Mycophenolic acid derivative and application thereof

Abstract

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

Description

Technical Field

[0001] This invention relates to a mycophenolic acid compound, stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and its use in the preparation of medicaments for treating ophthalmic diseases. Background Technology

[0002] Mycophenolic acid (MPA) has a variety of biological functions, mainly including: (1) It has a specific immunosuppressive effect: inhibiting lymphocyte proliferation, inducing apoptosis of lymphocytes and monocytes, and inhibiting the expression of cytokine products. (2) It has a good anti-inflammatory effect: MPA can reduce the expression of cell surface adhesion molecules, inhibit the aggregation of lymphocytes, mast cells, monocytes, leukocytes and macrophages to chronic inflammatory areas and vascularized areas, organ transplant rejection areas, and reduce the expression of intercellular microproteins, inhibiting their interaction with other cells, and inhibiting the continuous development of inflammation and rejection reactions. (3) It has an inhibitory effect on proliferating cells: MPA can inhibit the proliferation of non-immune cells such as vascular smooth muscle cells, vascular endothelial cells, dendritic cells, fibroblasts, glomerular mesangial cells and fibroblasts, as well as the formation of tubular structures of endothelial cells. It can also inhibit the formation of new blood vessels and the expression of cytokines. Its main mechanisms of action include: inhibiting the activity of inosine monophosphate dehydrogenase; inhibiting the expression of cytokines such as TNF-α, IFN-γ, IK-12, IL-10, and IL-4; inhibiting the expression of T cell-mediated IL-15 and IL-17 in peripheral blood circulation; reducing the expression of cell surface adhesion molecules; inhibiting the migration of lymphocytes, mast cells, monocytes, leukocytes, and macrophages to chronic inflammatory areas and vascularization; reducing the expression of intercellular microproteins; inhibiting the continued development of inflammation and rejection reactions; and inhibiting the proliferation, extracellular matrix production, contraction, and migration of mesangial cells. Currently, MPA is mainly used for organ transplantation, the treatment of systemic lupus erythematosus (SLE), autoimmune rheumatic diseases, diabetes, and as an adjunct therapy for pulmonary hypertension. In addition, its good tolerability and relatively few toxic side effects have led to its increasingly widespread application.

[0003] Oral formulations of mycophenolate mofetil and mycophenolate sodium have been approved for marketing for many years and have proven effective in treating organ transplant rejection. However, no liquid formulations of mycophenolate sodium and mycophenolate mofetil have yet entered clinical trials, primarily due to issues with stability and solubility. Especially for ophthalmic applications as eye drops, the formulations must be soluble, absorbable, and stable. Currently, no eye drop formulations have been successfully reported in clinical trials or approved for marketing. Therefore, it is essential to identify and develop prodrugs of mycophenolate mofetil suitable for ophthalmic eye drops. Summary of the Invention

[0004] This invention provides a series of mycophenolic acid derivatives, which have been greatly improved or enhanced in terms of solubility, solution stability, absorption and distribution in ocular tissues. It also provides compositions of these mycophenolic acid derivatives and their uses in ocular diseases.

[0005] On the one hand, the present invention provides a compound having the structure shown in formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having the structure shown in formula (I).

[0006]

[0007] Wherein, X is a bond, alkylene, alkenyl, or cycloalkylene;

[0008] R 1 For R 3 R 4 P(=O)-O- or R 3 R 4 P(=O)-;

[0009] R 3 and R 4 Each of these can be independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, or OR 6 or NR 5 R 6 ;

[0010] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group;

[0011] R 5 and R 6 Each can be independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, monophosphate or diphosphate;

[0012] R 2 Hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic, R 7 (O-alkylene) n -;

[0013] R 7 It can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclic.

[0014] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0015] Where X and R2 R 3 R 4 R 5 R 6 and R 7 The alkylene, alkenylene, cycloalkylene, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic or phosphorus-containing heterocyclic groups described herein may be optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic, haloaryl, aryl and heteroaryl.

[0016] In some embodiments, in the compounds of this invention, X is a bond, C is a carbon ... 1-6 Alkylene, C 2-6 imide or C 3-10 Cycloalkylene.

[0017] In some implementation schemes, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 .

[0018] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms.

[0019] In some implementation schemes, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate.

[0020] In other embodiments, in the compounds of the present invention, X is a bond, methylene, ethylene, methylmethylene, or ethylmethylene.

[0021] In other implementations, R 3 and R 4Each of the following C-type carbon atoms is independently substituted with hydrogen, hydroxyl, 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, OR 6 or NR 5 R 6 .

[0022] In other implementations, 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, monophosphate or diphosphate.

[0023] In some embodiments, in the compound of the present invention, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -

[0024] In some implementation schemes, 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.

[0025] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0026] In some embodiments, in the compound of the present invention, R 2For hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl, methoxytert-butyl, methoxyisobutyl, fluorine-substituted C 1-3 Alkyl, chlorinated C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, glycidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, thiaalkyl or R 7 (OC 1-3 Alkylene) n -

[0027] In some implementation schemes, R 7 C substituted with 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.

[0028] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0029] In some embodiments, in the compounds of the present invention, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein are independently selected from 1, 2, 3, or 4 groups chosen from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl and C 1-9 Substituents in heteroaryl groups are replaced.

[0030] In other embodiments, in the compounds of the present invention, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein may be independently and optionally replaced by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

[0031] In some embodiments, the compounds of the present invention have a structure as shown in formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of formula (II).

[0032]

[0033] Among them, R 2 R 3 and R 4 The definition is the same as that of formula (I);

[0034] R 8 H, deuterium, halogen, hydroxyl, or C 1-6 alkyl.

[0035] In some implementation schemes, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -

[0036] In some implementation schemes, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 .

[0037] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms.

[0038] In some implementation schemes, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate.

[0039] In some implementation schemes, 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.

[0040] In some implementation schemes, R 8 H, deuterium, halogen, hydroxyl, or C 1-3 alkyl.

[0041] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0042] In some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs,

[0043]

[0044]

[0045] In another aspect, the present invention also provides a pharmaceutical composition comprising the compounds described above, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, mediators, or combinations thereof.

[0046] In another aspect, the present invention provides the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment, or relief of ocular inflammation in a patient.

