Tyrosinase inhibitor and use thereof

Abstract

The present invention relates to a heterocyclic compound. The compound has excellent human tyrosinase (hTyr) inhibitory activity, can effectively inhibit melanin production, and can be used to prepare a safe and effective whitening product.

Description

A tyrosinase inhibitor and its uses

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. CN2024116325399, entitled "A Tyrosinase Inhibitor and Its Use Thereof", filed on November 15, 2024, and Chinese Patent Application No. CN2025110240029, entitled "A Tyrosinase Inhibitor and Its Use Thereof", filed on July 24, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a class of tyrosinase inhibitor compounds and their applications, which have anti-melanin production effects by inhibiting tyrosinase activity. Background Technology

[0004] Melanin is a crucial factor influencing the color of human skin, eyes, and hair. It protects the skin from ultraviolet radiation and prevents DNA mutations and the development of skin cancer. On the other hand, excessive melanin production can lead to hyperpigmentation disorders such as freckles, age spots, melasma, moles, and sunspots.

[0005] Tyrosinase, also known as polyphenol oxidase, is a copper-containing redox enzyme widely found in microorganisms, animals, and plants. Produced exclusively by melanocytes, tyrosinase is processed in the endoplasmic reticulum and Golgi apparatus before being transported to melanosomes, where it synthesizes melanin. Tyrosinase is a key rate-limiting enzyme in the melanin synthesis pathway, directly influencing melanin production. The expression and activity of tyrosinase determine the rate and yield of melanin production; higher tyrosinase activity results in a greater amount of melanin formation in the skin. The protein level of tyrosinase is regulated by the proteasome and lysosomal degradation systems, which hydrolyze misfolded or unfolded proteins during maturation.

[0006] Numerous inhibitors targeting tyrosinase have been developed, particularly hydroquinone and its derivatives, such as hydroquinone (also known as hydroquinone), arbutin, kojic acid, azelaic acid, 4-butylresorcinol, 4-hexylresorcinol, 4-phenylethylresorcinol, and dimethoxytolylpropylresorcinol. However, all these agents lack efficacy and / or safety, so currently only a few are used in clinical dermatology. For example, hydroquinone has been banned in skin-whitening products due to its high cytotoxicity; kojic acid has sensitizing and mutagenic properties; nicotinamide and its analogues have teratogenicity and intolerance in some populations; and arbutin is highly concentration-dependent.

[0007] Tyrosinase also participates in the production of neuromelanin, oxidizing dopa to dopaquinone. Overexpression of dopaquinone can cause nerve cell damage and death, indicating that tyrosinase is also associated with neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Tyrosinase also participates in the browning reaction of agricultural products such as fruits and vegetables. Tyrosinase inhibitors can be used as food preservatives and also as biological insecticides in agricultural pest control. In conclusion, tyrosinase inhibitors have broad application prospects in fields such as beauty and health care (e.g., whitening, fading spots, brightening, anti-aging, and moisturizing), disease treatment, pest control, and food preservation.

[0008] The unsatisfactory clinical efficacy of currently used tyrosinase inhibitors is primarily due to the fact that these compounds are tested using only mushroom tyrosinase (mTyr) isolated from the mushroom Agaricus bisporus, which is the only readily available commercially available active tyrosinase. In contrast, kinetic data or structural information on human tyrosinase (hTyr) is very scarce, mainly because obtaining sufficient quantities of hTyr from natural sources or through heterologous expression is extremely difficult. The catalytic activity and substrate specificity of mTyr differ significantly from those of mammalian enzymes. mTyr is a soluble oligomerase present in the cytosol, while hTyr is a highly glycosylated monomeric protein anchored to the melanosome membrane; hTyr shares only 14.2% homology with mTyr, and their active sites also differ significantly. Therefore, many mTyr inhibitors have yielded unsatisfactory results and significant discrepancies when further validated with hTyr (J Invest Dermatol. 2018 Jul; 138(7):1601-1608). Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a compound with excellent human tyrosinase (hTyr) inhibitory activity. This compound can inhibit melanin production activity and can be prepared into a safe and effective whitening product.

[0010] The inventors have unexpectedly discovered that compounds having the following formulas (I) to (IV) or their stereoisomers, tautomers, pharmaceutically acceptable salts, and solvates have excellent human tyrosinase (hTyr) inhibitory activity.

[0011] Therefore, according to a first aspect of the present invention, the present invention provides a heterocyclic compound having a structure of formula (I), formula (II), formula (III) or formula (IV), or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof:

[0012] Wherein, R1 may be the same or different, and is independently chosen from: H, D, halogen, CN, -N(R1a )2、-OR 1a R 1a -NHR 1b -OR 1b ;

[0013] R 1a Whether the two are the same or different, choose independently from: H, C 1-6 Alkyl, when R 1a C 1-6 In the case of alkyl groups, two adjacent R1 atoms can form 4-8 membered rings with the carbon, nitrogen, or oxygen atoms they are attached to;

[0014] R 1b Whether identical or different, it is independently selected from monosaccharide residues, oligosaccharide residues, polysaccharide residues, -P(=O)(OM)2, -P(=O)R 5a R 5b ;

[0015] M can be the same or different, and can be independently chosen from: H, C 1-6 alkyl;

[0016] R 5a R 5b Independently select from: C 1-6 alkyl;

[0017] m is selected from: 1, 2, 3, 4, 5;

[0018] The W ring is a partially saturated C4-C ring. 14 A heterocyclic alkyl group, wherein at least one ring atom in the W ring is independently chosen from N, O, or S(O). p ;

[0019] R a Whether the elements are the same or different, they can be independently chosen from H, D, halogen, and C. 1-6 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 5-14 heteroaryl, when R a C 1-6 Alkyl, C 2-10 alkenyl, C 2-10 When alkynyl group, R a It can form a ring consisting of 3-10 ring members together with its adjacent W ring atoms;

[0020] R aThe optional elements are F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, and -(CH2). r R a1 -(CH2) r OR a1 -(CH2) r SR a1 -(CH2) r C(O)R a1 -(CH2) r C(O)OR a1 -(CH2) r OC(O)R a1 -(CH2) r NR a1 R a1 -(CH2) r C(O)NR a1 R a1 -(CH2) r NR a1 C(O)R a1 -(CH2) r NR a1 C(O)OR a1 -NR a1 C(O)NR a1 R a1 -S(O) p NR a1 R a1 -NR a1 S(O) p R a1 -O(CH2) r OR a1 -S(O) p R a1 C 1-6 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -C 3-8 Heterocyclic alkyl substitution;

