol, HPLC methanol, HPLC tetrahydrofuran

[0191] 2. Experimental procedure

[0192] 2.1 Preparation of sample stock solution Take sample of relevant compound, place in centrifuge tube, add 1 mL of tetrahydrofuran at room temperature to completely dissolve sample, resulting in stock solution.

[0193] 2.2 Preparation of saturated sample solution Take sample of relevant compound, place in centrifuge tube, add 1 mL of pure water at room temperature. Place in shaker at room temperature for 1 hour. Take sample and place in refrigerated centrifuge, set centrifuge to 4000 rpm, 25 °C, centrifuge for 10 minutes. After removal, pipette supernatant saturated clear solution. Filter using 0.22 μm filter membrane.

[0194] 2.3 Preparation of standard curve solution Dilute stock solution with tetrahydrofuran in gradient. Dilute with vortexing to ensure homogeneity.

[0195] 2.4 Determination of sample solubility

[0196] Determine solubility using HPLC method.

[0197] 2.5 Determination of standard curve, pipette 200 μL of standard curve solution into syringe, inject 1 μL per injection starting with lowest concentration, record chromatographic peak area.

[0198] 2.6 Inject 1 μL of saturated solution, record chromatographic peak area.

[0199] 3. Comparison of clarity after centrifugation

[0200] Take pure water and place in centrifuge tube. Compare supernatant clear solution from step 2.2 with pure water. There should be no particulate, flocculent, or suspended solid particles in the clear solution. The clarity should be similar to the pure water.

[0201] 4. Calculation

[0202] 4.1 Calculate the standard curve regression equation by fitting the concentration versus chromatographic peak area.

[0203] 4.2 Calculate the concentration of the peak area measured from the saturated sample using the regression equation.

[0204] 4.3 Obtain solubility value in mg / mL. Results are shown in Table 2.

[0205] 5. HPLC method conditions

[0206] Column: YMC-Triart C8 5 μm 4.6 x 50 mm;

[0207] Method: mobile phase: 0.1% trifluoroacetic acid in methanol and ethanol; mobile phase gradient: 100% methanol as phase A, 100% ethanol as phase B, 10% B to 90% B, 3 mins; post-equilibration 10% ethanol, 0.5 mins; detection wavelength: full wavelength scan

[0208] Detection temperature: 40℃

[0209] Table 2 solubility test results

[0210] Conclusion: from the results of table 2, the solubility of the compound of the present application in aqueous solution is obviously improved compared with the control compound 1.

[0211] Test example 2: drug content detection in rabbit eye tissue

[0212] By detecting the drug content in different eye tissues of the blue rabbit, the distribution of the test compound in the eye tissue was detected. Nine blue rabbits (male, 3-5 months old) were placed in the animal room for 3 days and then used. A certain amount of compound was weighed, solvent (according to the difference of different compounds, the osmotic pressure and pH value meet the required range) was added, and ultrasonic oscillation was carried out until complete dissolution or stable suspension was formed, and the final concentration of the compound was 0.2-2%. The lower eyelid of the rabbit was pulled down, and 50 μL of compound solution or suspension was accurately dropped by using a pipette gun, and the left and right eyes were given at the same time. After administration, it was observed whether there was drug leakage. 0.5 h, 3 h, 6 h / 10 h after administration, 3 rabbits were euthanized, the eyeballs were removed and different eye tissue structures were peeled off (left and right eyes were taken at the same time), and the contents of the drug and metabolites in the conjunctiva, cornea, sclera and aqueous humor were detected by LC-MS / MS. The results are shown in Tables 3-5.

[0213] Table 3 concentration of drug and control compound 1 in conjunctiva of blue rabbit after eye drops of different concentrations of compound

[0214] BQL: lower than the lower limit of quantification

[0215] Table 4 concentration of drug and control compound 1 in cornea of blue rabbit after eye drops of different concentrations of compound

[0216] BQL: lower than the lower limit of quantification

[0217] Table 5 concentration of drug and control compound 1 in sclera of blue rabbit after eye drops of different concentrations of compound

[0218] BQL: lower than the lower limit of quantification

[0219] As can be seen from the data in Tables 3-5, compounds 2 and 9 of this application, as prodrugs of control compound 1, can be successfully converted into control compound 1 in the Qingzilan rabbit eye drops, and the drugs have a long residence time in the eyes and exhibit sustained-release characteristics.