[0047] In some implementations, the ocular inflammation is conjunctivitis, keratitis, dry eye, uveitis, scleritis, or post-cataract surgery inflammation.

[0048] 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

[0049] Definitions and general terms

[0050] Unless otherwise stated, the terms used in the specification and claims of this invention have the following definitions.

[0051] 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.

[0052] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0053] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0054] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0055] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0056] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0057] The term "patient" as used in this invention refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0058] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0059] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0060] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0061] The stereochemical definitions and rules used in this invention generally follow those 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.

[0062] Many organic compounds exist in an optically active form, meaning they possess 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 indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the plane-polarized light rotation caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

[0063] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some 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.

[0064] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). 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 E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0065] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0066] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0067] As used in this invention, the term "prodrug" refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; in existing inventions, esters that can serve as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in this invention contains a hydroxyl group, meaning it can be acylated to obtain the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0068] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating the obtained diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, 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).

[0069] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0070] The salts mentioned in this invention are pharmaceutically acceptable salts, and the term "pharmaceutically acceptable salts" is well known in the field, as described in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. Pharmaceutically acceptable, non-limiting examples of salts include inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, metaphosphates, sulfates, sulfites, nitrates, and perchlorates, and organic acid salts, such as carboxylates, sulfonates, sulfinates, and thiocarboxylates, specifically, but not limited to, methanesulfonates, ethanesulfonates, formates, acetates, succinates, benzoates, succinates, bis(hydroxynaphthyl) salts, salicylates, galactobionates, gluconates, mandelates, 1,2-ethanedisulfonates, 2-naphthalenesulfonates, carbonates, trifluoroacetates, glycolates, hydroxyethylsulfonates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malates, fumarates, lactates, lactobionates, or oxalic acid, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, undecanoate, valerate, etc. Furthermore, pharmaceutically acceptable salts also include those obtained by means of appropriate bases, such as alkali metals, alkaline earth metals, ammonium, and N+(C) salts. 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0071] Medicinal salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonide, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

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

[0073] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0074] The term "protecting group" or "PG" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. 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. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, etc. For a general description of protecting groups, please refer to: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0075] "Pharmaceutical composition" means a salt of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug, mixed with other chemical components, such as physiologically / pharmaceutical acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0076] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0077] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this 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.

[0078] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as... 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 C. Compounds enriched by this type of isotope can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (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) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compounds of formulas (I) and (II) can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagents with suitable isotopic labeling reagents, as described in the examples and preparation processes of this invention.

[0079] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered a substituent in compounds of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. The term "isotope enrichment factor" as used in this invention refers to the ratio between the isotopic abundance of the specified isotope and its natural abundance. If the substituent of the compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0080] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O), alkyl-C (=O), alkyl-S (=O), alkyl-S (=O)2-, hydroxy-substituted alkyl-S (=O), hydroxy-substituted alkyl-S (=O)2, carboxyalkoxy, etc.

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

[0082] The term "alkoxy" as used in this invention refers to an alkyl group, as defined herein, that is attached to the main carbon chain by an oxygen atom. Examples of such alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, etc. Furthermore, 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, etc.

[0083] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp2 double bond, wherein the alkenyl group may be independently and optionally substituted by one or more substituents described in this invention, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0084] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group with 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described in this invention, wherein specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), etc.

[0085] The term "cycloalkyl" or "carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-12 carbon atoms or bicyclic rings of 7-12 carbon atoms. Bicyclic carbocyclic rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic carbocyclic rings with 9 or 10 atoms can be bicyclic [5,6] or [6,6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of cyclic aliphatic groups include, but are by no means 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, etc. Furthermore, the "cyclic aliphatic group" or "carbocyclic", "carbocyclic group", and "cycloalkyl" may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0086] The terms “heterocyclic,” “heterocyclic group,” “heterocyclic alicyclic group,” or “heterocyclic” are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic systems in which one or more carbon atoms on the ring are independently and optionally substituted with heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic, and has only one connection point to another molecule. One or more hydrogen atoms on the ring are independently and optionally substituted with one or more substituents described herein. Some of these embodiments are that the "heterocycle", "heterocyclic group", "heterocyclic alicyclic group" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2, and when the ring is a three membered ring, there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally replaced by one or more oxygen atoms to obtain a group such as SO, SO2, PO, PO2).

[0087] Heterocyclic groups can be carbonyl or heteroatomyl. "Heterocyclic group" also includes groups formed by the fusion of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, oxazolyl, piperazine, homopiperazine, aziridine, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, homopiperidinyl, glycidyl, aziridineheptyl, oxacycloheptyl, thiohexacycloheptyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxacyclobutyl... 2-diazine Base, sulfur nitrogen 1-pyrrololin-1-yl, 2-pyrrololin-3-pyrrololin-1-yl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphane 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)acetone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)acetone-4-yl, 5,6-dihydro-4 H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-dihydropyridin-1(2H)-yl) acetone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridin-5-yl, 3H-indolyl-2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, quinazinyl and N-pyridinyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino, and those in which two carbon atoms on the ring are replaced by oxygen atoms, such as pyrimidinide groups. Furthermore, the heterocyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, oxo(=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0088] The term "aryl" or "aromatic ring" can be used alone or as a part of "aralkyl," "ararylalkoxy," or "aryloxyalkyl," referring to monocyclic, bicyclic, and tricyclic carbocyclic systems containing a total of 6-14 membered rings, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with only one attachment point connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O)2, carboxyalkoxy, etc.

[0089] The term "heteroaryl" or "heteroaromatic ring" refers to monocyclic, bicyclic, and tricyclic systems containing 5-14 membered rings, wherein at least one ring system is aromatic and contains one or more heteroatoms, wherein the heteroatoms have the meaning as described in this invention, wherein each ring system contains 3-7 membered rings and has only one attachment site connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "aromatic heterocyclic" or "heteroaromatic compound". Furthermore, the heteroaryl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, etc.

[0090] Other embodiments include, but are not limited to, the following monocyclic compounds: 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, 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-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following bis Cyclic, but 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]thiazolyl-2-yl, imidazo[1,5-a]pyridin-6-yl.

