CN115772202A

CN115772202A - Steroid compound and application thereof

Info

Publication number: CN115772202A
Application number: CN202211096652.0A
Authority: CN
Inventors: 兰小兵; 谢门门; 薛亚萍; 吴美容
Original assignee: Runer Eye Medicine Guangzhou Co ltd; Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
Current assignee: Runer Eye Medicine Guangzhou Co ltd; Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
Priority date: 2021-09-09
Filing date: 2022-09-08
Publication date: 2023-03-10

Abstract

The present invention relates to a steroid compound and a composition comprising said steroid compound. The steroid compound has a structure shown as a formula (I) or is shown as a formula (I)Stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structures shown. The compounds or compositions provided herein can be used to prepare medicaments for preventing, treating, or ameliorating ocular diseases in a patient.

Description

Steroid compound and application thereof

Technical Field

The invention relates to a steroid compound, a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug, and application thereof in preparing a medicament for treating ophthalmic diseases.

Background

Cataracts belong to the disease of the eye, occurring on the crystalline lens within the eyeball, and opacification of the crystalline lens is collectively called cataract. Aging, genetic, metabolic abnormalities, trauma, radiation, poisoning, localized dystrophy, etc. can cause damage to the lens capsule, increase its permeability, lose barrier function, or cause metabolic disturbance of the lens, denature lens proteins, and create opacity. If the lens of the eye changes from transparent to opaque, which affects the eye's ability to receive sunlight, the vision of the eye is affected. The eyeball turbidity is light, the influence on the vision is light, the vision is increased along with the gradual deepening of the turbidity, and the serious patient can cause blindness. Cataracts are one of the most common blinding eye diseases, and are the major cause of blindness. Since the mechanism of cataract formation is not clear, no breakthrough progress has been made in drug therapy. Therefore, the only treatment identified to be effective at present is surgical treatment.

Although the continuous progress of the cataract surgery provides great help for the treatment of cataract, the cure rate of the surgery treatment is still far lower than the incidence rate, and serious complications are possible to occur; on the other hand, surgical treatment of cataract is very costly, and even in developed countries, cataract imposes a great burden on the medical insurance system. Therefore, the prevention and treatment of the medicament play a role in promoting weight. Currently, the clinical treatments for cataracts include: aldose reductase inhibitors such as cataline (cataline, canarium, albuterol), facolin, bendazac lysine, and the like; anti-oxidative damage drugs such as glutathione, taurine, aspirin, and the like; nutritional and metabolic drugs such as vitamins, carotenoids, etc.; the Chinese medicinal composition comprises herba Dendrobii herba noctilus pill, QIJUDIHUANG pill, and Concha Haliotidis powder. The long-term clinical tests prove that the medicines for treating the cataract can only delay the deterioration of the cataract and can not reverse the condition of the cataract. Meanwhile, as China begins to step into an aging society, cataract patients are increasing, and the demand of cataract drugs is more urgent.

Therefore, there is a great clinical need for new ophthalmic external anti-cataract drugs that are safe, have good efficacy, have strong intraocular penetration and are stable in properties.

Disclosure of Invention

In a first aspect, the present invention provides a steroid compound having a structure represented by formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof:

wherein:

x is substituted O or N, or cycloalkyl or heteroaryl containing at least one heteroatom of O and N;

y is

R ⁱ And R ^j Each independently H, deuterium, hydroxy, amino, halogen, cyano, mercaptoA nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or haloalkoxyalkyl group;

n is 0, 1 or 2;

R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^g 、R ^h each independently is alkyl, haloalkyl, hydroxyalkyl, alkoxy, halo-or hydroxy-substituted alkoxy, alkylthio, halo-or hydroxy-substituted alkylthio, alkylamino, halo-or hydroxy-substituted alkylamino, alkoxyalkyl, halo-or hydroxy-substituted alkoxyalkyl, alkenyl or alkynyl;

each of the hydrogen atoms on ring a, ring B, ring C, and ring D is independently unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo-or hydroxy-substituted alkoxyalkyl, alkoxy, halo-or hydroxy-substituted alkoxy, alkoxyalkoxy, halo-or hydroxy-substituted alkoxyalkoxy, alkylamino, halo-or hydroxy-substituted alkylamino, alkylthio, halo-or hydroxy-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

In some embodiments, said X in formula (I) is O or N substituted with H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl; and the alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl may be optionally substituted with 1,2,3,4, 5 or 6 substituents selected from hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl and heteroaryl.

In some embodiments, in formula (I), X is cycloalkyl or heteroaryl containing at least one heteroatom selected from O and N, and a hydrogen atom on the cycloalkyl or heteroaryl is unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo-or hydroxyl-substituted alkoxyalkyl, alkoxy, halo-or hydroxyl-substituted alkoxy, alkoxyalkoxy, halo-or hydroxyl-substituted alkoxyalkoxy, alkylamino, halo-or hydroxyl-substituted alkylamino, alkylthio, halo-or hydroxyl-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

In some embodiments, R in formula (I) ⁱ And R ^j Each independently is H, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, or trifluoromethyl.

