Steroidal compound and use thereof

Abstract

The present invention relates to a steroidal compound and a use thereof. The steroidal compound of the present invention has a structure as shown in formula (I'), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I'). The present invention further provides a pharmaceutical composition comprising the steroidal compound of the present invention. The steroidal compound and the pharmaceutical composition provided by the present invention can be used for preparing medicines for preventing, treating, or relieving eye diseases of patients.

Description

Steroid compound and application thereof TECHNICAL FIELD

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

[0002] Cataract is a disease of the eye, which occurs on the lens in the eyeball, and 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 and turbidity is formed. 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 one will lead to blindness. Cataract is one of the most common causes of blindness, 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. Therefore, the only effective treatment method at present is surgical treatment.

[0003] Although the continuous progress of cataract surgery has provided great help for the treatment of cataract, the cure rate of surgical treatment is still far lower than the incidence rate, and there is a possibility of serious complications; on the other hand, the cost of surgical treatment of cataract is very high, and even in developed countries, cataract has brought a huge burden to the medical insurance system. Therefore, the prevention and treatment of drugs play a decisive role. At present, the therapeutic drugs for cataract in clinic include: ① aldehyde reductase inhibitors, such as cathalin (cathalin, calin, and baijining), falcotin, and benzyl daidzein; ② antioxidant damage drugs, such as glutathione, taurine, and aspirin; ③ nutritional and metabolic drugs, such as vitamins and carotenoids; ④ traditional Chinese medicine compounds, including shihujiaoyuan pill, qijujiang pill, and shijueming powder. However, these drugs for treating cataract have been proved by long-term clinical trials that they can only delay the deterioration of cataract, but cannot reverse the disease.

[0004] Therefore, it is still necessary to develop more safe, effective, strong intraocular penetration and stable new varieties of ophthalmic external anti-cataract drugs. SUMMARY

[0005] To solve one of the above technical problems in the prior art, the present application provides a new steroid compound and its application, particularly in the preparation of drugs for treating ophthalmic diseases.

[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, an N-oxide, 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, -OR 6 , or -NR 5 R 6 ;

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

[0010] R 5 and R 6 are each independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=O)-alkyl, monophosphate or diphosphate;

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

[0012] R 8 is 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 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8the 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, 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 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;

[0017] R x is 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 is 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), R2 R a R b R c R d R e R f The definitions of rings A, B, C, and D are the same as those in equation (I').

[0021] 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 a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the structure shown in formula (I-1), formula (I-2), formula (II-1), or formula (II-2).

[0022] In equations (I-1), (I-2), (II-1), and (II-2), R 1 Independently, it is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclic; R 2 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 1hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethenyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, fluorine-substituted C 1-3 hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethenyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, fluorine-substituted C

[0026] In some embodiments, the steroid compound is of Formula (I-1), Formula (I-2), Formula (II-1), and Formula (II-2), wherein R 1 is hydrogen.

[0027] In some embodiments, the steroid compound is of Formula (I-1), Formula (I-2), Formula (II-1), and Formula (II-2), 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 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, monophospho, or diphospho.

[0028] In some embodiments, the steroid compound is of Formula (I-1), Formula (I-2), Formula (II-1), and Formula (II-2), wherein R 3 is hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxy, ethoxy, t-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 6each independently 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(=O)-C 1-3 alkyl, monophosphate or diphosphate.

[0029] 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 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.

[0030] In some embodiments, the steroid compound is one in which R 3 is -NR 5 R 6 ; R 5 and R 6 each independently hydrogen, C 1-6 alkylene-OC(=O)-C 1-6 alkyl.

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

[0033] In some embodiments, in the steroid compound, 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.

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

[0036] In some embodiments, in the steroid compound, 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; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0037] In some embodiments, in the steroid compound, R 4 is R 7 (O-R 8 ) n ; R 7 is hydrogen, C 1-6 alkyl; R8 C 1-6 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0038] In some other embodiments, in the steroidal compound, R 4 For R 7 (OR 8 ) n -;R 7 For hydrogen, deuterium, C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl), vinyl, propenyl, allyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-8 cycloalkyl; R 8 C 1-3 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0039] In some other embodiments, in the steroidal compound, R 4 For R 7 (OR 8 ) n -;R 7 For hydrogen, C 1-4 Alkyl; R 8 C 1-3 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0040] In some other embodiments, in the steroidal compound, R 4 For R 7 (OR 8 ) n -;R 7 It is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; R 8 C 1-3 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0041] In some embodiments, the steroid compound has the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or is 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),

[0042] 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 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 3-8 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; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0043] 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 1-6alkylene; 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 1-6 alkyl; R 8 is C 1-6 alkylene; n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0044] 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.