[0021] R a1 Whether the two are the same or different, they can be independently chosen from H, D, and C. 1-6 Alkyl, C 2-10 Alkenyl, -(CH2) q OH, C 1-6 Haloalkyl, -(CH2) q -C 3-10 Cycloalkyl, -(CH2) q-C 3-10 Heterocyclic alkyl groups, -(CH2) q -Phenyl;

[0022] X is selected from: -C(R) a )3;-C(O)R a ;-C(O)NR a R a ;-C(O)OR a ;-NR a R a ;-NR a C(O)R a ;-NR a C(O)NR a R a ;-NR a C(O)OR a ;-OR a ;-S(O) p R a ;Optionally used by R a Replacement C 6-14 Aryl, C 5-14 heteroaryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups;

[0023] R2 is selected from: -NR a R a -OR a -C(O)R a -C(O)OR a -S(O) p R a ;

[0024] R3 is selected from: H, D, C 1-6 Alkyl, C 3-10 cycloalkyl, -NR a R a -OR a -C(O)R a -C(O)OR a -S(O) p R a ;

[0025] T is selected from CH or N;

[0026] Z is selected from: O, S, Se;

[0027] L1 is selected from the bond, -C(R) b )2NR b -、-C(O)-、-C(O)C(R b )2C(O)-、-C(O)NRb -、C(O)NR b NR b -、-C(O)NR b C(O)-、-C(O)O-、-NR b -、-NR b C(O)-、-NR b C(O)C(O)-、-NR b C(O)NR b -、-NR b C(O)O-、-NR b C=N-、-NR b N = CH-, -NR b C(S)-、-NR b C(S)NR b -O-, -OC(O)-, -OC(O)NR b -、-S-、-S(O) p -、-S(O) p NR b -;

[0028] R b Whether the two are the same or different, they can be independently chosen from H, D, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl;

[0029] R4 is C 1-6 Alkylene, C 2-10 imidene group, C 2-10 Ethyne group, C 3-10 Cycloalkylene, C 3-10 Heterocyclic alkyl, C 6-14 aryl or C 5-14 heteroaryl;

[0030] R4 may optionally be substituted with the following substituents: F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, -(CH2) r R a1 -(CH2) r OR a1 -(CH2) r SR a1 -(CH2) r C(O)R a1 -(CH2) r C(O)OR a1 -(CH2) r OC(O)R a1 -(CH2) r NR a1R a1 -(CH2) r C(O)NR a1 R a1 -(CH2) r NR a1 C(O)R a1 -(CH2) r NR a1 C(O)OR a1 -NR a1 C(O)NR a1 R a1 -S(O) p NR a1 R a1 -NR a1 S(O) p R a1 -O(CH2) r OR a1 -S(O) p R a1 C 1-6 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -C 3-8 Heterocyclic alkyl groups;

[0031] L2 is selected from the bond, -(CH2). t -,-(CH2) r O-, -(CH2) r NH-;

[0032] n is selected from: 0, 1, 2, 3, 4, 5;

[0033] p is selected from 0, 1, and 2;

[0034] r is selected from 0, 1, 2, 3, and 4;

[0035] q is selected from 0, 1, 2, 3, and 4;

[0036] t is selected from 1, 2, 3, and 4.

[0037] In some embodiments, in heterocyclic compounds (or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates) having formula (I), (II), (III), or (IV), R1 is selected from -OH, -OR. 1b m is selected from: 1, 2, 3;

[0038] Preferably, Selected from

[0039] R 1b Independently selected from monosaccharide residues, oligosaccharide residues, -P(=O)(OM)2, -P(=O)R 5a R 5b ;

[0040] M can be the same or different, and can be independently chosen from: H, C 1-4 alkyl.

[0041] In some embodiments, the heterocyclic compound has the structure of formula (I), wherein:

[0042] for

[0043] The W ring is a C4-C8 heterocyclic alkyl group containing a double bond, and at least two ring atoms in the W ring are independently selected from N, O or S; preferably, two ring atoms in the W ring are selected from N and O or N and S respectively;

[0044] R a Whether the two are the same or different, choose C independently. 1-6 Alkyl, or R a C 1-6 Alkyl groups, together with their adjacent ring atoms, form 3-5 membered rings; R a Optional F, OCF3, CF3, -OR a1 -NR a1 R a1 Replace; R a1 For H, C 1-6 alkyl;

[0045] n is selected from 0, 1, 2;

[0046] Preferably, the W ring is

[0047] Where Y is O or S;

[0048] R a The same or different, independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; or, R a It can form 3-5 membered rings together with its adjacent W ring atoms, R a Optionally replaced by -OH;

[0049] n is selected from 0, 1, 2;

[0050] More preferably, the W ring is

[0051] Ra Same or different, independently chosen from methyl, or R a It is a 5-membered ring formed by the n-propyl group and its adjacent W ring atoms;

[0052] n is selected from 1 and 2.

[0053] In some embodiments, when the heterocyclic compound has the structure of formula (II):

[0054] for

[0055] X is -NR a R a -NR a C(O)R a -NR a C(O)NR a R a -NR a C(O)OR a ;

[0056] R a Whether the two are the same or different, they can be independently chosen from H and C. 1-6 Alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Mixed aromatics;

[0057] R a Optionally, it can be F, CN, or -(CH2). r R a1 -(CH2) r OR a1 -O(CH2) r OR a1 C 1-6 Alkyl, C 2-8 Alkenyl substitution;

[0058] R a1 It is H, C 1-6 Alkyl, C 2-10 Alkenyl, -(CH2) q OH;

[0059] r is selected from 0, 1, 2, 3, and 4;

[0060] q is selected from 0, 1, 2, 3, and 4;

[0061] Preferably, R aWhether the same or different, independently selected from H, methyl, ethyl, propyl, butyl, pentyl, isopropyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, propenyl, allyl, phenyl, pyridyl, methoxy, morpholinyl,

[0062] Where: Y represents O and S; R a1 The same or different, independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; or, R a1 It can form 3-5 membered rings together with its adjacent W ring atoms; n is selected from 0, 1, 2;

[0063] More preferably, X is -NR a C(O)R a ;R a Whether the same or different, independently selected from H, methyl, ethyl, n-propyl, cyclopropane, cyclobutane, isopropyl, tert-butyl, pyridyl, propenyl,

[0064] In some embodiments, the heterocyclic compound has the structure of formula (III), wherein:

[0065] for

[0066] R2 is -OR a -SR a ;

[0067] R3 is hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, -NR a R a -OR a -SR a ;

[0068] R a Whether the same or different, independently chosen from hydrogen and C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl group; R a The optional elements are F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne substitution;

[0069] Preferably, R2 is -OR a R3 represents hydrogen and C. 1-6 Alkyl; R a Independently selectable from hydrogen and C 1-6 alkyl;

[0070] More preferably, R2 is -OR a R3 represents hydrogen, methyl, or ethyl; R a It can be independently selected from hydrogen, methyl, ethyl, or isopropyl.