[0220] Test Example 3: Cell Lens Protein Agglutination Assay

[0221] The inhibitory effect of the compound on lens protein aggregation was evaluated by detecting the aggregation level of the intracellular lens protein cryAA. HLE-B3 cells (purchased from ATCC) were seeded into 6-well plates (each well containing 2 crawling slides), 1×10 4 Cells / well; 24 h after seeding, pcDNA3.1-Flag-cryAA was transfected using lipofectamine 3000. Y118D Plasmids were transfected; the medium was changed and the transfection reagent was removed 4 h later; then 20 μM of the compound and 100 mM hydrogen peroxide were added to each well, and the mixture was incubated together for 48 h. The culture medium was discarded, and 1 mL of 4% paraformaldehyde was added to each well for fixation. The cells were then incubated with rabbit anti-Flag primary antibody and goat anti-rabbit IgG Alexa Fluor 488 secondary antibody. Fluorescence microscopy was used to photograph and analyze the number of fluorescent cells and the number of intracellular protein condensates in the smears from each well. Wells without the compound were used as controls, and the number of condensed cells in these wells was recorded as 100%. The effect of each compound on the formation of intracellular condensate proteins (inhibition rate, %) was calculated. The results are shown in Table 6.

[0222] Table 6. Inhibitory effects of different compounds on intracellular cryAA protein aggregation.

[0223] Conclusion: As can be seen from the data in Table 6, compound 9 of the present invention can significantly inhibit the aggregation of lens proteins, and its inhibitory ability is stronger than that of control compound 1.

[0224] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments are intended to be illustrative and non-limiting in all respects, and reference should be made to the appended claims rather than to the foregoing embodiments; thus, all variations within the meaning and scope of the equivalents of the appended claims are included herein.

Claims

1. A steroid compound having the structure of Formula (I’), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure of Formula (I’), wherein R 2 For R 3 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, -OR 6 or -NR 5 R 6 ; R 4 For R 7 (O-R 8 ) n -; R 5 and R 6 each independently is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=0)-alkyl, monophosphate, or diphosphate; R 7 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclyl; R 8 is alkylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene, or heteroarylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; wherein the alkylene, alkenylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene, heteroarylene, alkyl, alkenyl, alkynyl, hydroxylalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, or phosphorus-containing heterocyclyl group described in R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkyloxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl, and heteroaryl; R 10 selected from R a , R b , R c , R d , R e , R f , R g , R h , R i and R j are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkylthio, halo- or hydroxy-substituted alkylthio, alkylamino, halo- or hydroxy-substituted alkylthio, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkenyl or alkynyl; R x is halogen, hydroxy, amino, alkyl, carboxy, phosphato, sulfo or alkoxy; the hydrogen atoms on ring A, ring B, ring C, and ring D are unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, thiol, nitro, alkyl, halo-substituted or hydroxy-substituted alkyl, alkoxyalkyl, halo- or hydroxy-substituted alkoxyalkyl, alkoxy, halo- or hydroxy-substituted alkoxy, alkoxyalkoxy, halo- or hydroxy-substituted alkoxyalkoxy, alkylamino, halo- or hydroxy-substituted alkylamino, alkylthio, halo- or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

2. The steroid compound of claim 1, wherein, The steroidal compound has a structure as shown in Formula (I'-1) or Formula (I'-2), or is a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the structure shown in Formula (I'-1) or Formula (I'-2), In formula (I'-1) and formula (I'-2), R 2 , R a , R b , R c , R d , R e , R f , ring A, ring B, ring C and ring D have the same definitions as in formula (I').

3. The steroid compound according to claim 1 or 2, wherein, The steroid compound has a structure as shown in Formula (I-1), Formula (I-2), Formula (II-1), or Formula (II-2), or is a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the structure shown in Formula (I-1), Formula (I-2), Formula (II-1), or Formula (II-2), In formula (I-1), formula (I-2), formula (II-1), and formula (II-2), R 1 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclyl; R 2 R is as defined in formula (I’).