[0045] 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 1-6 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 1-6 alkylene-OC(=O)-C 1-6 alkyl.

[0046] 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(=O)-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 C1-3 alkylene-OC(=0)-C 1-3 alkyl.

[0047] In other 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 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-fluoro 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; 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.

[0048] In other 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(=0)-C 1-6 alkyl; R 7 is hydrogen or C 1-6 alkyl; R 8 is C 1-6 alkylene.

[0049] In other embodiments, in formula (III), formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII), R 4For R 7 (OR 8 ) n -;R 5 For hydrogen, R 6 C 1-3 Alkylene-OC(=O)-C 1-3 Alkyl, R 7 For example, hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, R 8 It can be methylene, ethylene, or propylene.

[0050] In some embodiments, the steroidal compound has one of the following structures, or its stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

[0051] In a second aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned steroidal compound, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0052] Thirdly, the present invention provides the use of the above-mentioned steroidal compound or pharmaceutical composition in the preparation of a medicament for the prevention, treatment, or relief of an eye disease in a patient.

[0053] In some implementations, the eye disease mentioned is one or more of cataracts, floaters, myopia, and presbyopia.

[0054] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below. Detailed Implementation

[0055] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0056] It should be further appreciated that certain of the present features can be, and herein will be, described in the context of separate embodiments for clarity sake, but can also be provided in combination in a single embodiment. Conversely, various features of the present application, which are, for brevity, described in the context of separate embodiments, can also be provided separately or in any suitable sub-combination.

[0057] Definitions and General Terminology

[0058] Unless otherwise defined, all terms used in connection with the present application, both in the specification and the claims, are intended to have the meaning commonly associated with them as set forth in the Dictionary of Scientific and Technical Terms (Yonkers, N.Y.: Chapman and Hall, 1994) or the Oxford English Dictionary. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an overly literal or overly formal sense.

[0059] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated by reference in their entirety.

[0060] Unless defined otherwise, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The following definitions are provided for certain terms used herein.

[0061] Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the application. These definitions should be applied in conjunction with the above general description and the following detailed description.

[0062] As used herein the term "patient" means a human (including adults and children) or other animal. In some embodiments, "patient" means a human.

[0063] The term "comprising" is used in the inclusive sense of "including" and "including or other inclusive terms so that the terms "comprising" and "comprises" are to be interpreted expansively, without limitation, to terms such as "including," "including or other inclusive terms.

[0064] "stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0065] "diastereomers" refer 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 or chiral separation methods such as electrophoresis or chromatography, e.g., HPLC.

[0066] 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.

[0067] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. An individual stereoisomer of a compound is designated by the letter R or S, indicating the absolute configuration of the molecule about its chiral center(s). When a given compound contains more than one chiral center, the stereochemistry of the compound is designated by the sequence of letters R or S, e.g., R, R; S, S; R, S; and S, R. For example, the four stereoisomers of pyrethrin I are as follows:

[0068] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in the racemic or enantiomerically enriched form, e.g., the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is in the (R)- or (S)-configuration with at least a 50% enantiomeric excess, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least a 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0069] Depending on the choice of starting materials and methods, the steroids of the application can be present in the form of one or more of possible isomers, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms), in the form of optically active (R)- or (S)-isomers, using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituents on the cycloalkyl can be in the cis or trans configuration.

[0070] Any mixture of stereoisomers can be separated into their individual isomers using standard techniques, such as preparative chromatography.

[0071] 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). Thus, individual stereochemical isomers or mixtures of their enantiomers, diastereomers, or geometric (or conformational) isomers, of the compounds of the application are within the scope of the application.

[0072] 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.

[0073] Any resulting racemate of an end product or intermediate can be resolved into the individual optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, which are obtained by treatment with the customary resolving agents. The racemates can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, the enantiomers can be prepared by asymmetric synthesis, e.g., see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0074] 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.

[0075] The salts referred to herein are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are those that are known in the art, as described in Berge et al., J. Pharmacol Sci, 1997, 66, 1-19. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, nitric acid, perchloric acid, and organic acids such as carboxylic acids, sulfonic acids, sulfinic acids, sulfamic acids, and the like, specifically, but not limited to, methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, succinic acid, benzoic acid, succinic acid, pamoic acid, salicylic acid, galactaric acid, glucoheptanoic acid, mandelic acid, 1,2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, carbonic acid, trifluoroacetic acid, glycolic acid, glycollyl sulfonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, malonic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, fumaric acid, lactic acid, lactobionic acid, or oxalic acid, or by other methods such as ion exchange procedures, as described in the literature. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, 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, and the like. Additionally, pharmaceutically acceptable salts can include salts of acidic groups that are formed by appropriate bases, such as alkali, alkaline earth, 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 or alkaline earth 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.