[0071] In some embodiments, the heterocyclic compound has the structure of formula (IV), wherein:

[0072] Selected from

[0073] T is N;

[0074] Z is S;

[0075] L1 is selected from the group consisting of bonds, -CH2NH-, -C(O)-, -C(O)NH-, C(O)NHNH-, -C(O)NHC(O)-, -C(O)O-, -NH-, -NHC(O)-, -NHC(O)C(O)-, -NHC(O)NH-, -NHC(O)O-, -NHC=N-, -NHC(S)-;

[0076] R4 is selected from C 1-6 Alkylene, C 2-10 imidene group, C 3-10 Cycloalkylene, C 3-10 Heterocyclic alkyl, C 6-14 Alpha-aryl, C 5- 14 heteroaryl;

[0077] R4 can be optionally replaced by F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NH2, NO2, -CH2OH, -OH, C 1-6 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl substitution;

[0078] L2 is selected from the bond, -(CH2). t -、-(CH2) r O-; r is selected from 0, 1, 2, 3, 4; t is selected from 1, 2, 3, 4;

[0079] R 1bWhether identical or different, it can be independently selected from monosaccharide residues, oligosaccharide residues, -P(=O)(OM)2, -P(=O)R 5a R 5b ;

[0080] Preferably, the monosaccharide residues are selected from: glucosyl, mannose, galactosyl, xylose, lythose, fucose, arabinose, rhamnose, fructose, sorbitol, and tagatose.

[0081] Preferably, the oligosaccharide residue is a disaccharide residue; more preferably, the disaccharide residue is selected from: lactosyl, maltulose, palaginose, lactulose, amygdalinose, menobiose, cellobiose, isomaltose, rutinose, and maltose.

[0082] The M can be the same or different, and can be independently chosen from: H, C 1-4 Alkyl; preferably, M is independently selected from H, methyl, or ethyl;

[0083] The R 5a R 5b Independently selected from: methyl, ethyl;

[0084] More preferably, L1 is selected from -C(O)-, -C(O)NH-, C(O)O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)O-;

[0085] R4 is selected from methylene, ethylene, propylene, isopropylene, morpholino, piperidinyl, piperazine, phenylene, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, furanyl, oxazolyl, dihydrooxazolyl, thiopheneyl, pyrazolyl, thiazolyl, dihydrothiazolyl, pyrrolyl, and imidazolyl.

[0086] R4 may be optionally substituted with F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NH2, NO2, -OH, methyl, ethyl, vinyl, or ethynyl.

[0087] L2 is selected from -O-, -CH2-, -CH2O-, and -CH2CH2O-.

[0088] R 1b Selected from glucosyl, mannose, galactosyl, rhamnose, fucose, fructose, arabinose, xylose, ribose, sucrose, lactose, trehalose, -P(=O)(OH)2, -P(=O)(OH)(OCH3), -P(=O)(OCH3)2, -P(=O)(OH)(OCH2CH3), -P(=O)(OCH2CH3)2, -P(=O)(CH3)2.

[0089] In some embodiments, the heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates of the present invention are selected from the following compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates:

[0090] According to a second aspect of the present invention, the present invention provides a composition comprising the heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates described in the first aspect, and a pharmaceutically acceptable carrier or a carrier for skin care products.

[0091] According to a third aspect of the invention, the invention provides the use of the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or compositions described in the second aspect for inhibiting the activity of tyrosinase in mammals. Accordingly, the invention also provides a method for inhibiting tyrosinase activity in mammals, comprising administering to a subject in need the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or compositions described in the second aspect.

[0092] In some embodiments, the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect are used as pharmaceuticals.

[0093] In some embodiments, the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect is used in the preparation of medicaments for treating hypermelanosis, skin care products, medicaments for pest and disease control, antifungal drugs, or anti-browning foods. Accordingly, the present invention also provides a method for treating or preventing hypermelanosis, comprising applying to a subject in need the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect. The present invention also provides a method for preventing pests and diseases, comprising applying to a subject in need the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect. The present invention also provides an antifungal method, comprising applying to a subject in need the heterocyclic compound described in the first aspect or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect. The present invention also provides a method for preventing browning in food, comprising adding to the food the heterocyclic compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or the composition described in the second aspect of the present invention.

[0094] In some embodiments, the hyperpigmentation is selected from freckles, age spots, melasma, moles, postinflammatory hyperpigmentation (also known as postinflammatory hyperpigmentation, PIH), or solar lentigines.

[0095] In some embodiments, the heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or the composition described in the second aspect are used to prepare skin care products with whitening, anti-aging, moisturizing, spot-fading, and / or brightening functions.

[0096] Reference Merging

[0097] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually identified and incorporated by reference.

[0098] The compounds of this invention may have one or more asymmetric centers. Unless otherwise stated, all chiral (enantiomers and diastereomers) and racemic forms of the compounds of this invention are included within the scope of this invention. These compounds may also have many geometric isomers in alkenes, C=N double bonds, etc., and all such stable isomers are covered in this invention. Cis and trans geometric isomers of the compounds of this invention are described herein and can be isolated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be isolated in optically active or racemic forms. How to prepare optically active isomers is well known in the art, for example by resolving the racemic form or by synthesis from optically active starting materials. Unless a specific stereochemistry or isomeric form is explicitly specified, a structure refers to all chiral (enantiomers and diastereomers) and racemic forms as well as all geometric isomeric forms.

[0099] When any variable (e.g., R1) appears more than once in any composition or structural formula of a compound, its definition for each occurrence is independent of its definition for each of the other occurrences. Thus, for example, if it indicates that a group is substituted by 0 to 2 R1 groups, that group may optionally be substituted by at most two R1 groups, and R1 is chosen independently from its definition each time it appears. Furthermore, combinations of substituents and / or variables are only permitted if these combinations produce a stable compound.

[0100] When the bond connecting a substituent is shown to pass through two atoms in the linking ring, the substituent may be attached to either atom in that ring. When a listed substituent does not specify which atom it is attached to the remainder of a compound having a given structural formula, the substituent may be attached to either atom in that substituent. Combinations of substituents and / or variables are permitted only if these combinations produce a stable compound.

[0101] According to the conventions of the art, In the structural formula of this paper, the bond is used to describe the connection point between the part or substituent and the parent nucleus or main structure.