In some embodiments, R in formula (I) ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^g 、R ^h Each independently is C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Hydroxyalkyl radical, C _1-3 Alkoxy, halo or hydroxy substituted C _1-3 Alkoxy radical, C _1-3 Alkylthio, halo or hydroxy substituted C _1-3 Alkylthio radical, C _1-3 Alkylamino, halo or hydroxy substituted C _1-3 Alkylamino radical, C _1-3 Alkoxy radical C _1-3 Alkyl, halo or hydroxy substituted C _1-3 Alkoxy radical C _1-3 Alkyl radical, C _2-6 Alkenyl or C _2-6 Alkynyl.

In some embodiments, the hydrogen atoms on ring B, ring C, and ring D in formula (I) are unsubstituted and any one or two hydrogen atoms on ring a are substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo-or hydroxyl-substituted alkoxyalkyl, alkoxy, halo-or hydroxyl-substituted alkoxy, alkoxyalkoxy, halo-or hydroxyl-substituted alkoxyalkoxy, alkylamino, halo-or hydroxyl-substituted alkylamino, alkylthio, halo-or hydroxyl-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

In some embodiments, none of the hydrogen atoms on ring a, ring B, ring C, and ring D in formula (I) are substituted.

In some embodiments, the compounds provided herein have a structure as shown in formulas (II), (III), (IV), or are stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of structures shown in formulas (II), (III), (IV):

wherein:

R ¹ and R ² Each independently is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl; or R ¹ And R ² And the N atom to which it is attached form a nitrogen-containing heterocyclic group;

R ³ is H, deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryloxy or hydroxy-substituted alkoxy;

R ⁴ is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl, heterocyclyl OR alkyl- (C = O) OR ⁶ ；

R ⁵ Is H, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or haloalkoxyalkyl;

R ⁶ is alkyl, haloalkyl, hydroxyalkyl, carboxylAlkyl, aryl, cycloalkyl or heterocyclyl;

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Or R ⁶ Optionally substituted with 1,2,3,4, 5, or 6 substituents selected from the group consisting of hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl, and heteroaryl.

In some embodiments, the compounds provided herein have a structure as shown in formulas (V), (VI), (VII), or are stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of structures shown in formulas (V), (VI), (VII):

R ¹ and R ² Each independently is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl; or R ¹ And R ² And the N atom to which it is attached, together form a nitrogen-containing heterocyclic group;

R ⁴ is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoric acidArylalkyl, aryl, heteroaryl, benzyl, cycloalkyl, heterocyclyl OR alkyl- (C = O) OR ⁶ ；

R ⁶ is alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, aryl, cycloalkyl or heterocyclyl;

In some embodiments, R is as described in formulas (II) - (VII) ¹ And R ² Each independently is C _1-6 Alkyl radical, C _6-10 Aryl radical, C _2-9 Heteroaryl, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _1-6 Phosphoalkyl, benzyl, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group.

In some embodiments, R is described in formulas (II) - (VII) ¹ And R ² Each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate.

In some embodiments, R is as described in formulas (II) - (VII) ¹ And R ² And the N atom to which they are attached, together form a 5-7 membered nitrogen-containing heterocyclic group.

In some casesIn one embodiment, R is represented by the general formulae (II) to (VII) ³ Is H, deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Halogenoalkoxy radical C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkoxy radical C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Haloalkylamino, C _1-6 Alkylthio radical, C _3-6 Cycloalkyl, C _2-9 Heterocyclic group, C _6-10 Aryl radical, C _2-9 Heteroaryl, C _6-10 Aryloxy radical, C _6-10 Arylamino, C _2-9 Heteroaryloxy or hydroxy-substituted C _1-6 An alkoxy group.

In some embodiments, R is as described in formulas (II) - (VII) ³ Is H, deuterium, hydroxyl, amino, F, cl, br, I, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

In some embodiments, R is as described in formulas (II) - (VII) ⁴ Is C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _6-10 Aryl radical, C _2-9 Heteroaryl group, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _1-6 Phosphoalkyl, benzyl, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group.

In some embodiments, R is described in formulas (II) - (VII) ⁴ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate.

In some embodiments, R is described in formulas (II) - (VII) ⁴ Is alkyl- (C = O) OR ⁶ ；R ⁶ Is C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _6-10 Aryl radical, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group.

In some embodiments, R is as described in formulas (II) - (VII) ⁴ Is alkyl- (C = O) OR ⁶ ；R ⁶ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate.

In some embodiments, R is as described in formulas (II) - (VII) ⁵ Is H, deuterium, hydroxyl, amino, halogen, cyano, mercapto, nitro, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical C _1-6 Alkyl or C _1-6 Halogenoalkoxy radical C _1-6 An alkyl group.

In some embodiments, R is as described in formulas (II) - (VII) ⁵ Is H, deuterium, hydroxyl, amino, halogen, cyano, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl or trifluoromethyl.

In some embodiments, R is described in formulas (II) - (VII) ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Or R ⁶ Optionally substituted with 1,2,3,4, 5 or 6 substituents selected from hydroxy, amino, F, cl, br, I, cyano, carboxy, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl and halophenyl.