[0076] 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.

[0077] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0078] 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.

[0079] "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.

[0080] 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.

[0081] "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.

[0082] 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.

[0083] 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.

[0084] 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

[0085] Furthermore, the heavier isotopes, 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.

[0086] 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 optionally replaced with a particular substituent. Unless otherwise indicated, a given optional substituent can occupy any available substitutable position of the group. When more than one position in the given structure can be substituted with an indicated range of substituents, the substituents can be the same or different at each position. The substituents described herein can be, but are not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, heteroaryloxy, oxo (=0), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like.

[0087] 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.

[0088] 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.

[0089] The term "alkenyl" denotes a straight-chain or branched-chain monovalent hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, or from 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 "trans", "cis", or "E", "Z" groups, wherein 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.

[0090] The term "alkynyl" denotes a straight-chain or branched-chain monovalent hydrocarbon group having from 2 to 12 carbon atoms, or from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, or from 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, wherein specific examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0091] 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.

[0092] 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, and wherein only one heteroatom 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).

[0093] Heterocyclyl can be carbon-based or heteroatom-based. "Heterocyclyl" also includes groups in which the heterocyclyl group is annelated to a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin-1-yl, 2-oxo-5-azabicyclo[2.2.1]hept-5-yl, 2-oxo-5-azabicyclo[2.2.2]oct-5-yl, quinolizinyl, and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like. In the present application, reference to a heterocyclyl group is meant to also include the corresponding N-oxides. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin-1-yl, 2-oxo-5-azabicyclo[2.2.1]hept-5-yl, 2-oxo-5-azabicyclo[2.2.2]oct-5-yl, quinolizinyl, and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like. In the present application, reference to a heterocyclyl group is meant to also include the corresponding N-oxides. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin-1-yl, 2-oxo-5-azabicyclo[2.2.1]hept-5-yl, 2-oxo-5-azabicyclo[2.2.2]oct-5-yl, quinolizinyl, and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like. In the present application, reference to a heterocyclyl group is meant to also include the corresponding N-oxides. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin-1-yl, 2-oxo-5-azabicyclo[2.2.1]hept-5-yl, 2-oxo-5-azabicyclo[2.2.2]oct-5-yl, quinolizinyl, and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms, such as pyrimidinedionyl. Also, the heterocyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0), alkyl-C(=0), alkyl-S(=0), alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0), hydroxy-substituted alkyl-S(=0)2, carboxyalkoxy, and the like. In the present application, reference to a heterocyclyl group is meant to also include the corresponding N-oxides.

[0094] The term "aryl" or "aromatic ring" can be used alone or as part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" and refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing in combination 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. 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. In the present application, reference to aryl groups also includes aryl groups further losing one hydrogen atom to form divalent radicals.

[0095] The term "heteroaryl" or "heteroaromatic ring" refers to monocyclic, bicyclic, and tricyclic ring systems containing in combination 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 given in the present application, 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 heteroaryl groups also includes heteroaryl groups further losing one hydrogen atom to form divalent radicals.

[0096] 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; and the following bicyclic rings, but is 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.

[0097] 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; forms of primary, secondary, tertiary amines and quaternary ammonium salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced by substitution, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[0098] The term "halogen" means F, Cl, Br or I.

[0099] The term "halo" as used herein means one or more of the halogens F, Cl, Br or I.

[0100] The term "hydroxy" as used herein means one or more hydroxyl groups.

[0101] The term "substituted" when used between two groups means that the group preceding the substituent is substituted with the group following the substituent, e.g., "aryl substituted alkyl" means that the alkyl group is substituted with an aryl group, "alkoxycarbonyl substituted alkyl" means that the alkyl group is substituted with an alkoxycarbonyl group.

[0102] When multiple groups of the present application are used in conjunction, the substituent relationship proceeds from left to right, e.g., "arylalkyl" indicates an aryl group substituted on the alkyl group, "alkoxyalkoxy" indicates an alkoxy group substituted on the alkoxy group.

[0103] The term "unsaturated" as used herein refers to a moiety containing one or more degrees of unsaturation.