[0102] The hyphen "-" that does not appear between two letters or symbols is used to indicate the connection point of a substituent. For example, -CONH2 is connected by a carbon atom.

[0103] As used herein, the term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by a group selected from the specified groups, provided that the substitution does not exceed the normal valence state of the specified atom. When the substituent is an oxo or ketone (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on the aromatic moiety. Unless otherwise specified, substituents are named as those entering the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the connection point of this substituent to the core structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0104] As used herein, the term "optionally substituted" refers to a group having 0, 1, 2, or more substituents. For example, "when R1 is C..." 1-6 When alkyl, optional F substitution covers "C". 1-6 Alkyl groups and F-substituted C 1-6 "alkyl". Those skilled in the art will understand that for any group containing one or more substituents, these groups will not introduce any one or more stereoimpractical, synthetically infeasible and / or inherently unstable substitution or substitution patterns.

[0105] As used herein, the terms "alkyl" or "alkylene" refer to branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C..." 10 Alkyl (or alkylene) refers to compounds including C1, C2, C3, C4, C5, C6, C7, C8, C9, and C6. 10 Alkyl (or alkylene). Additionally, for example, "C1-C6 alkyl" indicates a monovalent alkyl group having 1 to 6 carbon atoms, and "C1-C6 alkylene" indicates a divalent group derived from an alkyl group. Alkyl or alkylene groups can be unsubstituted or substituted, such that one or more of their hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), etc.; examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-.

[0106] "Alkenyl" or "alkenylene" refers to a hydrocarbon chain that includes a straight-chain or branched configuration and has one or more carbon-carbon double bonds that can exist at any stable point along the chain. The carbon-carbon double bonds can be E or Z configurations. For example, "C..." 2-10Alkenyl (or alkenylyl) refers to compounds including C2, C3, C4, C5, C6, C7, C8, C9, and C6. 10 Alkenyl (or alkenyl); "alkenyl" indicates a divalent group derived from an olefin. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.; examples of alkenyl groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, and -CH=CHCH2CH2-.

[0107] "Alynyl" or "hypoynyl" refers to a hydrocarbon chain that includes a straight-chain or branched configuration and has one or more carbon-carbon triple bonds that can exist at any stable point along the chain. For example, "C 2-10 "Alynyl" (or "ethynyl group") refers to compounds including C2, C3, C4, C5, C6, C7, C8, C9, and C6. 10 Alkynyl (or ynylene); examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.; ynylene represents a divalent unsaturated hydrocarbon chain containing at least one triple bond. Examples of ynylene groups include, but are not limited to, -C≡C-, -C≡CCH2-, -CH2C≡C-, -C≡CCH2CH2-, -CH2C≡CCH2-, -CH2CH2C≡C-, and -C≡CCH2CH2CH2-.

[0108] When the term "alkyl" is used with another group, such as in "arylalkyl," this combination more specifically defines the substituted alkyl group containing at least one substituent. For example, "arylalkyl" refers to a substituted alkyl group as defined above, wherein at least one substituent is aryl, such as benzyl. Therefore, the term aryl (C 0-4 Alkyl groups include substituted lower alkyl groups having at least one aryl substituent and also include aryl groups directly bonded to another group, i.e., aryl(CO)alkyl groups. The term "heteroarylalkyl" refers to a substituted alkyl group as defined above, wherein at least one substituent is a heteroaryl group.

[0109] When referring to substituted alkenyl, ynyl, alkylene, alkenyl, or ynylene groups, these groups are substituted by one to three substituents as defined above for the substituted alkyl group.

[0110] The term "alkoxy" refers to an oxygen atom substituted with an alkyl group or a substituted alkyl group as defined herein. For example, the term "alkoxy" includes the -OC group. 1-6Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc.

[0111] It should be understood that those skilled in the art will select all groups (including, for example, alkoxy, thioalkyl, and aminoalkyl) to provide stable compounds.

[0112] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic cyclic hydrocarbon substituent. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,

[0113] etc., which can be substituted on any available atom of the ring.

[0114] The term "cycloalkylene" refers to a divalent, non-aromatic, saturated or partially unsaturated ring that does not contain heteroatoms, including monocyclic rings of 3-10 carbon atoms or bicyclic or tricyclic rings of 7-10 carbon atoms. Bicyclic systems can be [4,5], [5,5] systems. Examples of cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexylene, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene, etc., which may optionally be substituted on any available atom of the ring.

[0115] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially saturated monocyclic or polycyclic non-aromatic cyclic group, wherein at least one ring has at least one heteroatom (including but not limited to O, S, or N), and the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each heteroatom-containing ring in the group may contain 1 or 2 oxygen or sulfur atoms and / or 1 to 4 nitrogen atoms, limited by the total number of heteroatoms in each ring being 4 or less, and further limited by the ring containing at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heterocyclic alkyl group may be independently unsubstituted or substituted by one or more substituents described in this patent. Examples of such heterocyclic alkyl groups include, but are not limited to, azazolinyl, pyrrolidinyl, oxazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoacheptyl, aacheptyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxopentane and tetrahydro-1,1-dioxothiopheneyl, quininecycloyl, etc.

[0116] The term "heterocyclic alkylene" refers to a saturated or partially saturated monocyclic or polycyclic non-aromatic cyclic group, wherein at least one ring has at least one heteroatom (including but not limited to O, S, or N), and the heterocyclic alkylene group is a divalent group. Heterocyclic systems can be attached to the host structure at any heteroatom or carbon atom to form stable compounds. Hydrogen atoms on one or more rings may be independently and optionally substituted or unsubstituted by one or more substituents described in this invention. Examples of heterocyclic alkyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridylene, piperidinylene, piperazineylene, pyrrolidinylene, tetrahydrofuranylene, dihydrofuranylene, tetrahydrothiopheneylene, tetrahydropyranylene, dihydropyranylene, tetrahydrothiaranylene, azapyrocyclobutylene, oxopyrocyclobutylene, thionocyclobutylene, epoxypropylene, azapyrocycloheptanylene, oxopyrocycloheptanylene, thionocycloheptanylene, N-morpholinylene, 2-morpholinylene, 3-morpholinylene, thionomorpholinylene, and others. Oxazonyl, diazazonyl, thiazazonyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, dithiaalkyl, dithiamonyl, dihydrothiopheneyl, dioxopentylcycloyl, dihydropyrazinyl, dihydropyridyl, dihydropyrazolyl, dihydropyrrolyl, 1,4-dithiaalkyl, morpholinyl, piperazinyl, and piperidinyl. In other embodiments, the heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, azapyrocycloheptanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, etc. The term "partially saturated heterocyclic alkyl" as used herein refers to a heterocyclic alkyl group containing at least one double or triple bond, such as -C=C-, -C≡C-, -C=N-, -N=N-. Examples of these partially saturated heterocyclic alkyl groups include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, dihydroimidazolyl, dihydrooxazolyl, dihydrothiazolyl, dihydropyrazolyl, dihydroisoxazolyl, dihydroisothiazolyl, tetrahydropyridyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydropyridazinyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0117] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0118] It can be substituted on any available carbon or nitrogen atom.