[0091] The term “heteroatom” refers to one or more O, S, N, P, and Si atoms, including N, S, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (e.g., N in 3,4-dihydro-2H-pyrrole), NH (e.g., NH in pyrroleyl), or NR (e.g., NR in N-substituted pyrroleyl).

[0092] The term "monophosphate" refers to

[0093] The term "bisphosphonate" refers to

[0094] The term "halogen" refers to F, Cl, Br, or I.

[0095] In this invention, "halogenated" means replacing the following group with a halogen, and the number of halogens can be one or more.

[0096] In this invention, "hydroxyl-substituted" means that the group following it is replaced by a hydroxyl group, and the number of substitutions can be one or more.

[0097] When the term "substituted" is used between two groups in this invention, it is preceded by a substituent, such as "aryl-substituted alkyl" indicating that the alkyl group has an aryl substituent, and "alkoxycarbonyl-substituted alkyl" indicating that the alkyl group has an alkoxycarbonyl substituent.

[0098] When multiple groups of the present invention are used in combination, from left to right, they are in a substitution relationship, such as "arylalkyl", which means aryl-substituted alkyl, and "alkoxyalkoxy", which means alkoxy-substituted alkoxy.

[0099] The term "unsaturated" as used in this invention means that a structural portion contains one or more degrees of unsaturation.

[0100] Description of the compounds of the present invention

[0101] On the one hand, the present invention provides a compound having the structure shown in formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having the structure shown in formula (I).

[0102]

[0103] Wherein, X is a bond, alkylene, alkenyl, or cycloalkylene;

[0104] R 1 For R 3 R 4 P(=O)-O- or R 3 R 4 P(=O)-;

[0105] R 3 and R 4 Each of these can be independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, or OR 6 or NR 5 R 6 ;

[0106] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group;

[0107] R 5 and R 6 Each can be independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, monophosphate or diphosphate;

[0108] R 2 Hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic, R 7 (O-alkylene) n -;

[0109] R 7 It can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclic.

[0110] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0111] Where X and R 2 R 3 R 4 R 5 R 6 and R 7 The alkylene, alkenylene, cycloalkylene, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic or phosphorus-containing heterocyclic groups described herein may be optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic, haloaryl, aryl and heteroaryl.

[0112] In some embodiments, in the compounds of this invention, X is a bond, C is a carbon ... 1-10 Alkylene, C 2-10 imide or C 3-12 Cycloalkylene.

[0113] In some embodiments, in the compounds of this invention, X is a bond, C is a carbon ... 1-6 Alkylene, C 2-6 imide or C 3-10 Cycloalkylene.

[0114] In some embodiments, in the compound of the present invention, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Halogenated alkyl, OR 6 or NR 5 R 6 .

[0115] In some embodiments, in the compound of the present invention, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 .

[0116] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms.

[0117] In some embodiments, in the compound of the present invention, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxyalkyl, C 1-10 Haloalkyl, C 3-12 Cycloalkyl, monophosphate, or diphosphate.

[0118] In some embodiments, in the compound of the present invention, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate.

[0119] In other embodiments, in the compounds of the present invention, X is a bond, methylene, ethylene, methylmethylene, or ethylmethylene.

[0120] In other implementations, R 3 and R 4 Each of the following C-type carbon atoms is independently substituted with hydrogen, hydroxyl, 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, OR 6 or NR 5 R 6 .

[0121] In other implementations, R 5 and R 6Each 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, monophosphate or diphosphate.

[0122] In some embodiments, in the compound of the present invention, R 2 For hydrogen, deuterium, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-12 cycloalkyl, C 1-12 Heterocyclic group, R 7 (OC 1-10 Alkylene) n -

[0123] In some embodiments, in the compound of the present invention, R 7 For hydrogen, deuterium, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-12 cycloalkyl or C 1-12 Heterocyclic group.

[0124] In some embodiments, in the compound of the present invention, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -

[0125] In some embodiments, in the compound of the present invention, R 7 For hydrogen, deuterium, C 1-10 Alkyl, C2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-12 cycloalkyl or C 1-12 Heterocyclic group.

[0126] In some embodiments, in the compound of the present invention, 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.

[0127] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0128] In some embodiments, in the compound of the present invention, R 2 For hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl, methoxytert-butyl, methoxyisobutyl, fluorine-substituted C 1-3 Alkyl, chlorinated C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, glycidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, thiaalkyl or R 7 (OC 1-3 Alkylene) n -

[0129] In some implementation schemes, R 7 C substituted with 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. 1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, or thiaalkyl.

[0130] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0131] In some embodiments, in the compounds of the present invention, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein are independently selected from 1, 2, 3, or 4 groups chosen from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl and C 1-9 Substituents in heteroaryl groups are replaced.

[0132] In other embodiments, in the compounds of the present invention, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein may be independently and optionally replaced by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

[0133] In some embodiments, the compounds of the present invention have a structure as shown in formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of formula (II).

[0134]

[0135] Among them, R 2 R 3 and R 4 The definition is the same as that of formula (I);

[0136] In some implementation schemes, R 8 H, deuterium, halogen, hydroxyl, or C 1-6 alkyl.

[0137] In some implementation schemes, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -

[0138] In some implementation schemes, R 2 C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -

[0139] In some implementation schemes, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 .

[0140] In some implementation schemes, R3 and R 4 Each is an independent hydroxyl group.

[0141] Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms.

[0142] In some implementation schemes, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate.

[0143] In some implementation schemes, 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.

[0144] In some implementation schemes, R 7 C 1-6 alkyl.

[0145] In some implementation schemes, R 8 H, deuterium, halogen, hydroxyl, or C 1-3 alkyl.

[0146] n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0147] In some embodiments, the compounds of the present invention have one of the following structures, or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs,

[0148]

[0149]

[0150] In some embodiments, the method for preparing the compound includes the following steps:

[0151]

[0152] S1, Mycophenolic acid and R2 The -OH reaction yields compound m-1;

[0153] S2, compound m-1 and R 1 The -XY reaction yields compound (I); where Y is a halogen, which can be fluorine, chlorine, bromine, or iodine.

[0154] In some implementations, Y is chlorine or bromine.