[0104] Description of the compounds of the present application

[0105] The present application provides a steroid compound having a structure as shown in formula (I'), or 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'),

[0106] wherein R 2 is

[0107] R 3 is hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=O)-alkyl, monophosphate or diphosphate; 6 or -NR 5 R 6 ;

[0108] R 4 is R 7 (O-R 8 ) n -;

[0109] R 5 and R 6 are each independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, alkylene-OC(=O)-alkyl, monophosphate or diphosphate;

[0110] R 7 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or heterocyclyl;

[0111] R 8 is alkylene, cycloalkylene, heteroalkylene, heterocyclylene, arylene or heteroarylene;

[0112] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0113] wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8the 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, aryl, and heteroaryl;

[0114] R 10 selected from

[0115] R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j each independently is 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;

[0116] R x is halogen, hydroxyl, amino, alkyl, carboxyl, phosphato, sulfato, or alkoxy;

[0117] 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.

[0118] 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),

[0119] In Formula (I’-1) and Formula (I’-2), R2 R a R b R c R d R e R f R 1 R

[0120] 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 is 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),

[0121] In some embodiments, R 1 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclyl; R 2 is defined as in Formula (I’).

[0122] In some embodiments, 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.

[0123] In some embodiments, R 1 is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, or thioxanyl.

[0124] In some embodiments, the steroid compound is of the formula: 3 hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkoxyC 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 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 1-6 alkylene-OC(=0)-C 1-6 alkyl, monophospho, or diphospho.

[0125] In some embodiments, the steroid compound is of the formula: 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=0)-C 1-6 alkyl.

[0126] In some embodiments, the steroid compound is of the formula: 5 and R 6 are each independently hydrogen, C 1-6 alkylene-OC(=0)-C 1-6 alkyl. In some embodiments, the steroid compound is of the formula: 5 hydrogen, R 6 is C 1-6 alkylene-OC(=0)-C 1-6 alkyl.

[0127] In some embodiments, the steroid compound is of the formula: 3C 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.

[0128] In some embodiments, R in the steroidal compound 4 For R 7 (OR 8 ) n -;R 7 For hydrogen, deuterium, 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; R 8 C 1-6 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0129] In some specific embodiments, in the steroidal compound, R 7 It is hydrogen or C 1-6 Alkyl group. In some specific embodiments, R in the steroidal compound. 7 It is hydrogen or C 1-3 alkyl.

[0130] In other embodiments, in the steroidal compound, R 4 For R 7 (OR 8 ) n -;R 7hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethenyl, propenyl, allyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyC 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.

[0131] In some embodiments, the steroid compound has n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0132] In some embodiments, the steroid compound has n is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0133] In some embodiments, the steroid compound has the structure of Formula (III), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the structure of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII),

[0134] In the above Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), and Formula (VIII), R 4 is R 7 (O-R 8 ) n -; 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, monophospho, or diphospho; R 7 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-9Heterocyclic group; R 8 C 1-6 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0135] In other embodiments, in formulas (III), (IV), (V), (VI), (VII), and (VIII), where R 4 For R 7 (OR 8 ) n -;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; R 7 Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-8 cycloalkyl; R 8 C 1-3 Alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0136] In some embodiments, the steroidal compound has one of the following structures, or its stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug.

[0137] The pharmaceutical compositions, formulations, and administration methods of the present invention

[0138] The pharmaceutical compositions of this invention comprise any of the steroidal compounds of this invention. The pharmaceutical compositions may further comprise pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators, or combinations thereof.

[0139] The pharmaceutical composition can be used to treat eye diseases, and in particular, it has a good therapeutic effect on cataracts, floaters, myopia, or presbyopia.

[0140] 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.

[0141] When used for therapy, therapeutically effective amounts of the steroid compounds of the present application can be administered as the chemically raw pharmaceutical and also as an active ingredient of a pharmaceutical composition. Accordingly, the present teachings also provide pharmaceutical compositions comprising a therapeutically effective amount of a steroid compound of the present application and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., reduction in viral load. When the active ingredient is administered alone, this term refers to that ingredient alone. When combinations are used, this term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. In accordance with another aspect of the present teachings, there are also provided methods for preparing a pharmaceutical formulation, comprising admixing a steroid compound of the present application with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to steroid compounds, materials, compositions, and / or dosage forms which 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.

[0142] 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.

[0143] Use of the compounds and compositions of the present invention

[0144] Use of the steroid compounds or pharmaceutical compositions of the present invention in the manufacture of a medicament for preventing, managing, treating or alleviating an ocular condition in a patient.

[0145] In some embodiments, the ocular condition is cataracts, floaters, myopia or presbyopia.

[0146] An "effective amount" or "effective dose" of the steroid compounds or pharmaceutically acceptable compositions of the present invention means an amount effective at managing or alleviating the severity of one or more of the conditions mentioned herein. The compounds and compositions thereof according to the methods of the present invention can be used to manage or alleviate the severity of the conditions in any amount and by any route of administration effective for that purpose. The exact amount required will vary depending on the subject's condition, age, general condition, severity of infection, special factors, mode of administration, etc. The compounds or compositions of the present invention can be administered in combination with one or more other therapeutic agents, as discussed herein.