In some embodiments, the compound has the structure shown below, or is a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof:

in a second aspect, the present invention provides a composition comprising a compound of the first aspect, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

In a third aspect, the present invention provides the use of a compound according to the first aspect or a composition according to the second aspect in the manufacture of a medicament for the prevention, treatment or alleviation of an ocular disease in a patient.

In some embodiments, the ocular disease is cataract or muscae volitantes.

The compound provided by the invention has good activity in inhibiting protein aggregation caused by intracellular lens protein mutation, has no toxic or side effect on lens cells, has good water solubility, is easy to be absorbed by organisms, and has good clinical application prospect.

Detailed Description

Definitions and general terms

Unless otherwise indicated, the terms used in the specification and claims have the following definitions.

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

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

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with CAS version of the periodic Table of the elements, and with handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", thomas Sorrell, university Science Books, sausaltio: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A 50.

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

Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or of mixtures thereof, for example racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms). The optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers): e.g., R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformers.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester, aliphatic (C1-24) ester, acyloxymethyl ester, carbonic ester, carbamate and amino acid ester. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: t.higuchi and v.stella, pro-drugs as Novel Delivery Systems, vol.14oftha.c.s.symposium Series, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, j.rautio et al, produgs: design and clinical applications, nature Review Drug Discovery,2008,7,255-270, and S.J. Hecker et al, prodrugs of Phosphonates and Phosphonates, journal of medical chemistry,2008,51, 2328-2345.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, enantiomers, racemates and solutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, jeffrey Aub é, elsevier, oxford, UK, 2012); eliel, e.l. stereochemistry of carbon Compounds (McGraw-Hill, NY, 1962); wilen, s.h. tables of solving Agents and Optical solutions p.268 (e.l.eliel, ed., univ.of note Dame Press, note Dame, IN 1972); chiral Separation Techniques: APraccal Approach (Subramanian, G.Ed., wiley-VCH Verlag GmbH & Co.KGaA, weinheim, germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energybarrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The salts mentioned in the present invention are pharmaceutically acceptable salts, wherein "pharmaceutically acceptable salts" are well known in the art, such as: berge et al, describe the description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmacol Sci,1997,66,1-19. Examples of pharmaceutically acceptable, non-limiting salts include inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, sulfite, nitrate, perchlorate, and organic acid salts, such as carboxylate, sulfonate, sulfinate, thiocarboxylate, and the like, specifically such as, but not limited to, methanesulfonate, ethanesulfonate, formate, acetate, succinate, benzoate, succinate, pamoate, salicylate, galactarate, glucoheptanoate, mandelate, 1,2-ethyldisulfonate, 2-naphthalenesulfonate, carbonate, trifluoroacetate, glycolate, isethionate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate, or oxalic acid, or these salts may be obtained by other methods described above, such as ion exchange methods. Other pharmaceutically acceptableSalts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, caproates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, laurates, lauryl sulfates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, undecanoates, valerics, and the like. In addition, pharmaceutically acceptable salts also include salts obtained with appropriate bases, such as alkali metals, alkaline earth metals, ammonium, and N + (C) _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

Pharmaceutically acceptable salts can be formed with inorganic and organic acids such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen/dihydrogen phosphate, polypetalose, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

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

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.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "protecting group" or "PG" refers to a substituent that, when reacted with another functional group, is generally used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group, and typical carboxyl protecting groups include-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, protective Groups in Organic Synthesis, john Wiley&Sons, new york,1991; kocienski, protecting Groups, thieme, stuttgart,2005。

By "pharmaceutical composition" is meant a mixture of one or more salts 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 the pharmaceutical composition is to facilitate the administration of the compound to the organism.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

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

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present ³ H， ¹⁴ C and ¹⁸ those compounds of F, or in which a non-radioactive isotope is present, e.g. ² H and ¹³ C. the isotopically enriched compounds can be used forMetabolic Studies (use of) ¹⁴ C) Reaction kinetics study (using, for example ² H or ³ H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including measurement of the tissue distribution of drugs or substrates, or in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formulae (I), (II), (III), (IV) can be prepared by conventional techniques known to those skilled in the art or by employing suitable isotopically labelled reagents in place of the original used unlabelled reagents as described in the examples and preparations of this invention.

In addition, heavier isotopes are, in particular, deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-d ₆ 、DMSO-d ₆ Those solvates of (a).

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the above general formula, or as specified in the examples,subclasses, and class of compounds encompassed by the present invention. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (= O), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O), alkyl-S (= O) ₂ -, hydroxy-substituted alkyl-S (= O) ₂ Carboxyalkoxy, and the like.

The term "alkyl" as used herein denotes a saturated straight or branched chain monovalent hydrocarbon group of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH)) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2,3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3,3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical resulting from the elimination of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylidene, and the like.

The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom, examples of which include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.

The term "alkenyl" means a straight or branched chain monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted with one or more substituents described herein, including the positioning of the groups as "trans", "cis" or "E", "Z", wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH = CH) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one position of which is unsaturated, i.e. one C-C is a sp triple bond, wherein the alkynyl radical may be independently and optionally substituted with one or more substituents as described herein, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH) ₂ C ≡ CH), and so forth.