[0155] In some other embodiments, the method for preparing the compound includes the following steps:

[0156]

[0157] S1, Mycophenolic acid reacts with a compound containing a PG protecting group to give compound p-1;

[0158] S2, compound p-1 and R 2 -OH reacts under alkaline conditions to give compound p-2;

[0159] S3, compound p-2 is deprotected by the PG protecting group to give compound p-3;

[0160] S4, compound p-3 and R 1 The -XY reaction yields compound (I).

[0161] In some implementations, the PG protection base is TBS.

[0162] In some embodiments, Y is a halogen, which may be fluorine, chlorine, bromine or iodine; preferably, Y is chlorine or bromine.

[0163] Compositions, formulations and administration of the compounds of the present invention

[0164] The pharmaceutical composition comprises any of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

[0165] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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 carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0166] When applicable for treatment, a therapeutically effective amount of the compound of the present invention may be administered as an unprocessed chemical drug or as an active ingredient in a pharmaceutical composition. Therefore, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term "therapeuticly effective amount" as used herein refers to the total amount of each active component sufficient to demonstrate a meaningful patient benefit (e.g., reduction of viral load). When administered alone using a single active ingredient, the term refers only to that component. When used in combination, the term refers to the combined amount of active ingredients that, regardless of combination, sequential or simultaneous administration, produce a therapeutic effect. The carrier, diluent, or excipient must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. According to another aspect of the present invention, a method for preparing a pharmaceutical formulation is also provided, comprising mixing the compound of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients. As used in this invention, the term "pharmaceutically acceptable" means that the compounds, raw materials, compositions, and / or dosage forms of this invention are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, within the limits of reasonable medical judgment.

[0167] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may also include other ingredients commonly used in the art in relation to the type of formulation, such as flavoring agents, for example, such formulations suitable for oral administration may include flavoring agents.

[0168] Uses of the compounds and compositions of the present invention

[0169] The use of the compounds or pharmaceutical compositions of the present invention in the preparation of a medicament for the prevention, treatment, or relief of ocular inflammation in a patient.

[0170] Specifically, the ocular inflammation mentioned refers to conjunctivitis, keratitis, dry eye, uveitis, scleritis, or post-cataract surgery inflammation.

[0171] The “effective amount” or “effective dose” of the compounds or pharmaceutically acceptable compositions of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions thereof can be administered at any dosage and via any route of administration to effectively treat or reduce the severity of the disease. The precise amount required will vary depending on the patient’s condition, which may depend on race, age, the patient’s general condition, the severity of the infection, specific factors, the route of administration, etc. The compounds or compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed in the present invention.

[0172] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0173] General Synthesis Process

[0174] Generally, the 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 content of the present invention.

[0175] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0176] The examples described below are in Celsius unless otherwise stated. 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 stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0177] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0178] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0179] Silica gel columns were used. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, d6-DMSO, CD3OD, or d6-acetone as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. 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 were expressed in Hertz (Hz).

[0180] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316ATCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0181] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0182] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table a.

[0183] Table a

[0184] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0185] The HPLC preparation process conditions are as follows:

[0186] (1) Take an appropriate amount of the mixture of diastereomers containing the compound and dissolve it in the mobile phase;

[0187] (2) Set the flow rate of the mobile phase, the detection wavelength, and the column temperature;

[0188] (3). Take an appropriate amount of the sample solution from step (1) and inject it into the high performance liquid chromatograph. Record the chromatogram to complete the separation and analysis of the isomers.

[0189] Chromatographic column: a normal-phase chiral chromatographic column with silica gel containing polysaccharide derivatives on its surface as the stationary phase; more specifically, the chromatographic column used is Daicel AD-H (10*250nm, 5μm) or Daicel AD (20*250nm, 5μm).

[0190] 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, in the mobile phase mixture, the volume proportion of n-hexane, n-pentane, isohexane, and n-heptane is 10-20%, the volume proportion of methanol, ethanol, isopropanol, and acetonitrile is 20-95%, the volume proportion of diethylamine, triethylamine, trifluoroacetic acid, and glacial acetic acid is 0-2%, and the total amount of all components in the mobile phase is 100%; more specifically, in the mobile phase mixture, the volume proportion of n-hexane is 15-20%, the volume proportion of isopropanol is 80-90%, the volume proportion of diethylamine and triethylamine is 0.5-1%, and the total amount of all components in the mobile phase is 100%.

[0191] Detection wavelength: 250nm~320nm;

[0192] Flow rate: 0.5–10 mL / min; more specifically, 2–5 mL / min;

[0193] Column temperature: 10~35℃.

[0194] The following abbreviations are used throughout this invention:

[0195] AcOH: Acetic acid

[0196] Boc2O, BOC anhydride: di-tert-butyl dicarbonate

[0197] Boc: tert-butyloxycarbonyl

[0198] Bu4NHSO4: Tetrabutylammonium hydrogen sulfate

[0199] CH3CN: Acetonitrile

[0200] DCM: Dichloromethane

[0201] DIPEA: N,N-Diisopropylethylamine

[0202] EA: Ethyl acetate

[0203] HCl: Hydrogen chloride

[0204] HCl / EA: Ethyl acetate solution of hydrogen chloride

[0205] H2O: water

[0206] NaOH: Sodium hydroxide

[0207] NaI: Sodium iodide

[0208] K2CO3: Potassium carbonate

[0209] rt, rt: room temperature

[0210] PE: Petroleum ether

[0211] THF: Tetrahydrofuran

[0212] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0213] DMAP: 4-Dimethylaminopyridine

[0214] TBAI: Tetrabutylammonium iodide

[0215] DMF: Dimethylformamide

[0216] p-TsOH: p-Toluenesulfonic acid

[0217] TFA: Trifluoroacetic acid

[0218] TBAF: Tetrabutylammonium fluoride

[0219] Example

[0220] Example 1, Synthesis of Compound 1

[0221]

[0222] Step 1: Synthesis of methyl mycophenolate (compound 1-1)

[0223] Mycophenolic acid (5 g, 15.6 mmol) was dissolved in methanol (30 mL), and p-toluenesulfonic acid (0.54 g, 3.1 mmol) was added. The mixture was stirred at room temperature for 8 h. After the reaction was complete, the methanol was removed by concentration under reduced pressure. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (20 mL * 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to give 5.1 g of white solid.