[0147] In order that those skilled in the art can better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in further detail.

[0148] General synthetic procedures

[0149] Generally, the steroid compounds of the present invention can be prepared by the methods described herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0150] Those skilled in the art will recognize that the chemical reactions described herein can be used to prepare many of the other compounds of the present invention and that other methods for preparing the compounds of the present invention are also within the scope of the present invention. For example, the synthesis of those compounds of the present invention which are not exemplified herein can be successfully performed by a person skilled in the art by applying the methods described herein to the synthesis of the other compounds of the present invention using appropriate reagents and reaction conditions according to the teachings of the present invention. In addition, other reagents and / or reaction conditions known to a person skilled in the art can be used in place of those described herein to synthesize the compounds of the present invention.

[0151] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich, Sigma, Merck, Bide, Aladdin, Acros, 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 Company, Guangzhou Chemical Reagent Factory, Tianjin Haohuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haian Chemical Factory.

[0152] 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 as received.

[0153] 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 by syringe. Glassware was oven- or flame-dried.

[0154] 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).

[0155] Low resolution mass spectrometry (MS) data were determined by a spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was kept at 30 °C) of Agilent 6320 series LC-MS, a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied for LC-MS spectrometer.

[0156] 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.

[0157] The following abbreviations are used throughout the present invention:

[0158] AcOH: acetic acid; Boc2O, BOC anhydride: di-tert-butyl dicarbonate; Boc: tert- butyloxycarbonyl; Bu4NHSO4: tetrabutylammonium hydrogen sulfate; CH3CN: acetonitrile; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; HC1: hydrogen chloride; HC1 / EA: ethyl acetate solution of hydrogen chloride; H2O: water; NaOH: sodium hydroxide; Nal: sodium iodide; K2CO3: potassium carbonate; rt, r.t.: room temperature; PE: petroleum ether; THF: tetrahydrofuran; EDCI: l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP: 4-dimethylaminopyridine; TBAI: tetrabutylammonium iodide; DMF: dimethylformamide; p-TsOH: p-toluenesulfonic acid; TAF: trifluoroacetic acid; TBAF: tetrabutylammonium fluoride

[0159] First step: p-nitrophenyl chloroformate (2.02 g, 10.0 mmol) was dissolved in 20 mL dry dichloromethane, cooled to 0 °C under nitrogen protection, a solution of lanosterol (4.27 g, 10.0 mmol) and pyridine (0.791 g, 10.0 mmol) in dichloromethane (50 mL) was added slowly dropwise, after the dropwise addition, the temperature was allowed to rise to room temperature naturally and the reaction was carried out overnight. 30 mL water was added, the liquid was separated, the organic layer was washed with 30 mL saturated sodium chloride, then dried with anhydrous sodium sulfate, the obtained crude product was concentrated under reduced pressure and purified by silica gel column, eluent: PE-5% EA / PE, to obtain compound 1-1 (3.50 g, white solid). 1 H NMR (500 MHz, CDC13) δ 8.28 (d, 2H), 7.39 (d, 2H), 5.10 (t, 1H), 4.48 (dd, 1H), 2.10 - 1.99 (m, 5H), 1.99 - 1.15 (m, 24H), 1.06 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H), 0.91 (d, 3H), 0.88 (s, 3H), 0.69 (s, 3H) ppm.

[0160] Second step: dodecanediol monomethyl ether (0.560 g, 1.00 mmol) was dissolved in 10 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and potassium tert-butoxide (0.117 g, 1.05 mmol) was added. After the addition was completed, the reaction was continued to stir at 0 °C for 30 min. Compound 1-1 (0.592 g, 1.00 mmol) was added, and after the addition was completed, the reaction was continued to react at 0 °C for 2 h. 20 mL of water and 30 mL of ethyl acetate were added, and the liquid was separated. The organic layer was washed with 20 mL of saturated sodium chloride twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column, and eluent: 20% EA / PE-100% EA-4% MeOH / DCM, to obtain compound 1 (0.600 g, white solid). LCMS (APCI), m / z, [M+23] + = 1036; 1 H NMR (500 MHz, CDC13) δ 5.09 (t, 1H), 4.34 (dd, 1H), 4.28 - 4.24 (m, 2H), 3.74 (t, 2H), 3.66 - 3.62 (m, 42H), 3.56 - 3.52 (m, 2H), 3.37 (s, 3H), 2.07 - 1.96 (m, 5H), 1.96 - 1.81 (m, 2H), 1.80 - 1.10 (m, 22H), 0.99 (s, 3H), 0.94 (s, 3H), 0.91 (d, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.68 (s, 3H) ppm.