The term "cycloalkyl" refers to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including monocyclic rings of 3 to 12 carbon atoms or bicyclic rings of 7 to 12 carbon atoms. The bicyclic carbocyclic ring having 7 to 12 atoms may be bicyclo [4,5]，[5,5]，[5,6]Or [6,6]The bicyclic carbocyclic ring having 9 or 10 atoms at the same time may be a bicyclo [5,6]Or [6,6]And (4) preparing the system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloaliphatic radicals include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. And the "cycloaliphatic" or "carbocycle", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein a substituent may beBut are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O), alkyl-S (= O) ₂ -, hydroxy-substituted alkyl-S (= O) ₂ Carboxyalkoxy, and the like.

The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more carbon atoms in the ring are independently and optionally substituted with a heteroatom having the meaning described herein, which ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, having only one point of attachment to another molecule. One or more of the ring hydrogen atoms are independently and optionally substituted with one or more substituents as described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered ring monocyclic (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give, for example, SO ₂ ，PO，PO ₂ When the ring is a three-membered ring, in which there is only one heteroatom), or 7-to 10-membered bicyclic rings (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give, for example, SO ₂ ，PO，PO ₂ The group of (ii).

The heterocyclic group may be a carbon-based or heteroatom group. "Heterocyclyl" likewise includes groups formed by the union of heterocyclic groups with saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thialkyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl,piperidinyl, homopiperidinyl, epoxypropyl, azepinyl, oxepanyl, thiepinyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepin

Radical, diaza

Radical, S-N-aza

Pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, pyrazolidinimidazolyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinylalkyl 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1- (piperazin-1-yl) ethanon-4-yl, 2-hydroxy-1- (5,6-dihydro-1,2,4-triazin-1 (4H) -yl) ethanon-4-yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1- (5,6-dihydropyridin-1 (2H) -yl) ethanon-4-yl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 2-methyl-5,6,7,8-tetrahydro- [1,2,4]Triazole [1,5-c]Pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazole [4,3-c]Pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo [2.2.1]Heptane-5-yl, 2-oxo-5-azabicyclo [2.2.2 ]]Octane-5-yl, quinolizinyl and N-pyridyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and wherein two carbon atoms in the ring are replaced by oxygen atoms such as pyrimidinedione. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, oxo (= O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O), alkyl-S (= O) 2-, hydroxy-substituted alkyl-S (= O) ₂ Carboxyl groupAlkoxy, and the like.

The term "aryl" may be used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl", and refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing a total of 6-14 members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 members rings and only one attachment point is attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O), alkyl-S (= O) ₂ -, hydroxy-substituted alkyl-S (= O) ₂ Carboxyalkoxy, and the like.

The term "heteroaryl" denotes monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 membered rings, 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 described herein, wherein each ring system contains 3-7 membered rings and only one attachment point is attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic" or "heteroaromatic. And the heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (= O) -, alkyl-S (= O) ₂ -, hydroxy-substituted alkyl-S (= O) ₂ Carboxyalkoxy and the like.

In still other embodiments, heteroaryl includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, 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, 3534-oxadiazolyl, 5248-oxadiazolyl, 5362-oxadiazolyl, 5725-triazolyl, 3434-oxadiazolyl, 5248-oxadiazolyl, 425732-thiooxazolyl, 4232-thiazolinyl, 4232-thiadiazolyl; the following bicyclic rings are also included, but by no means limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl.

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

The term "halogen" refers to F, cl, br or I.

The term "halo" as used herein means a substitution of the group attached thereto with a halogen, and the number of the substitution may be one or more.

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

When "substituted" is used in the context of the present invention between two groups, it is preceded by a substituent, e.g., "aryl-substituted alkyl" means having an aryl substituent on the alkyl group and "alkoxycarbonyl-substituted alkyl" means having an alkoxycarbonyl substituent on the alkyl group.

When a plurality of groups of the present invention are used in combination, the substitution relationships, such as "arylalkyl" for aryl substituted alkyl, "alkoxyalkoxy" for alkoxy substituted alkoxy, are sequential from left to right.

The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.

In the present invention, substances which can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, 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, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants 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 salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

When therapeutically useful, a therapeutically effective amount of a compound of the present invention may be administered as a raw chemical, or may be provided as an active ingredient in a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention 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 sufficient to show meaningful patient benefit (e.g., reduction in viral load). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the terms refer to combined amounts of the active ingredients which, when combined, administered sequentially or simultaneously, result in a therapeutic effect. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein, means that the compounds, materials, compositions, and/or dosage forms of the present invention 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 problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example, such formulations which are suitable for oral administration may include flavouring agents.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions thereof according to the methods of the invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General synthetic procedure