[0224] LCMS(ESI), m / z, [M+1] + =335.

[0225] 1 H NMR(400MHz, CDCl3)δ5.24(td,J=6.9,1.0Hz,1H),5.20(s,2H),3.76(s,3H),3.62(s,3H), 3.38(d,J=6.9Hz,2H),2.42–2.37(m,2H),2.33–2.28(m,2H),2.15(s,3H),1.80(s,3H)ppm.

[0226] Step 2: Synthesis of (E)-6-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid methyl ester (compounds 1-2)

[0227] Compound 1-1 (0.5 g, 1.5 mmol) was dissolved in DMF (10 mL), and sodium iodide (20 mg, 0.15 mmol), tetrabutylammonium iodide (60 mg, 0.15 mmol), and potassium carbonate (0.52 g, 3.7 mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes, and then di-tert-butylchloromethyl phosphate (0.87 mL, 3.7 mmol) was added. The mixture was stirred at 40 °C for 20 h. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL * 3). The organic phases were combined and washed sequentially with saturated saline solution (10 mL) and water (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with ethyl acetate (5 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 1 / 1) to obtain 0.66 g of yellow oil.

[0228] LCMS(ESI), m / z, [M+1] + =557.

[0229] Step 3: Synthesis of (E)-6-(6-methoxy-7-methyl-3-oxo-4-((phosphoryloxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid methyl ester (compound 1)

[0230] Compounds 1-2 (1.17 g, 2.1 mmol) were dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was prepared to give 415 mg of a white solid, with a yield of 45%.

[0231] LCMS(ESI), m / z, [M+1] + =445;

[0232] 1 H NMR(500MHz,MeOD)δ5.75(d,J=10.7Hz,2H),5.25(s,2H),5.23(d,J=6.8Hz,1H),3.79(s,3H),3.56(s, 3H),3.54(d,J=6.8Hz,2H),2.39(t,J=7.5Hz,2H),2.26(t,J=7.5Hz,2H),2.21(s,3H),1.80(s,3H)ppm;

[0233] 31 P NMR (202MHz, CDCl3) δ1.66(s)ppm.

[0234] Example 2, Synthesis of Compound 2

[0235]

[0236]

[0237] Step 1: Synthesis of ethyl mycophenolate (compound 2-1)

[0238] Mycophenolic acid (5 g, 15.6 mmol) was dissolved in ethanol (40 mL), and p-toluenesulfonic acid (2.7 g, 15.6 mmol) was added. The system was refluxed at 80 °C for 2 h. After the reaction was complete, the system was concentrated under reduced pressure to remove the ethanol. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (20 mL * 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to give 5.4 g of a brownish-yellow solid.

[0239] LCMS(ESI), m / z, [M+1] + =349.

[0240] Step 2: Synthesis of (E)-6-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid ethyl ester (compound 2-2)

[0241] Compound 2-1 (1.5 g, 4.3 mmol) was dissolved in DMF (20 mL), and sodium iodide (60 mg, 0.43 mmol), tetrabutylammonium iodide (160 mg, 0.43 mmol), and potassium carbonate (1.49 g, 10.8 mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes, and then di-tert-butylchloromethyl phosphate (2.5 mL, 10.8 mmol) was added. The mixture was stirred at 50 °C for 20 h. After the reaction was complete, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed sequentially with saturated saline solution (20 mL) and water (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain 2.3 g of yellow oil.

[0242] LCMS(ESI), m / z, [M+1] + =571.

[0243] Step 3: Synthesis of (E)-6-(6-methoxy-7-methyl-3-oxo-4-((phosphoryloxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid ethyl ester (compound 2)

[0244] Compound 2-2 (1.2 g, 2.1 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was prepared to give 240 mg of a white solid.

[0245] LCMS(ESI), m / z, [M+1] + =459.

[0246] 1 H NMR(500MHz,MeOD)δ5.75(d,J=10.7Hz,2H),5.25(s,2H),5.23(d,J=7.0Hz,1H),4.00(q,J=7.1Hz,2H),3.79(s,3H),3. 54(d,J=6.8Hz,2H),2.38(t,J=7.6Hz,2H),2.26(t,J=7.4Hz,2H),2.22(s,3H),1.81(s,3H),1.15(t,J=7.1Hz,3H)ppm;

[0247] 31 P NMR(202MHz,MeOD)δ-2.28(s)ppm.

[0248] Example 3, Synthesis of Compound 3

[0249]

[0250] Step 1: Synthesis of isopropyl mycophenolate (compound 3-1)

[0251] Mycophenolic acid (5 g, 15.6 mmol) was dissolved in isopropanol (40 mL), and p-toluenesulfonic acid (2.7 g, 15.6 mmol) was added. The system was refluxed at 80 °C for 4 h. After the reaction was complete, the system was concentrated under reduced pressure to remove isopropanol. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (20 mL * 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to give 4.8 g of a brownish-yellow solid.

[0252] LCMS(ESI), m / z, [M+1] + =363.

[0253] Step 2: Synthesis of (E)-6-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid isopropyl ester (compound 3-2)

[0254] Compound 3-1 (1.5 g, 4.1 mmol) was dissolved in DMF (20 mL), and sodium iodide (60 mg, 0.4 mmol), tetrabutylammonium iodide (150 mg, 0.4 mmol), and potassium carbonate (1.43 g, 10.3 mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes, and then di-tert-butylchloromethyl phosphate (2.4 mL, 10.3 mmol) was added. The mixture was stirred at 90 °C for 15 h. After the reaction was complete, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed sequentially with saturated saline solution (20 mL) and water (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered under reduced pressure, and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 2.2 g of yellow oil.

[0255] LCMS(ESI), m / z, [M+1] + =585.

[0256] Step 3: Synthesis of (E)-6-(6-methoxy-7-methyl-3-oxo-4-((phosphoryloxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid isopropyl ester (compound 3)

[0257] Compound 3-2 (1.2 g, 2.05 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was prepared to give 390 mg of a white solid.