[0119] The term "arylene" refers to a divalent aromatic ring group formed by removing two hydrogen atoms from the carbon atom of an aromatic ring. Examples of arylene groups can include phenylene, naphthylene, and anthracene, which may optionally be substituted on any available carbon or nitrogen atom. The term "heteroarylene" refers to a substituted and unsubstituted aromatic group having at least one heteroatom (including but not limited to O, S, or N) in at least one ring, preferably having one, two, or three heteroatoms selected from O, S, and N. Each heteroatom-containing ring of a heteroarylene may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, limited by the total number of heteroatoms in each ring being four or less and each ring having at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. Heteroaryles that are bicyclic or tricyclic must include at least one fully aromatic ring, but the other one or more fused rings may be aromatic or non-aromatic.

[0120] Examples of monocyclic heteroaryl groups include pyrrole, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.

[0121] Examples of bicyclic heteroaryl groups include indole, benzothiazolyl, benzo-m-dioxacyclopentenyl, benzoxazolyl, benzothiophene, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzopyranyl, inazinyl, benzofuranyl, chromonel, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazole, pyrrolopyridyl, furanopyridyl, dihydroisoindole, tetrahydroquinolinyl, etc.

[0122] Examples of tricyclic heteroaryl groups include carbazolyl, benzoindolyl, phenanthrollinyl, acridinel, phenanthidyl, xanthonyl, etc.

[0123] The term "hybrid aryl" refers to a substituted or unsubstituted divalent aromatic ring group having at least one heteroatom (including but not limited to O, S or N) in at least one ring. Examples of heteroaryl groups include, but are not limited to, iminofuranyl, imoxazolyl, imoxazolyl, imoxadiazolyl, imoxenyl, imoxazolyl, imoxazolyl, imoxadiazolyl, imoxadiazolyl, imoxenyl, imoxazol ...adiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiazolyl, imoxadiaz

[0124] Unless otherwise specified, when referring to a clearly named aryl (e.g., phenyl), arylene (e.g., phenylene), cycloalkyl (e.g., cyclohexyl), cycloalkylene (e.g., cyclohexylene), heterocycloalkyl (e.g., pyrrolyl, piperidinyl, and morpholinyl), heterocycloalkylene (e.g., pyrrolylene, piperidinyl, and morpholinyl), heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furanyl), or heteroaryl (e.g., furanyl, oxazolyl), the reference means a ring having 0 to 3, preferably 0 to 2, substituents selected as needed from the substituents described above for aryl, arylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene, heteroaryl, and / or heteroaryl.

[0125] The term "heteroatoms" should include oxygen, sulfur, and nitrogen.

[0126] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0127] The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-, and trifluoromethyl.

[0128] The term "haloalkoxy" refers to an alkoxy group having one or more halogen substituents. For example, "haloalkoxy" includes OCF3.

[0129] The term "sugar" refers to monosaccharides, oligosaccharides, and polysaccharides.

[0130] Monosaccharides include, for example, trioses (e.g., D-glyceraldehyde, dihydroxyacetone, etc.); tetraoses (e.g., D-erythrose, D-erythulose, D-threose, erythritol, etc.); pentoses (e.g., L-arabinose, D-xylose, L-lythose, D-arabinose, D-ribose, D-ribulose, D-xylulose, L-xylulose, etc.); and hexoses (e.g., D-glucose, D-tarose, D-succinobiose, D-galactose, D-fructose, L-galactose). Sugars (e.g., L-mannose, D-tagatose, etc.); heptoses (e.g., aldoheptose, hippose, etc.); deoxyglucoses (e.g., 2-deoxy-D-ribose, 6-deoxy-L-galactose, 6-deoxy-L-mannose, etc.); amino sugars (e.g., D-glucosamine, D-galactosamine, sialic acid, aminouronic acid, muramic acid, etc.); uronic acids (e.g., D-glucuronic acid, D-mannuronic acid, L-guluronic acid, D-galacturonic acid, L-iduronic acid, etc.).

[0131] Oligosaccharides are sugars that, upon hydrolysis, produce 2–10 mol of monosaccharides; they are also called oligosaccharides. Examples of oligosaccharides include, but are not limited to, sucrose, maltose, isomaltose, lactose, maltotriose, maltotetraose, maltopentose, neohesperidin, rutin, and stachyose. Common oligosaccharides are disaccharides that hydrolyze to produce 2 mol of monosaccharides, such as lactose, maltulose, palaginose, lactulose, amygdalinose, menobiose, cellobiose, isomaltose, rutin, and maltose. Examples of trisaccharides include raffinose, panose, menotriose, and gentianose, while examples of tetrasaccharides include stachyose.

[0132] Examples of polysaccharides include cellulose, quince seeds, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, heparan sulfate, hyaluronic acid, astragalus gum, keratin sulfate, chondroitin, xanthan gum, mucin sulfate, guar gum, dextran and keratin sulfate, black locust Bingham, succinyl dextran, carotenic acid, etc.

[0133] The term "sugar residue" refers to the group obtained by removing a hydroxyl group from a sugar, which can be any isomer, such as D-type, L-type, or a mixture thereof.

[0134] Examples of monosaccharide residues include, but are not limited to, the following: erythrosyl, glucosyl, mannose, galactosyl, rhamnose, fucose, fructose, arabinose, and ribosyl; examples of oligosaccharide residues include, but are not limited to, the following: lactose, maltulose, palaginose, lactulose, amygdalinose, menobiose, cellobiose, isomaltose, rutinose, maltose, raffinose, and stachyose.

[0135] Throughout the specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds and intermediate compounds that can be used as pharmaceutically acceptable compounds and / or as intermediate compounds that can be used to prepare pharmaceutically acceptable compounds.