[0161] Example 2: Synthesis of compound 2

[0162] First step: synthesis of compound 2-1

[0163] Lanosterol (10.0 g, 23.4 mmol), 1-(methylsulfonyl)-4-nitrobenzene (14.1 g, 70.3 mmol), iron trisacetylacetonate (0.8 g, 2.3 mmol), sodium bicarbonate (5.9 g, 70.3 mmol) were added to a 1 L two-necked flask, and methanol 60 mL and dichloromethane 300 mL were added. The reaction was protected by nitrogen replacement, and phenylsilane (7.6 g, 70.3 mmol) was added under ice bath stirring. The reaction was allowed to naturally rise to room temperature and stirred for 12 h. After the reaction was completed, the reaction liquid was concentrated to dryness, and acetonitrile 300 mL was used to beat three times, and then filtered and dried to obtain compound 2-1 (10.4 g, white solid). 1H NMR (500 MHz, CDC13) δ 3.26 (d, J = 11.3 Hz, 1H), 2.13 - 1.99 (m, 4H), 1.97 - 1.88 (m, 1H), 1.78 - 1.66 (m, 5H), 1.65 - 1.56 (m, 4H), 1.55 - 1.26 (m, 13H), 1.23 - 1.15 (m, 2H), 1.09 - 0.99 (m, 8H), 0.93 (d, J = 6.3 Hz, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.71 (s, 3H) ppm.

[0164] Second Step: Synthesis of compound 2-2

[0165] The starting compound 2-1 (0.222 g, 0.500 mmol) was dissolved in 5 mL dry dichloromethane, cooled to 0 °C under nitrogen protection, pyridine (0.079 g, 0.100 mmol) was added, then p-nitrophenyl chloroformate (0.111 g, 0.550 mmol) was added, after addition, the temperature was naturally increased to room temperature and reacted overnight. 10 mL water was added, 30 mL dichloromethane was added, the organic layer was washed with 30 mL saturated sodium chloride, then dried with anhydrous sodium sulfate, the obtained crude product was concentrated under reduced pressure, and purified by silica gel column, eluent: PE-20% EA / PE, the primary purified product was washed with 10 mL acetonitrile for 20 minutes, filtered, and the filter cake was dried to obtain compound 2-2 (0.150 g, white solid). 1 H NMR (500 MHz, CDC13) δ 3.26 (d, J = 11.3 Hz, 1H), 2.13 - 1.99 (m, 4H), 1.97 - 1.88 (m, 1H), 1.78 - 1.66 (m, 5H), 1.65 - 1.56 (m, 4H), 1.55 - 1.26 (m, 13H), 1.23 - 1.15 (m, 2H), 1.09 - 0.99 (m, 8H), 0.93 (d, J = 6.3 Hz, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.71 (s, 3H) ppm.

[0166] Third Step: Synthesis of compound 2

[0167] Tetramethylene glycol monomethyl ether (0.0512 g, 0.246 mmol) was dissolved in 2 mL of dry tetrahydrofuran, cooled to 0 °C under nitrogen protection, and potassium tert-butoxide (0.029 g, 0.258 mmol) was added. After the addition was completed, the reaction was continued to be stirred at 0 °C for 30 min. Compound 2-2 (0.150 g, 0.246 mmol) was added, and after the addition was completed, the reaction was continued to be stirred at 0 °C for 2 h. 5 mL of water and 10 mL of ethyl acetate were added, and the mixture was separated. The organic layer was washed with 20 mL of saturated sodium chloride solution twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography, and eluted with 20% EA / PE-60% EA to obtain compound 2 (0.083 g, white solid). LCMS (APCI), m / z, [M+23] + = 701; 1 H NMR (500 MHz, CDC13) δ 4.35 (dd, 1H), 4.32 - 4.23 (m, 2H), 3.73 (t, 2H), 3.69 - 3.62 (m, 10H), 3.57 - 3.53 (m, 2H), 3.38 (s, 3H), 2.08 - 1.98 (m, 4H), 1.96 - 1.64 (m, 7H), 1.63 - 1.12 (m, 21H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91 (d, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.69 (s, 3H) ppm.