[0258] LCMS(ESI), m / z, [M+1] + =473;

[0259] 1 H NMR(500MHz,MeOD)δ5.75(d,J=10.8Hz,2H),5.25(s,2H),5.24–5.22(m,1H),4.84(dd,J=12.5,6.3Hz,1H),3.79(s,3H), 3.54(d,J=7.0Hz,2H),2.37–2.34(m,2H),2.26(t,J=7.3Hz,2H),2.21(s,3H),1.81(s,3H),1.13(s,3H),1.12(s,3H)ppm;

[0260] 31 P NMR(202MHz,MeOD)δ-2.28(s)ppm.

[0261] Example 4

[0262]

[0263]

[0264] Step 1: Synthesis of (E)-6-(4-((tert-butyldimethylsilyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid (compound 4-1)

[0265] Mycophenolic acid (50 g, 156.1 mmol) was dissolved in DMF (300 mL), imidazole (63.76 g, 936.5 mmol) was added, and TBSCl (94.1 g, 624.3 mmol) was added in portions. The system was protected under nitrogen and stirred at room temperature for 8 h. After the reaction was complete, the system was quenched with water (200 mL) in an ice bath and extracted with ethyl acetate (250 mL * 3). The organic phases were combined and washed successively with saturated brine (250 mL) and water (250 mL). The organic phases were dried over anhydrous sodium sulfate, filtered under reduced pressure and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (210 mL). Water (210 mL) and acetic acid (210 mL) were added, and the system was stirred at room temperature for 6 h. The reaction was completed, the system was quenched with water (200 mL), and extracted with ethyl acetate (250 mL * 3). The organic phases were combined and washed successively with saturated brine (250 mL) and water (250 mL). The organic phases were dried with anhydrous sodium sulfate, filtered under reduced pressure and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give 57 g of white solid.

[0266] LCMS(ESI), m / z, [M+1] + =435;

[0267] 1 H NMR (500MHz, CDCl3) δ5.20(t,J=6.1Hz,1H),5.07(s,2H),3.74(s,3H),3.38(d,J=6.2Hz,2H),2. 43–2.40(m,2H),2.29(t,J=7.6Hz,2H),2.15(s,3H),1.76(s,3H),1.03(s,9H),0.24(s,6H)ppm.

[0268] Step 2: Synthesis of (E)-6-(4-((tert-butyldimethylsilyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid-2-methoxyethyl ester (compound 4-2)

[0269] Compound 4-1 (3 g, 6.9 mmol) was dissolved in dichloromethane (20 mL), and DMAP (80 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 10 minutes. EDCI (1.59 g, 8.3 mmol), triethylamine (1.9 mL, 13.8 mmol), and ethylene glycol monomethyl ether (0.7 mL, 8.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed successively with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain 3.2 g of a pale purple oil.

[0270] LCMS(ESI), m / z, [M+1] + =493.

[0271] Step 3: Synthesis of (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid-2-methoxyethyl ester (compound 4-3)

[0272] Compound 4-2 (3.2 g, 6.5 mmol) was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride trihydrate (2.2 g, 7.1 mmol) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed successively with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain 2.4 g of yellow oil.

[0273] LCMS(ESI), m / z, [M+1] + =379.

[0274] Step 4: Synthesis of (E)-6-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid-2-methoxyethyl ester (compound 4-4)

[0275] Compound 4-3 (1 g, 2.6 mmol) was dissolved in DMF (10 mL), and NaI (40 mg, 0.26 mmol), tetrabutylammonium iodide (0.1 g, 0.26 mmol), and potassium carbonate (0.91 g, 6.6 mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes, and then di-tert-butylchloromethyl phosphate (1.5 mL, 6.6 mmol) was added. The mixture was stirred at 60 °C for 8 hours. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL * 3). The organic phases were combined and washed sequentially with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 1.2 g of yellow oil.

[0276] LCMS(ESI), m / z, [M+1] + =601;

[0277] 1 H NMR(500MHz, CDCl3)δ5.78(d,J=10.3Hz,2H),5.23(td,J=6.9,1.2Hz,1H),5.15(s,2H),4.18–4.16(m,2H),3.76(s,3H ),3.56–3.53(m,4H),3.37(s,3H),2.44–2.41(m,2H),2.31–2.29(m,2H),2.19(s,3H),1.79(s,3H),1.42(s,18H)ppm.

[0278] Step 5: Synthesis of (E)-6-(6-methoxy-7-methyl-3-oxo-4-((phosphoryloxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid-2-methoxyethyl ester (compound 4)

[0279] Compound 4-4 (1.6 g, 2.6 mmol) was dissolved in DCM (20 mL), and trifluoroacetic acid (1.0 mL, 13.3 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to prepare a white solid of 0.44 g.

[0280] LCMS(ESI), m / z, [M+1] + =489;

[0281] 1H NMR(500MHz,DMSO)δ5.62(d,J=10.7Hz,2H),5.29(s,2H),5.16–5.13(m,1H),4.04–4.02(m,2H),3. 72(s,3H),3.45–3.42(m,4H),3.22(s,3H),2.37–2.33(m,2H),2.19–2.15(m,5H),1.74(s,3H)ppm;

[0282] 31 P NMR(202MHz,DMSO)δ-3.22(s)ppm.

[0283] Example 5, Synthesis of Compound 5

[0284]

[0285] Step 1: Synthesis of 2-(2-methoxyethoxy)ethyl-(E)-6-(4-((tert-butyldimethylsilyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (compound 5-1)

[0286] Compound 4-1 (2 g, 4.6 mmol) was dissolved in dichloromethane (20 mL), and DMAP (60 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 10 minutes. EDCI (1.1 g, 5.5 mmol), triethylamine (1.3 mL, 9.2 mmol), and diethylene glycol monomethyl ether (0.7 mL, 5.9 mmol) were added sequentially, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed successively with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain 2.4 g of a pale purple oil.

[0287] LCMS(ESI), m / z, [M+1] + =537.

[0288] Step 2: Synthesis of 2-(2-methoxyethoxy)ethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (compound 5-2)

[0289] Compound 5-1 (2.4 g, 4.5 mmol) was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride trihydrate (1.7 g, 4.9 mmol) was added. The mixture was stirred at room temperature for 5 h. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed successively with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM / MeOH = 50 / 1) to obtain 1.6 g of yellow oil.

[0290] LCMS(ESI), m / z, [M+1] + =423.