[0136] The heterocyclic compounds described in this patent (compounds of formulas (I), (II), (III), and (IV)) may exist in free form (unionized) or may form salts also within the scope of this invention. Unless otherwise specified, references to the inventive compounds should be understood to include references to both the free form and their salts. The term "salt" means an acidic and / or basic salt formed using inorganic and / or organic acids and bases. Additionally, for example, when compounds of formulas (I), (II), (III), and (IV) contain both a basic moiety (e.g., an amine or pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid), the term "salt" may include zwitterions (internal salts). Preferred are pharmaceutically acceptable (i.e., physiologically acceptable and non-toxic) salts, such as acceptable metal and amine salts, wherein the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be used, for example, in separation or purification steps that may be employed during preparation, and are therefore covered within the scope of this invention. For example, salts of compounds of formulas (I), (II), (III), and (IV) can be formed by reacting compounds of formulas (I), (II), (III), and (IV) with a certain amount (e.g., an equivalent amount) of an acid or base in a medium such as a salt-precipitating medium or in an aqueous medium, followed by freeze-drying.

[0137] Examples of acid addition salts include acetates (e.g., those formed with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphates, hemisulfates, heptanoates, caproate salts, hydrochlorides (forming with hydrochloric acid), and hydrobromide. Salts (forming with hydrogen bromide), hydroiodates, 2-hydroxyethanesulfonates, lactates, maleates (forming with maleic acid), methanesulfonates (forming with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those forming with sulfuric acid), sulfonates (e.g., those mentioned herein), tartrates, thiocyanates, toluenesulfonates, such as p-toluenesulfonate, undecanoate, etc.

[0138] Examples of basic salts include ammonium salts; alkali metal salts, such as sodium, lithium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts formed with organic bases (e.g., organic amines), such as trialkylamines, such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabimethamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized using reagents such as: lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, and butyl groups), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, and stearyl groups), aralkyl halides (e.g., bromides of benzyl and phenethyl groups), etc. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0139] As used in this article, “medicinal” refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues within the scope of reasonable pharmaceutical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0140] As used herein, "medicinal salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acidic or basic salt. Examples of medicinal salts include, but are not limited to, inorganic or organic acid salts with a basic group (e.g., amine); and basic or organic salts with an acidic group (e.g., carboxylic acid). Medicinal salts include parent compounds formed from, for example, non-toxic inorganic or organic acids, which are commonly non-toxic salts or quaternary ammonium salts. For example, these commonly used non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and hydroxyethanesulfonic acid, etc.

[0141] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, these salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture thereof; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0142] The carriers used in the skincare products of this invention can be ionic or nonionic surfactants, additional thickeners of (meth)acrylic acid thickening polymers, ethoxylated or nonethoxylated fatty alcohols, co-thickeners, penetrants, fragrances, dyes, plasticizers, buffers, and various cosmetic excipients such as waxes, volatile or non-volatile cyclic or linear or branched siloxanes, wherein the siloxanes are organically modified, particularly alkoxylated or amino-modified, or unmodified, such as silicone rubber, ceramides, pseudoceramides, plant, mineral or synthetic oils, vitamins or provitamins such as panthenol, sunscreens, reducing agents, emulsifiers, preservatives, mineral fillers, pearlescent agents, flakes, sunscreens, proteins, anionic, nonionic, cationic or amphoteric fixed polymers, humectants, emollients, soothing agents, antifoaming agents, antiperspirants, free radical scavengers, bactericides, chelating agents, anti-dandruff agents, antioxidants, alkalizing agents, acidifying agents, etc.

[0143] This invention covers all stereoisomers of the compounds of this invention, whether in mixtures, pure forms, or substantially pure forms. Stereoisomers may include compounds that are optical isomers by having one or more chiral atoms, and compounds that are optical isomers by restrictive rotation around one or more bonds (restricted rotation isomers). The definition of the compounds of this invention covers all possible stereoisomers and mixtures thereof. It particularly covers racemic forms and separated optical isomers with specified activities. Racemic forms can be resolved by physical methods, for example, by fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers may be obtained from racemates by common methods (e.g., forming a salt with an optically active acid and then crystallizing).

[0144] This invention includes all isotopes of atoms appearing in the compounds of this invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a non-limiting general example, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14C. The isotopically labeled compounds of the present invention can generally be prepared using common techniques known to those skilled in the art, or can be prepared using a suitable isotopically labeled reagent instead of the originally used unlabeled reagent, through a method similar to that described herein.

[0145] This invention also covers prodrugs and solvates of the compounds of this invention. The term "prodrug" means a compound that undergoes chemical transformation through metabolic or chemical processes after administration to obtain compounds of formula (I), (II), (III), (IV) and / or their salts and / or solvates. Prodrugs within the scope and spirit of this invention are any compounds that, upon in vivo transformation, provide a bioactive agent (i.e., compounds of formula (I), (II), (III), (IV)). For example, compounds containing a carboxyl group can form physiologically hydrolyzable esters, which are used as prodrugs by hydrolysis in the body to obtain compounds of formula (I), (II), (III), (IV) themselves. Oral administration of these prodrugs is preferred because in many cases hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be used in cases where the ester itself is active or where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of formula (I), (II), (III), (IV) include C 1-6 Alkylbenzyl, 4-methoxybenzyl, dihydroindene, phthalyl, methoxymethyl, C 1-6 Alkyloxy-C 1-6 Alkyl groups (e.g., acetoxymethyl, neopentyloxymethyl, or propionyloxymethyl), C 1-6 Alkoxycarbonyloxy-C 1-6 Esters of alkyl groups (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)-methyl) and other well-known physiologically hydrolyzable esters used in penicillin and cephalosporin technologies, for example. These esters can be prepared using commonly known techniques in the art.

[0146] Various forms of prodrugs are well known in the art. Examples of these prodrug derivatives are shown below:

[0147] a) Bundgaard, H. (ed.), Design of Prodrugs, Elsevier (1985) and Widder, K. et al. (eds.), Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0148] b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” in Krosgaard-Larsen, P. et al. (eds.), A Textbook of Drug Design and Development, pp. 113–191, Harwood Academic Publishers (1991); and

[0149] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8: 1-38 (1992).

[0150] Compounds of formulas (I), (II), (III), and (IV) and their salts may exist in their tautomer forms, wherein hydrogen atoms are transferred to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within the scope of this invention. Furthermore, the inventive compounds may have trans and cis isomers.

[0151] It should be further understood that solvates (e.g., hydrates) of compounds of formulas (I), (II), (III), and (IV) are also within the scope of this invention. Solvation methods are well known in the art. Detailed Implementation

[0152] Detailed Implementation

[0153] Abbreviations and abbreviations: TLC: Thin-layer chromatography; DCM: Dichloromethane; TsCl: p-Toluenesulfonyl chloride; TEA: Triethylamine; Triphosgene: Di(trichloromethyl)carbonate; DAST: Diethylaminosulfur trifluoride; EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride; HOBT: 1-Hydroxybenzotriazole; DIEA: N,N-Diisopropylethylamine; DMF: N,N-Dimethylformamide; TMSBr: Trimethylbromosilane; TFA: Trifluoroacetic acid; Tf2O: Trifluoroacetic anhydride; Py: Pyridine.