In general, the compounds of the invention may be prepared by the methods described herein. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, inc., arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, guangdong Guanghua chemical reagent factory, guangzhou chemical reagent factory, tianjin HaoLiyu Chemicals Co., ltd, qingdao Tenglong chemical reagent Co., ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) purchased from QingIsland oceanographic plants. Nuclear magnetic resonance spectroscopy with CDC1 ₃ 、d ₆ -DMSO、CD ₃ OD or d ₆ Acetone as solvent (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets), d (doublets), t (triplets), q (quatets), m (multiplets), br (broadpeds), dd (doublets), dt (doublets), and double triplets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were determined by Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and G1315B DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector applied to the analysis, and an ESI source applied to the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm,5 μm in size. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Time (min)	A(CH ₃ CN，0.1％HCOOH)	B(H ₂ O，0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

The process conditions for HPLC preparation are as follows:

(1) Taking a proper amount of diastereoisomer mixture containing the compound, and dissolving by using a mobile phase;

(2) Setting the flow velocity, the detection wavelength and the column temperature of the mobile phase;

(3) Injecting a proper amount of the sample solution obtained in the step (1) into a high performance liquid chromatograph, recording a chromatogram, and completing separation and analysis of isomers;

a chromatographic column: a normal phase chiral chromatographic column with silica gel containing polysaccharide derivatives on the surface as a stationary phase; more specifically, the column used was either xylonite AD-H (10 x 250nm,5 um) or xylonite AD (20 x 250nm,5 um).

Mobile phase: a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid; more specifically, the volume ratio of n-hexane, n-pentane, isohexane and n-heptane in the mixture of the mobile phase is 10-20%, the volume ratio of methanol, ethanol, isopropanol and acetonitrile is 20-95%, the volume ratio of diethylamine, triethylamine, trifluoroacetic acid and glacial acetic acid is 0-2%, and the total amount of the components in the mobile phase is 100%; more specifically, the volume ratio of n-hexane in the mixture of the mobile phase is 15-20%, the volume ratio of isopropanol is 80-90%, the volume ratio of diethylamine and triethylamine is 0.5-1%, and the sum of the components in the mobile phase is 100%.

Detection wavelength: 250 nm-320 nm;

flow rate: 0.5-10 mL/min; more specifically 2-5 mL/min;

column temperature: 10-35 ℃.

The following acronyms are used throughout the invention:

AcOH: acetic acid

Boc ₂ O, BOC anhydride: di-tert-butyl dicarbonate

Boc: tert-butyloxycarbonyl radical

Bu ₄ NHSO ₄ : tetrabutylammonium hydrogen sulfate

CH ₃ CN: acetonitrile

CDI: n, N' -carbonyldiimidazole

DCM: methylene dichloride

DIPEA: n, N-diisopropylethylamine

EA: ethyl acetate

HCl: hydrogen chloride

HCl/EA: solution of hydrogen chloride in ethyl acetate

H ₂ O: water (I)

NaOH: sodium hydroxide (NaOH)

NaI: sodium iodide

K ₂ CO ₃ : potassium carbonate

rt, r.t.: at room temperature

Example 1: synthesis of Compound 1

324.3mg of CDI was added to a 25mL two-necked flask, dissolved in dichloromethane (8 mL) and stirred at 0 ℃ under argon. Lanosterol 583.4mg dissolved in dichloromethane (6 mL) was added dropwise thereto, and after the addition was completed, the mixture was stirred at room temperature for 1 hour. Further, 140mg of ethanolamine diluted with methylene chloride (4 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added 30mL of ethyl acetate, and the mixture was washed with 5mL of 10% hydrochloric acid each time, and the organic layer was washed twice with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate for 2 hours. The mixture was filtered and concentrated to obtain a white solid powder, which was dried by air blowing at 40 ℃ for 4 hours to obtain 0.76g of a white solid.

¹ H NMR(500MHz,Chloroform-d)δ5.10(s,1H),4.50(dd,J＝11.7,4.5Hz,1H),2.16–1.98(m,8H),1.98–1.80(m,3H),1.80–1.61(m,9H),1.58(d,J＝16.9Hz,9H),1.50(p,J＝9.1Hz,2H),1.45–1.35(m,2H),1.35–1.23(m,4H),1.23–1.11(m,2H),1.00(s,4H),0.96(t,J＝4.1Hz,1H),0.93–0.83(m,13H),0.69(s,3H)ppm.

Example 2: synthesis of Compound 2

Step 1, lanosterol (1g, 2.343mmol) was weighed out into a reaction flask, dissolved in 10ml of dichloromethane, and pyridine (0.114ml, 1.406mmol) was added dropwise under ice bath, and stirred for 15 minutes under ice bath. Triphosgene (0.344g, 1.172mmol) diluted with 10ml of dichloromethane was added dropwise to the reaction, and after the addition was completed, stirring was carried out at room temperature for 20 hours. Work-up gave 1.319g of crude compound 2-1 as a white solid.

Step 2, aniline (0.07ml, 0.77mmol) and triethylamine (0.21ml, 1.53mmol) were measured and dissolved in a reaction flask with 5ml dichloromethane, compound 2-1 (300mg, 0.61mmol) dissolved in 5ml dichloromethane was added dropwise under ice bath, and after the dropwise addition was completed, the reaction was stirred at room temperature for one hour. Sampling TLC detection, and the raw material reaction is complete. The reaction solution was post-treated and purified by silica gel column chromatography to give 2 58mg of compound.