[0291] Step 3: Synthesis of 2-(2-methoxyethoxy)ethyl-(E)-6-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (compound 5-3)

[0292] Compound 5-2 (1.6 g, 3.8 mmol) was dissolved in DMF (10 mL), and NaI (57 mg, 0.38 mmol), tetrabutylammonium iodide (0.14 g, 0.38 mmol), and potassium carbonate (1.3 g, 9.5 mmol) were added sequentially. The mixture was stirred at room temperature for 10 minutes, and then di-tert-butylchloromethyl phosphate (2.2 mL, 9.5 mmol) was added. The mixture was stirred at 60 °C for 8 hours. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL * 3). The organic phases were combined and washed sequentially with saturated brine (20 mL) and water (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE / EA = 3 / 1) to obtain 1.4 g of yellow oil.

[0293] LCMS(ESI), m / z, [M+1] + =645.

[0294] Step 4: Synthesis of 2-(2-methoxyethoxy)ethyl-(E)-6-(6-methoxy-7-methyl-3-oxo-4-((phosphoryloxy)methoxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (compound 5)

[0295] Compound 5-3 (1.4 g, 2.2 mmol) was dissolved in DCM (20 mL), and trifluoroacetic acid (0.8 mL, 10.9 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the filtrate was concentrated under reduced pressure to prepare a white solid of 0.38 g.

[0296] LCMS(ESI), m / z, [M+1] + =533;

[0297] 1 H NMR(500MHz,DMSO)δ5.61(d,J=10.7Hz,2H),5.29(s,2H),5.15–5.13(m,1H),4.03–4.01(m,2H),3.72(s,3H) ,3.52–3.47(m,4H),3.43–3.39(m,4H),3.22(s,3H),2.37–2.33(m,2H),2.19–2.15(m,5H),1.74(s,3H)ppm;

[0298] 31 P NMR(202MHz,DMSO)δ-3.22(s)ppm.

[0299] Compound solubility test

[0300] 1. Instruments and Materials

[0301] Instruments: Shimadzu LC-20ADXR; shaker; glassware; pipette.

[0302] Materials: pH 7.2 PBS buffer, pure water, HPLC ethanol, HPLC methanol, HPLC tetrahydrofuran

[0303] Experimental process

[0304] 1.1 Preparation of compound sample standards:

[0305] Take a sample of the relevant compound, place it in a centrifuge tube, add 1 mL of tetrahydrofuran at room temperature to completely dissolve the sample, and obtain the concentration of the mother liquor.

[0306] 1.2 Preparation of saturated sample solutions for compounds:

[0307] 1.2.1 Take the relevant compound sample and place it in a centrifuge tube. Add 1 mL of PBS solution at room temperature. Place the tube on a shaker and shake for 1 hour at room temperature. Remove the sample and place it in a refrigerated centrifuge. Set the centrifuge speed to 4000 rpm and the temperature to 25°C, and centrifuge for 10 minutes. After centrifugation, aspirate the supernatant saturated clear solution. Filter the solution using a 0.22 μm filter membrane.

[0308] 1.2.2 Take the relevant compound sample and place it in a centrifuge tube. Add 1 mL of pure water at room temperature. Place the tube on a shaker and shake for 1 hour at room temperature. Remove the sample and place it in a refrigerated centrifuge. Set the centrifuge speed to 4000 rpm and the temperature to 25°C, and centrifuge for 10 minutes. After centrifugation, aspirate the supernatant saturated clear solution. Filter the solution using a 0.22 μm filter membrane.

[0309] 1.3 Preparation of standard curve solution: Take the stock solution and dilute it serially with tetrahydrofuran. Vortex thoroughly after dilution.

[0310] 1.4 Determination of sample solubility:

[0311] The specific solubility was determined using HPLC.

[0312] 1.5 Determine the standard curve. Take 200 μL of the standard curve solution and put it into the inner tube. Inject 1 μL of the solution starting from the lowest concentration and record the peak area.

[0313] 1.6 Inject 1 μL of saturated solution and record the chromatographic peak area.

[0314] 2. Comparison of clarity after centrifugation

[0315] 2.1 Place PBS solvent into a centrifuge tube. Compare the clear supernatant solution from method 1.2.1 with the PBS solution. The clear solution contains no particulate, flocculent, or suspended solid particles. The clarity is similar to that of the PBS solution.

[0316] 3. Calculation

[0317] 3.1 Calculate the standard curve regression equation by fitting the concentration and chromatographic peak area.

[0318] 3.2 The concentration was calculated using a regression equation based on the peak area measured for the saturated sample.

[0319] 3.3 Obtain the solubility value (unit: mg / mL)

[0320] 4. HPLC method conditions

[0321] 4.1 Column: Waters BEH C18 x Bridge 5μm 4.6 x 50mm;

[0322] Methods: Mobile phase: 0.1% trifluoroacetic acid in acetonitrile and water; Mobile phase gradient: 100% water as phase A, 100% acetonitrile as phase B, 10% B to 90% B, 3 mins; followed by equilibration with 10% acetonitrile, 0.5 mins; Detection wavelength: full wavelength scan.

[0323] 4.2 Detection temperature: 25℃

[0324] Table 1. Solubility Test Results

[0325]

[0326] Conclusion: As shown in Table 1, the solubility of the compound of the present invention in aqueous solution and PBS buffer is significantly improved compared with mycophenolic acid, which can meet the requirements of eye drops.

[0327] Compound stability testing

[0328] 1. HPLC method conditions

[0329] 1.1 Chromatographic column: Aglient SB c18 5μm 4.6 x 150mm

[0330] Method 1: Mobile phase: 0.1% trifluoroacetic acid in acetonitrile and water; Mobile phase gradient: 100% water as phase A, 100%...

[0331] Acetonitrile was used as phase B, 10%–90% B, for 3 mins; followed by equilibration with 10% acetonitrile for 0.5 mins; detection wavelength: full wavelength scan.

[0332] 1.2 Detection temperature: 25℃

[0333] 2. Take a sample and perform HPLC analysis on the set date. Obtain the sample purity by integrating the peak area. Determine the sample stability based on changes in sample purity.