[0154] Preparation Example:

[0155] Preparation route I: Preparation of compound 1

[0156] Step 1: Preparation of 4-(2,4-dimethoxyphenyl)thiazole-2-amine (-3)

[0157] Compound-1 (7.0 g, 27.02 mmol) was added to 60 mL of anhydrous ethanol, followed by compound-2 (2.06 g, 27.02 mmol). The reaction was stirred at 85°C for 2 hours, and TLC analysis showed that the starting material was almost completely consumed. The reaction solution was concentrated to a minimum volume, poured into saturated sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL x 3). After drying and filtration, the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1) to give 4.2 g of compound-3.

[0158] Step 2: Preparation of 1-(4-(2,4-dimethoxyphenyl)thiazolyl-2-yl)-3-(1-hydroxy-2-methylpropane-2-yl)thiourea(-6)

[0159] Compound-3 (300 mg, 1.27 mmol) and compound-5 (340 mg, 1.91 mmol) were added to DCM (3 mL). The reaction mixture was stirred at room temperature for 20 min, then heated to 40 °C. Compound-4 (147 mg, 1.65 mmol) was then added to the system and stirred for 12 h. TLC analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL * 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-6 (42 mg, yield 9.0%).

[0160] Step 3: Preparation of N-(4-(2,4-dimethoxyphenyl)thiazolyl)-4,4-dimethyl-4,5-dihydrooxazol-2-amine (-7)

[0161] Compound-6 (42 mg, 0.11 mmol) was added to tetrahydrofuran (2.5 mL) / H₂O (0.2 mL), and the reaction was stirred at room temperature. Then, NaOH (13 mg, 0.33 mmol) and TsCl (24 mg, 0.13 mmol) were added to the system sequentially, and the reaction was stirred at room temperature for 30 minutes. TLC plate analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL * 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC plate to obtain compound-7 (24 mg, yield 63.2%).

[0162] Step 4: Preparation of 4-(2-((4,4-dimethyl-4,5-dihydrooxazol-2-yl)amino)thiazol-4-yl)-1,3-benzenediol (compound 1)

[0163] Compound-7 (24 mg, 0.072 mmol) was added to anhydrous DCM (2 mL), and the reaction was stirred at room temperature. Then, BBr3 (0.4 mL) was added dropwise to the system, and stirring continued for 20 minutes. TLC analysis showed that the starting material was almost completely consumed. Methanol was added dropwise to the system under ice bath conditions to quench the reaction, and the pH was adjusted to 5-6 with Na2CO3 (aq). Extraction was performed using DCM (50 mL x 3), and the organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 1 (1.2 mg, yield 5.5%) with a purity of 99.84%. LCMS ([M+H) + ):306.09. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),9.58(s,1H),8.69(s,1H),7.54(d,J=8.5Hz,1H),7 .22(s,1H),6.27(dd,J=8.5,2.5Hz,1H),6.23(d,J=2.4Hz,1H),4.34(s,2H),1.32(s,6H).

[0164] Compounds 2 through 13 were prepared by the methods and general steps described in Route A, as in the foregoing schemes and examples, with compound 4 replaced by a suitable alcohol (Step 2). The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0165] Preparation Route II: Preparation of Compound 14

[0166] Step 1: Preparation of 2,4-bis-isopropoxycarbonyloxy-acetophenone (-3)

[0167] Compound 2,4-dihydroxyacetophenone-1 (10 g, 65.73 mmol) and Et3N (27.6 mL, 197 mmol) were added to 150 mL of DCM. Isopropyl chloroformate-2 (20.14 g, 164.31 mmol) was then added dropwise to the system. The reaction mixture was stirred at 0°C for 30 minutes, and TLC analysis showed that the starting materials were almost completely consumed. The reaction solution was poured into water (150 mL) and extracted with DCM (150 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give 21.32 g of compound-3. LCMS ([M+Na) + ):347.22.1 H NMR (400MHz, DMSO) δ8.02(dd,J=7.8,1.2Hz,1H),7.38-7.32(m,2H),4.95-4.81(m,2H),2.53(s,3H),1.32(d,J=3.4Hz,6H),1.31(d,J=3.4Hz,6H).

[0168] Step 2: Preparation of 2-bromo-(2,4-bis-isopropoxycarbonyloxy)-acetophenone (-4)

[0169] Compound-3 (21.32 g, 65.73 mmol) was added to tetrahydrofuran (200 mL), and the reaction was stirred at room temperature. Then, Ph(CH3)3NBr3 (24.71 g, 65.73 mmol) was added to the system, and the reaction was stirred at 60 °C for 30 minutes. The reaction solution was concentrated to a minimum volume, poured into water (150 mL), and extracted with ethyl acetate (150 mL * 3). After drying with anhydrous Na2SO4, the solution was filtered and concentrated to give 26.51 g of compound-4. LCMS ([M+Na) + ):425.07. 1 H NMR (400MHz, DMSO) δ7.96 (d, J = 8.6Hz, 1H), 7.38-7.37 (m, 1H), 7.35-7.30 (m, 1H) ),4.92-4.85(m,2H),4.59(s,2H),1.32(d,J=1.3Hz,6H),1.31(d,J=1.3Hz,6H).

[0170] Step 3: Preparation of 4-(2,4-bis-isopropoxycarbonyloxy-phenyl)-1,3-thiazolyl-2-amine (-5)

[0171] Compound-4 (26.51 g, 65.74 mmol) was added to 100 mL of anhydrous ethanol, followed by thiourea-2 (5 g, 65.74 mmol). The reaction was stirred at 85°C for 30 minutes, and TLC analysis showed that the starting material was almost completely consumed. The reaction mixture was concentrated to a minimum volume, poured into saturated sodium bicarbonate (500 mL), and extracted with ethyl acetate (150 mL x 3). The extract was dried over anhydrous Na₂SO₄, filtered, and the organic phase was concentrated to obtain a crude product. The crude product was then slurried at room temperature (petroleum ether / ethyl acetate = 10 / 1, 50 mL) to yield 23 g of compound-5. LCMS ([M+H) + ):381.28. 1H NMR (400MHz, DMSO) δ7.92(d,J=8.6Hz,1H),7.31-7.07(m,4H),6.76(s,1H),4.94-4.77(m,2H),1.32(d,J=6.2Hz,6H),1.27(d,J=6.2Hz,6H).