¹ H NMR(500MHz,Chloroform-d)δ7.39(d,J＝7.9Hz,2H),7.30(t,J＝7.8Hz,2H),7.05(t,J＝7.4Hz,1H),6.53(s,1H),5.11(t,J＝7.2Hz,1H),4.51(dd,J＝11.9,4.4Hz,1H),2.04(tt,J＝11.6,5.8Hz,5H),1.86–1.80(m,0H),1.79–1.73(m,1H),1.72–1.65(m,6H),1.61(s,3H),1.57–1.48(m,1H),1.45–1.39(m,1H),1.39–1.31(m,2H),1.30–1.24(m,2H),1.23–1.14(m,2H),1.02(s,3H),0.97(s,3H),0.91(dd,J＝10.2,8.1Hz,10H),0.70(s,3H)ppm。

Example 3: synthesis of Compound 3

Propanol (0.06ml, 0.77mmol) and triethylamine (0.21ml, 1.53mmol) were measured out and dissolved in 2ml of dichloromethane, compound 2-1 (300mg, 0.61mmol) dissolved in 2ml of dichloromethane was added dropwise in ice bath, and after the addition was completed, the reaction was stirred at room temperature for 1 hour. Sampling TLC detection, and completing the raw material reaction. The reaction solution was post-treated and purified by silica gel column chromatography to give 3 162mg of a white solid compound.

¹ H NMR(500MHz,Chloroform-d)δ5.10(t,J＝7.2Hz,1H),4.35(dd,J＝11.7,4.4Hz,1H),4.08(t,J＝6.8Hz,2H),2.11–1.99(m,5H),1.97–1.83(m,1H),1.81–1.74(m,2H),1.73–1.65(m,7H),1.60(s,3H),1.52(ddd,J＝19.7,10.4,7.6Hz,1H),1.45–1.36(m,1H),1.35–1.24(m,2H),1.22–1.12(m,2H),1.10–1.03(m,1H),1.01(s,3H),0.98–0.94(m,7H),0.91(d,J＝7.1Hz,6H),0.88(s,3H),0.69(s,3H)ppm。

Example 4: synthesis of Compound 4

2-butyn-1-ol (0.06ml, 0.77mmol) and pyridine (0.12ml, 1.53mmol) were weighed into a reaction flask, dissolved in 2ml of dichloromethane, and chloroformyl lanosterol (300mg, 0.61mmol) dissolved in 2ml of dichloromethane was added dropwise in ice bath, and after completion of the addition, the reaction was stirred at room temperature for one hour. Sampling TLC detection, and completing the raw material reaction. The reaction solution was subjected to silica gel column chromatography to purify the reaction solution to obtain 276mg of a white solid.

¹ H NMR(500MHz,Chloroform-d)δ5.10(t,J＝7.2Hz,1H),4.69(dq,J＝4.6,2.3Hz,2H),4.36(dd,J＝11.7,4.3Hz,1H),2.12–1.98(m,6H),1.97–1.90(m,1H),1.86(t,J＝2.4Hz,3H),1.82–1.77(m,1H),1.76–1.73(m,1H),1.68(s,4H),1.60(s,3H),1.54–1.47(m,1H),1.42(dddd,J＝17.9,11.5,8.5,3.6Hz,1H),1.30(tq,J＝13.8,5.7,4.2Hz,2H),1.21–1.10(m,2H),1.01(s,3H),0.95(s,3H),0.94–0.85(m,10H),0.69(s,3H)ppm。

Other specific compounds provided by the present invention can be obtained by using a procedure similar to the above-described method for synthesizing compound 1, in place of the corresponding raw materials.

Example 5: effect of Compounds on intracellular aggregation of lens protein mutants

The lens is the only biconvex transparent body in the body that is rich in high concentrations of proteins and has elasticity and can alter its focusing power. The lens fibers have a high concentration of lens proteins. The lens protein superfamily comprises α -, β -and γ -lens proteins, which are some of the most abundant intracellular proteins in the human body. Several factors, including mutations in lens proteins, can lead to protein aggregation-one of the most important causes of cataract formation.

This example examined the effect of the compounds provided by the present invention on the intracellular aggregation of crystallin mutants, α B-R120G, α a-Y118D, β B2-V187E, γ C-G129C and γ D-W43R, using the following methods:

inoculating HeLa cells with good state into a 12-hole plate paved with cell slide in advance, wherein the cell density is 40-50%; culturing for about 24h, wherein the cell density is about 80%, so that the expression vector of the crystallin mutant can be transfected to cells, and the specific operation is carried out according to a scheme suggested by a transfection reagent Lipofectamine TM 2000; after transfection, DMEM fresh culture medium is replaced for continuous culture, and then the crystallin mutant is expressed in a large amount in cells to form a certain proportion of aggresome; replacing the cell culture medium with opti-MEM, and adding the compound of the invention to a final concentration of 4uM; after culturing for 4h, changing into a DMEM fresh culture medium, and culturing for 4h; the preparation of the immunofluorescent slide comprises the following steps: washing with PBS, fixing with 4% paraformaldehyde, washing with PBS, incubating at 0.4% Triton X-100 ℃ at room temperature, washing with PBS, sealing at room temperature, washing with PBS, incubating with primary antibody, incubating with fluorescent secondary antibody from corresponding source at room temperature, washing with PBS, sealing with DAPI-fluorocount-G fluorescent sealing agent, and standing at room temperature in a dark place for about 1 hour; the compound is observed by a microscope, and the single-blind statistics of the aggregation condition in the cells is adopted to analyze the drug effect of the compound.