[0168] Example 3: Synthesis of compound 3

[0169] Tetramethylene glycol monomethyl ether (0.390 g, 1.86 mmol) was dissolved in 10 mL of dry tetrahydrofuran, and potassium tert-butoxide (0.220 g, 1.95 mmol) was added at room temperature. The mixture was cooled to 0 °C under nitrogen protection, stirred for 30 min, and compound 1-1 (1.10 g, 1.86 mmol) was slowly added. After the addition was completed, the reaction was continued to be stirred at room temperature for 4 h. 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was separated. The organic layer was washed with 20 mL of saturated sodium chloride solution once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 3 (0.300 g, transparent oil). LCMS (APCI), m / z, [M+23] + = 684; 1H NMR (500 MHz, CDC13) δ 5.10 (t, 1H), 4.35 (dd, 1H), 4.27 (t, 2H), 3.73 (t, 2H), 3.69 - 3.61 (m, 10H), 3.58 - 3.52 (m, 2H), 3.38 (s, 3H), 2.10 - 1.97 (m, 5H), 1.97 - 1.82 (m, 2H), 1.81 - 1.63 (m, 8H), 1.60 (s, 3H), 1.59 - 1.45 (m, 3H), 1.45 - 1.22 (m, 6H), 1.20 - 1.10 (m, 2H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91 (d, 3H), 0.90 (s, 3H), 0.87 (s, 3H), 0.69 (s, 3H) ppm.

[0170] Example 4: Synthesis of compound 4

[0171] Compound 1-1 (1.80 g, 3.04 mmol) was added slowly under nitrogen protection at 0°C, and the mixture was stirred at room temperature for 4 h. Water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The organic layer was washed with saturated sodium chloride aqueous solution (100 mL) once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column to obtain compound 4 (0.500 g, white solid). LCMS (APCI), m / z, [M+23] = 772. + 1 H NMR (500 MHz, CDC13) δ 5.10 (t, 1H), 4.35 (dd, 1H), 4.29 - 4.25 (m, 2H), 3.73 (t, 3H), 3.67 - 3.63 (m, 18H), 3.57 - 3.53 (m, 2H), 3.38 (s, 3H), 2.09 - 1.97 (m, 5H), 1.97 - 1.82 (m, 2H), 1.82 - 1.63 (m, 6H), 1.60 (s, 3H), 1.60 - 1.34 (m, 6H), 1.34 - 1.23 (m, 3H), 1.21 - 1.11 (m, 2H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91 (d, 3H), 0.90 (s, 3H), 0.87 (s, 4H), 0.69 (s, 3H) ppm.

[0172] Example 5: Synthesis of compound 5

[0173] ​Octaethylene glycol monomethyl ether (1.300 g, 3.37 mmol) was dissolved in 20 mL of dry tetrahydrofuran, potassium tert-butoxide (0.400 g, 3.54 mmol) was added at room temperature, and the mixture was cooled to 0 °C under nitrogen protection, stirred for 30 min, and then compound 1-1 (2.00 g, 3.37 mmol) was slowly added. After the addition was completed, the mixture was allowed to naturally warm to room temperature and reacted for 4 h. 50 mL of water and 30 mL of ethyl acetate were added for liquid separation. The organic layer was washed once with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 5 (0.470 g, white solid). LCMS (APCI), m / z, [M+23] + = 860; 1 H NMR (500 MHz, CDCl3) δ 5.10 (t, 1H), 4.35 (dd, 1H), 4.31-4.23 (m, 2H), 3.73 (t, 2H), 3.67-3.63 (t, 26H), 3.57-3.53 (m, 2H), 3.38 (s, 3H), 2.08-1.98 (m, 5H), 1.97-1.81 (m, 2H), 1.81-1.64 (m, 8H), 1.60 (s, 3H), 1.60-1.44 (m, 3H), 1.45-1.23 (m, 6H), 1.20-1.12 (m, 2H), 1.00 (s, 3H), 0.95 (s, 3H), 0.91 (d, 3H), 0.90 (s, 3H), 0.87 (s, 3H), 0.69 (s, 3H) ppm.

[0174] Test Example 1: Solubility Test

[0175] 1. Instruments and Materials

[0176] Instruments: Shimadzu LC-20ADXR; shaker; glass instruments; pipette.

[0177] Materials: pH = 7.2 PBS buffer, pure water, HPLC ethanol, HPLC methanol, HPLC tetrahydrofuran

[0178] 2. Experimental Process

[0179] 2.1 Preparation of Compound Sample Standard Compound sample was taken into a centrifuge tube, 1 mL of tetrahydrofuran was added at room temperature to completely dissolve the sample, and the concentration of the mother liquor was obtained.