4. The steroid compound of claim 3, wherein, R 1 is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or C 1-9 heterocyclyl; Preferably, R 1 C groups substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or fluorine. 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, or thiaalkyl.

5. The steroid compound of any one of claims 1-4, wherein, R 3 is hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, -OR 6 or -NR 5 R 6 ; R 5 and R 6 each independently is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 1-6 alkylene-OC(=0)-C 1-6 alkyl, monophospho or diphospho.

6. The steroid compound of any one of claims 1-5, wherein, R 3 is hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, methoxymethyl, fluorine-substituted C 1-3 alkyl, chlorine-substituted C 1-3 alkyl, -OR 6 or -NR 5 R 6 ; R 5 and R 6 each independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, methoxymethylfluoro-substituted C 1-3 alkyl, chloro-substituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 alkylene-OC(=0)-C 1-3 alkyl, monophospho- or diphospho- groups.

7. The steroid compound of any one of claims 1-6, wherein, R 4 For R 7 (O-R 8 ) n -; R 7 is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or C 1-9 heterocyclyl; R 8 is C 1-6 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

8. The steroid compound of any one of claims 1-7, wherein, R 4 For R 7 (O-R 8 ) n -; R 7 is hydrogen, deuterium, halogen, cyano, nitro, hydroxy, amino, carboxy, formyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl, C 1-3 haloalkyl or C 3-8 cycloalkyl; R 8 is C 1-3 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

9. The steroid compound according to any one of claims 1 to 8, wherein, The steroid compound has the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), In formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4 is R 7 8 n 5 and R 6 each independently is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 1-6 alkylene-OC(=O)-C 1-6 alkyl, monophospho, or diphospho; R 7 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-9 heterocyclyl; R 8 is C 1-6 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;​​​ Preferably, R 5 and R 6 Each independently is hydrogen, C 1-6 Alkylene-OC(=O)-C 1-6 alkyl; Preferably, R 7 is hydrogen or C 1-6 alkyl; R 8 is C 1-6 alkylene; More preferably, R 5 is hydrogen, R 6 is C 1-6 alkylene-OC(=O)-C 1-6 alkyl; R 7 is hydrogen or C 1-6 alkyl; R 8 is C 1-6 alkylene.

10. The steroid compound of claim 9, wherein, R 5 and R 6 each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-butoxy, isopropoxy, methoxymethylfluoro substituted C 1-3 alkyl, chloro substituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1-3 alkylene-OC(=O)-C 1-3 alkyl, monophosphate or diphosphate; R 7 is hydrogen, deuterium, C 1-4 alkyl, vinyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkyl or C 3-8 cycloalkyl; R 8 is C 1-3 alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; Preferably, R 5 and R 6 Each independently is hydrogen, C 1-3 Alkylene-OC(=O)-C 1-3 alkyl; R is preferably hydrogen or C1-4alkyl, more preferably hydrogen or methyl. 7 R is hydrogen or C1-4alkyl, more preferably hydrogen or methyl. 1-4 R is hydrogen or C1-4alkyl, more preferably hydrogen or methyl. 8 R is hydrogen or C1-4alkyl, more preferably hydrogen or methyl. 1-3 R is hydrogen or C More preferably, R 5 is hydrogen, R 6 is C 1-3 alkylene-OC(=O)-C 1-3 alkyl, R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, R 8 is methylene, ethylene or propylene.

11. The steroid compound according to any one of claims 1-10, wherein, The steroidal compound has one of the following structures, or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 12. A pharmaceutical composition comprising the steroid compound of any one of claims 1-11, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

13. Use of the steroid compound of any one of claims 1-11 or the pharmaceutical composition of claim 11 in the manufacture of a medicament for preventing, managing, treating, or alleviating an ocular disease in a patient.

14. The use according to claim 13, wherein, The ocular disease comprises at least one of cataract, presbyopia, myopia, and floaters.

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