The aggregation of the compound of the invention on various lens protein mutants in HeLa cells is statistically analyzed by the method. According to experimental results, the compounds 1,2,3 and 4 provided by the invention have good activity in the aspect of inhibiting protein aggregation caused by intracellular lens protein mutation, and the activity is improved by 50-80% compared with that of lanosterol.

Example 6: cytotoxicity assays for compounds

This example uses the following method to test the cytotoxicity of the compounds of the invention:

1. the cytotoxicity of the compound is detected by an MTT (3- (4,5-dimethyl-2-thiazole) -2,5-ditolyl tetrazole bromide) method. The method comprises exposing cells in exponential growth phase to a compound, removing the compound, allowing the cells to proliferate for 2-3 population doubling times, thereby distinguishing proliferating viable cells from non-proliferating viable cells, and determining the number of viable cells by MTT dye reduction. The MTT-formazan product is dissolved in a proper solvent and quantified by a spectrophotometry.

The method comprises the following specific steps: suspending human lens epithelial cells, adding the human lens epithelial cells into a 96-well plate for culture, diluting the compound by multiple ratios by using a culture medium for at least 5 concentration gradients, adding the compound when the cells enter an exponential growth phase, and setting a control group without the compound; and (3) continuing culturing the cells at the end of the growth period after adding the compound, adding a fresh culture medium and MTT into each well, wrapping the culture plate with aluminum foil for culturing for 4-8 h, adding DMSO into each well to dissolve residual MTT-formazan crystals, adding a glycine buffer solution into each well containing DMSO, and recording the light absorption value at 570 nm.

The drug concentration is used as the abscissa (X axis) and the absorbance is used as the ordinate (Y axis) to draw a curve graph, and a percentage inhibition curve is obtained.

2. HLE-B3 cells in a good state are inoculated into a 12-hole plate, and the cell density is 40-50%; after the culture is carried out for about 24 hours and the cell density is about 80 percent, cell transfection can be carried out, and crystallins alpha A-Y118D, alpha B-R120G, beta B2-V187E, gamma C-G129C and gamma D-W43R mutants and an unloaded control group are transfected respectively. The specific operation is carried out according to the proposal of a transfection reagent Lipofectamine TM 2000; after 4h of transfection, DMEM fresh culture medium is replaced to continue to culture for 16h, and then the lens protein mutant is expressed in a large amount in cells; digesting and blowing off with 0.25% pancreatin (EDTA), inoculating to a 96-well plate, culturing 2000 cells in each well for 12 hours; replacing the cell culture medium with opti-MEM, adding the compound of the invention, setting two concentration gradients with a final concentration of 5uM or 50nM, and incubating for 12 hours; add 10. Mu.L of CKK-8, incubate for 1 hour, and measure absorbance at 450 nm.

The compound provided by the invention has no cytotoxicity to normal lens epithelial cells and cell strains transfected with various lens protein mutants through statistical analysis by the method, and the cell activity is improved to a certain extent.

The experimental results show that the compounds 1,2,3 and 4 provided by the invention have no toxic or side effect on lens cells and have good safety.

Example 7: determination of Water solubility of Compounds

In this example, the water solubility of the compound was measured by the following method.

1. Determination of the intrinsic solubility

The concentration of the saturated solution formed when the drug does not contain any impurities, does not dissociate or associate in the solvent, or does not interact with each other, is one of the important physical parameters of the drug, and is of particular interest for the new compounds.

The method comprises the following specific steps: under the condition of measuring several supersaturated solutions with different degrees, the prepared solution is continuously oscillated at constant temperature to reach the dissolution equilibrium, after centrifugation or filtration, the supernatant is taken out and diluted properly, and the concentration of the medicine in the saturated solution is measured. And drawing by taking the measured concentration of the drug solution as an ordinate and the ratio of the mass of the drug to the volume of the solvent as an abscissa, and extrapolating the straight line to the position where the ratio is zero to obtain the characteristic solubility of the drug.

2. Determination of equilibrium solubility

The method comprises the following specific steps: taking several medicines, preparing a series of solutions from unsaturated solution to saturated solution, oscillating to balance under constant temperature, filtering with filter membrane, analyzing the filtrate, determining the actual concentration S of the medicine in the solution, and plotting the concentration c of the prepared solution, wherein the turning point of the curve is the equilibrium solubility of the medicine.