[0180] 2.2 Preparation of saturated sample solution of the compound of interest Take the sample of the compound of interest and place it in a centrifuge tube. Add 1 mL of pure water at room temperature. Place it on a shaker at room temperature for 1 hour. Take the sample and place it in a refrigerated centrifuge. Set the centrifuge to 4000 rpm at 25 °C for 10 minutes. After removal, pipette the supernatant clear saturated solution. Filter using a 0.22 μm filter.

[0181] 2.3 Preparation of standard curve solution Take the stock solution and dilute it with tetrahydrofuran in a gradient. Dilute by vortexing.

[0182] 2.4 Determination of sample solubility

[0183] Determine the solubility using the HPLC method.

[0184] 2.5 Determination of standard curve, pipette 200 μL of the standard curve solution into the syringe. Start with a low concentration and inject 1 μL of each. Record the peak area of the chromatogram.

[0185] 2.6 Inject 1 μL of the saturated solution and record the peak area of the chromatogram.

[0186] 3. Comparison of clarity after centrifugation

[0187] 3.1 Take pure water and place it in a centrifuge tube. Compare the supernatant clear solution from step 2.2 above with the 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.

[0188] 4. Calculation

[0189] 4.1 Calculate the concentration versus the peak area of the chromatogram to obtain a standard curve regression equation.

[0190] 4.2 Calculate the concentration of the peak area of the saturated sample using the regression equation.

[0191] 4.3 Obtain the solubility value in mg / mL. The results are shown in Table 2.

[0192] 5. HPLC method conditions

[0193] 5.1 Column: YMC-Triart C8 5 μm 4.6 x 50 mm;

[0194] Method: Mobile phase: 0.1% trifluoroacetic acid in methanol and ethanol; mobile phase gradient: 100% methanol as phase A and 100% ethanol as phase B, 10% B to 90% B in 3 mins; post equilibration 10% ethanol for 0.5 mins; detection wavelength: full wavelength scan

[0195] 5.2 Detection temperature: 40 °C

[0196] Table 2 Solubility test results

[0197] Conclusion: From the results of Table 2, the solubility of the compound of the present application in aqueous solution is significantly improved compared with lanosterol, which is beneficial to the development of eye drops.

[0198] Test Example 2: Detection of drug content in rabbit eye tissue

[0199] The drug content in different eye tissues of the blue rabbits was detected to detect the distribution of the test compound in the eye tissues. Nine blue rabbits (male, 3-5 months old) were placed in the animal room for 3 days for adaptation. 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 performed until complete dissolution or stable suspension was formed. 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 using a pipette gun. The left and right eyes were given at the same time, and whether the drug solution leaked was observed after administration. At 0.5 h, 3 h, 6 h / 10 h after administration, 3 rabbits were euthanized, and the eyeballs were removed and different eye tissue structures were peeled off (left and right eyes were taken at the same time). The contents of the original 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.

[0200] Table 3 Concentrations of the original drug and lanosterol in the conjunctiva of blue rabbits after eye drops of different concentrations of compounds

[0201] BQL: below the lower limit of quantification

[0202] Table 4 Concentrations of the original drug and lanosterol in the cornea of blue rabbits after eye drops of different concentrations of compounds

[0203] BQL: below the lower limit of quantification

[0204] Table 5 Concentrations of the original drug and lanosterol in the sclera of blue rabbits after eye drops of different concentrations of compounds

[0205] BQL: below the lower limit of quantification

[0206] Conclusion: After eye drops of compound 5, a high concentration of lanosterol can be detected in each tissue of the eye (conjunctiva, cornea, sclera), indicating that it has good permeability.

[0207] Test Example 3: Cell lens protein agglutination test

[0208] 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 hours later; then, 20 μM of the compound and 100 mM hydrogen peroxide were added to each well, and the mixture was incubated for 48 hours. 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 was calculated (inhibition rate, %).

[0209] Conclusion: Testing revealed that the compound of this invention significantly inhibits the aggregation of lens proteins.

[0210] 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

A steroid compound having a structure as shown in Formula (I’), or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown in 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. The steroid compound according to 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'). 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’). 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. 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. 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. 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. 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. 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. The steroid compound according to claim 9, wherein, R 4 For R 7 (O-R 8 ) n -; R 5 and R 6 each independently is 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 C 7 alkyl, R 1-4 alkyl, R 8 alkyl, R 1-3 alkylene; 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. 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, 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. Use of the steroid compound of any one of claims 1-11 or the pharmaceutical composition of claim 12 in the manufacture of a medicament for preventing, managing, treating, or alleviating an ocular disease in a patient. Use according to claim 13, wherein, The ocular disease is at least one of cataract, presbyopia, myopia, and floaters. The ocular disease is at least one of cataract, presbyopia, myopia, and floaters.

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