[0334] Table 2. Stability test results of compound 4 in eye drop formulations

[0335]

[0336] Preparation method: Add 80% water to a beaker, then add citric acid, sodium citrate, benzalkonium chloride, sodium chloride, and polysorbate 80, and stir until dissolved. Add compound 4 and stir well. Adjust the pH with 1 mol / L sodium hydroxide solution and ensure the API is completely dissolved. Add water to bring the volume to a final volume and stir well. Filter using a 0.22-micron polyethersulfone filter.

[0337] Conclusion: Compound 4 exhibits good stability when formulated as eye drops.

[0338] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments are intended to be illustrative and non-limiting in all respects, and reference should be made to the appended claims rather than to the foregoing embodiments; thus, all variations within the meaning and scope of the equivalents of the appended claims are included herein.

Claims

1. A compound having a structure as shown in Formula (I), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having a structure as shown in Formula (I), in, X is a bond, alkylene, alkenyl, or cycloalkylene; R 1 For R 3 R 4 P(=O)-O- or R 3 R 4 P(=O)-; R 3 and R 4 Each of these can be independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, or OR 6 or NR 5 R 6 ; Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group; R 5 and R 6 Each can be independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, monophosphate or diphosphate; R 2 Hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic, R 7 (O-alkylene) n -; R 7 It can be hydrogen, deuterium, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, or heterocyclic. n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Where X and R 2 R 3 R 4 R 5 R 6 and R 7 The alkylene, alkenylene, cycloalkylene, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocyclic or phosphorus-containing heterocyclic groups described herein may be optionally replaced by 1, 2, 3 or 4 substituents selected from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclic, haloaryl, aryl and heteroaryl.

2. The compound according to claim 1, wherein, X is the key, C 1-10 Alkylene, C 2-10 imide or C 3-12 Cycloalkylene, preferably, X is a bond, C 1-6 Alkylene, C 2-6 imide or C 3-10 Cycloalkylene; And / or, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Halogenated alkyl, OR 6 or NR 5 R 6 Preferably, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 ; Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms; And / or, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-10 Alkyl, C 1-10 Hydroxyalkyl, C 1-10 Alkoxyalkyl, C 1-10 Haloalkyl, C 3-12 Cycloalkyl, monophosphate or diphosphate, preferably, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate.

3. The compound according to claim 1, wherein, X represents a bond, methylene, ethylene, methylmethylene, or ethylmethylene; And / or, R 3 and R 4 Each of the following C-type carbon atoms is independently substituted with hydrogen, hydroxyl, 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, OR 6 or NR 5 R 6 ; And / or, 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, monophosphate or diphosphate.

4. The compound according to claim 1, wherein, R 2 For hydrogen, deuterium, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-12 cycloalkyl, C 1-12 Heterocyclic group, R 7 (OC 1-10 Alkylene) n -, preferably, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -; And / or, R 7 For hydrogen, deuterium, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 1-10 Hydroxyalkyl, C 1-10 Alkoxy C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-12 cycloalkyl or C 1-12 Heterocyclic group, preferably, 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 groups; n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

5. The compound according to claim 1, wherein, R 2 For hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, methoxybutyl, methoxytert-butyl, methoxyisobutyl, fluorine-substituted C 1-3 Alkyl, chlorinated C 1-3 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, glycidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, dithiaalkyl, thiaalkyl or R 7 (OC 1-3 Alkylene) n -; And / or, R 7 C substituted with 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; n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

6. The compound according to claim 1, wherein, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein are independently selected from 1, 2, 3, or 4 groups chosen from deuterium, hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkoxy C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 1-9 Heterocyclic group, C 6-10 Halogenated aryl, C 6-10 Aryl and C 1-9 Substituents in heteroaryl groups are replaced.

7. The compound according to claim 6, wherein, X, R 2 R 3 R 4 R 5 R 6 and R 7 The groups described herein may be independently and optionally replaced by 1, 2, 3 or 4 substituents selected from hydroxyl, amino, halogen, cyano, carboxyl, mercapto, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or halophenyl.

8. The compound according to claim 1, having a structure as shown in formula (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of formula (II). in, R 2 R 3 and R 4 The definition is the same as that of formula (I); R 8 H, deuterium, halogen, hydroxyl, or C 1-6 alkyl.

9. The compound according to claim 8, wherein, R 2 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, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -; Preferably, R 2 C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-9 Heterocyclic group, R 7 (OC 1-6 Alkylene) n -; And / or, R 3 and R 4 Each is independently hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 6 or NR 5 R 6 Preferably, R 3 and R 4 Each is independently a hydroxyl group; Optionally, R 3 and R 4 Together with the attached P atom, it forms a phosphorus-containing heterocyclic group consisting of 5-6 atoms; And / or, R 5 and R 6 Each is independently hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, monophosphate, or diphosphate; And / or, 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; preferably, R 7 C 1-6 alkyl; And / or, R 8 H, deuterium, halogen, hydroxyl, or C 1-3 alkyl; n can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

10. The compound according to any one of claims 1-9, wherein, The compound has one of the following structures, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, or a thereof.

11. A method for preparing the compound according to any one of claims 1-10, comprising the following steps: S1, Mycophenolic acid and R 2 The -OH reaction yields compound m-1; S2, compound m-1 and R 1 The -XY reaction yields a compound of formula (I); wherein Y is a halogen, which may be fluorine, chlorine, bromine or iodine; preferably, Y is chlorine or bromine.

12. A method for preparing the compound according to any one of claims 1-10, comprising the following steps: S1, Mycophenolic acid reacts with a compound containing a PG protecting group to give compound p-1; preferably, the PG protecting group is TBS; S2, compound p-1 and R 2 -OH reacts under alkaline conditions to give compound p-2; S3, compound p-2 is deprotected by the PG protecting group to give compound p-3; S4, compound p-3 and R 1 The -XY reaction yields a compound of formula (I); wherein Y is a halogen, which may be fluorine, chlorine, bromine or iodine; preferably, Y is chlorine or bromine.

13. A pharmaceutical composition comprising the compound of any one of claims 1-10, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium, or combination thereof.

14. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 13 in the preparation of a medicament for the prevention, treatment, therapy, or relief of ocular inflammation in a patient.

15. The use according to claim 14, wherein the ocular inflammation is conjunctivitis, keratitis, dry eye, uveitis, scleritis, or post-cataract surgery inflammation.

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