The detailed procedures for the above solubility determination can be found in the provisions of the chinese pharmacopoeia 2020 edition.

The experimental results show that the compounds 1,2,3 and 4 provided by the invention have good water solubility, are easy to be absorbed by organisms and have good clinical application prospects.

Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, it is intended that all such modifications and alterations be included within the scope of this invention as defined in the appended claims.

Claims

1. A steroid compound having a structure according to formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a structure according to formula (I):

wherein:

y is

R ⁱ And R ^j Each independently of the others is H, deuterium,Hydroxy, amino, halogen, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or haloalkoxyalkyl;

n is 0, 1 or 2;

each hydrogen atom on ring a, ring B, ring C, and ring D is independently unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo-or hydroxyl-substituted alkoxyalkyl, alkoxy, halo-or hydroxyl-substituted alkoxy, alkoxyalkoxy, halo-or hydroxyl-substituted alkoxyalkoxy, alkylamino, halo-or hydroxyl-substituted alkylamino, alkylthio, halo-or hydroxyl-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, or heteroaryloxy.

2. The compound of claim 1, wherein X in formula (I) is O or N substituted with H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl; and the alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, phosphoalkyl, aryl, heteroaryl, benzyl, cycloalkyl or heterocyclyl may be optionally substituted with 1,2,3,4, 5 or 6 substituents selected from hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, haloaryl, aryl and heteroaryl;

or, X is cycloalkyl or heteroaryl containing at least one heteroatom of O and N, and the hydrogen atom on the cycloalkyl or heteroaryl is unsubstituted or at least one hydrogen atom is substituted with deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, halo-or hydroxyl-substituted alkoxyalkyl, alkoxy, halo-or hydroxyl-substituted alkoxy, alkoxyalkoxy, halo-or hydroxyl-substituted alkoxyalkoxy, alkylamino, halo-or hydroxyl-substituted alkylamino, alkylthio, halo-or hydroxyl-substituted alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino or heteroaryloxy.

3. The compound of claim 1 or 2, having a structure according to formula (II), (III), (IV), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein:

R ⁵ Is H, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or haloalkoxyalkyl;

4. The compound of claim 3, having a structure according to formula (V), (VI), (VII), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

5. a compound according to any one of claims 1 to 4, wherein R is ¹ And R ² Each independently is C _1-6 Alkyl radical, C _6-10 Aryl radical, C _2-9 Heteroaryl group, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _1-6 Phosphoalkyl, benzyl, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group; preferably methyl, ethyl, n-propyl, isopropylAlkyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate;

or, said R ¹ And R ² And the N atom to which they are attached, together form a 5-7 membered nitrogen-containing heterocyclic group.

6. A compound according to any one of claims 1 to 5, wherein R is ³ Is H, deuterium, hydroxy, amino, halogen, cyano, carboxy, mercapto, nitro, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Halogenoalkoxy radical C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, C _1-6 Alkoxy radical C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Haloalkylamino, C _1-6 Alkylthio radical, C _3-6 Cycloalkyl radical, C _2-9 Heterocyclic group, C _6-10 Aryl radical, C _2-9 Heteroaryl group, C _6-10 Aryloxy radical, C _6-10 Arylamino, C _2-9 Heteroaryloxy or hydroxy-substituted C _1-6 An alkoxy group;

preferably, said R is ³ Is H, deuterium, hydroxyl, amino, F, cl, br, I, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

7. A compound according to any one of claims 1 to 6, wherein R is ⁴ Is C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _6-10 Aryl radical, C _2-9 Heteroaryl group, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _1-6 Phosphoalkyl, benzyl, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group, preferably methyl, ethyl,N-propyl, isopropyl, n-butyl, t-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate;

or, said R ⁴ Is alkyl- (C = O) OR ⁶ (ii) a Wherein R is ⁶ Is C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Carboxyalkyl, C _6-10 Aryl radical, C _3-6 Cycloalkyl or C _2-9 A heterocyclic group; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl, tetrahydrofuryl, benzyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, carboxymethyl, carboxyethyl, methyl monophosphate, methyl diphosphate or ethyl monophosphate.

8. A compound according to any one of claims 1 to 7, wherein R is ⁵ Is H, deuterium, hydroxyl, amino, halogen, cyano, mercapto, nitro, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy radical C _1-6 Alkyl or C _1-6 Halogenoalkoxy radical C _1-6 An alkyl group;

preferably, said R is ⁵ Is H, deuterium, hydroxy, amino, halogen, cyano, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl or trifluoromethyl.

9. A compound according to any one of claims 1 to 8, wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ Or R ⁶ Optionally substituted with 1,2,3,4, 5 or 6 substituents selected from hydroxy, amino, F, cl, br, I, cyano, carboxy, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl and halophenyl.

10. The compound of any one of claims 1-9, wherein the compound has the structure shown below, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

11. a composition comprising a compound of any one of claims 1-10, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

12. Use of a compound according to any one of claims 1 to 10 or a composition according to claim 11 in the manufacture of a medicament for preventing, treating or ameliorating an ocular disorder in a patient;

preferably, the ocular disease is cataract or muscae volitantes.