[0172] Step 4: Preparation of 4-(2-(3-((1S,2S)-2-hydroxycyclopentyl)ureido)thiazolyl-4-yl)-1,3-phenylene diisopropyl dicarbonate (-7)

[0173] Compound-5 (200 mg, 0.53 mmol) and TEA (212 mg, 2.10 mmol) were added to DCM (5 mL), and the reaction was stirred at 0°C. Then, 1 mL of DCM containing triphosgene (52 mg, 0.17 mmol) was added to the system, and stirring continued. Next, 1 mL of DCM containing compound-6 (181 mg, 1.31 mmol) and TEA (212 mg, 2.10 mmol) was added to the system. The reaction was carried out at room temperature for 3 h. LCMS showed that the starting material was almost completely consumed. The reaction solution was poured into water (50 mL) and extracted with DCM (50 mL * 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC plate to obtain compound-7 (77 mg, yield 28.8%).

[0174] Step 5: Preparation of diisopropyl(4-(2-(((3aS,6aR)-3a,5,6,6a-tetrahydro-4H-cyclopentano[d]oxazol-2-yl)amino)thiazolyl)-1,3-phenylene)dicarbonate (-8)

[0175] Compound-7 (77 mg, 0.15 mmol) was added to DCM (2 mL), and the reaction was stirred at room temperature. Then, DAST (37 mg, 0.23 mmol) was added to the system, and stirring was continued for 15 minutes. TLC plate analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water and extracted with DCM (50 mL * 3). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC plate to obtain compound-8 (65 mg, yield 87.8%).

[0176] Step 6: Preparation of 4-(2-(((3aS,6aR)-3a,5,6,6a-tetrahydro-4H-cyclopentano[d]oxazol-2-yl)amino)thiazol-4-yl)-1,3-benzenediol (compound 14)

[0177] Compound-8 (65 mg, 0.13 mmol) was added to methanol (4 mL), and the reaction was stirred at room temperature. Then, an aqueous solution of NaOH (4 N, 1 mL) was added to the system, and stirring was continued for 30 min. TLC analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL * 3). The organic phases were combined, washed with saturated sodium chloride (10 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 14 (6.0 mg, yield 14.3%). Purity: 99.8%. LCMS ([M+H) + ):318.17. 1 H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.40(s,1H),8.61(s,1H),7.59(d,J=8.3Hz,1H),7.21(s,1H),6.3 0-6.22(m,2H),5.35(t,J=6.2Hz,1H),4.42(t,J=6.2Hz,1H),2.00(d,J=14.0Hz,1H),1.80-1.51(m,5H).

[0178] Compounds 15 through 17 were prepared by the methods and general steps described above in the route, with compound 6 replaced by an appropriate alcohol (Step 4) as described in the foregoing schemes and examples. The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0179] Preparation route: Preparation of compound 18

[0180] Step 1: Preparation of diisopropyl(4-(2-(3-methoxyureo)thiazolyl-4-yl)-1,3-phenylene) dicarbonate (-2)

[0181] Compound-5 (100 mg, 0.26 mmol) and TEA (80 mg, 0.79 mmol) were added to anhydrous DCM (5 mL). The reaction was stirred at 0°C. A DCM solution of triphosgene (25 mg, 0.08 mmol) in 2 mL was added dropwise to the system and stirred for 5 minutes. Then, a DCM solution of compound-1 (43 mg, 0.52 mmol) in 2 mL was added dropwise to the system and stirring was continued for 0.5 hours. TLC plate analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (20 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-2 (20 mg, yield 16.8%).

[0182] Step 2: Preparation of 1-(4-(2,4-dihydroxyphenyl)thiazolyl)-3-methoxyurea (compound 18)

[0183] Compound-2 (20 mg, 0.04 mmol) was added to methanol (2 mL), followed by 0.5 mL of NaOH aqueous solution (4 N). The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 18 (2 mg, yield 16.1%) with a purity of 97.6%. LCMS ([M+H) + ):282.09. 1 H NMR (400MHz, DMSO) δ11.22(d,J=12.7Hz,2H),10.21(s,1H),9.47(s,1H),7.61(d,J=8.9Hz,1H),7.31(s,1H),6.31-6.26(m,2H),3.65(s,3H).

[0184] Compounds 19 through 23 were prepared by the methods and general steps described above in the route, with compound-1 replaced by an appropriate amine (Step 1) as described in the foregoing schemes and examples. The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0185] Preparation route: Preparation of compound 24

[0186] Step 1: Preparation of 4-(2,4-bis-isopropoxycarbonyloxy-phenyl)-1,3-selenozol-2-amine (-2)

[0187] Compound-4 (24.0 g, 59.55 mmol) was added to anhydrous ethanol (240 mL), followed by compound-1 (7.32 g, 59.55 mmol). The reaction was stirred at 90 °C for 1 h. TLC analysis showed that the starting material was almost completely consumed. The reaction solution was concentrated to obtain a crude product, which was then poured into water. NaHCO3 (aq) was added to adjust the pH to approximately 9, and DCM (150 mL * 3) was added for extraction. The organic phases were combined, washed with saturated sodium chloride (20 mL * 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound-2 (22.5 g, yield 88.6%).

[0188] Step 2: Preparation of N-(4-(2,4-bis-isopropoxycarbonyloxy-phenyl)selenozazole-2-yl)-isobutyramide(-4)

[0189] Compound-2 (400 mg, 0.94 mmol) and triethylamine (192 mg, 1.87 mmol) were added to DCM (12 mL), and the reaction was stirred at 0°C. Then, compound-3 (149 mg, 1.41 mmol) in DCM (2 mL) was added to the system, and the reaction was stirred at room temperature for 1 h. TLC plate analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (20 mL) and extracted with DCM (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride (20 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound-4 (250 mg, yield 53.6%).

[0190] Step 3: Preparation of N-(4-(2,4-dihydroxyphenyl)selenozazole-2-yl)isobutyramide (compound 24)

[0191] Compound-4 (250 mg, 0.50 mmol) was added to THF / MeOH (4 mL / 4 mL), followed by 2 mL of NaOH aqueous solution (4 N). The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 24 (141 mg, yield 86.5%) with a purity of 99.50%. LCMS ([M+H) + ):327.05. 1 H NMR(400MHz,DMSO)δ12.43(s,1H),11.21(s,1H),9.49(s,1H),7.93-7.82(m,1H) ,7.63-7.61(m,1H),6.29(dq,J=4.7,2.4Hz,2H),2.82-2.71(m,1H),1.15(s,6H).

[0192] Compounds 25 through 38 were prepared by the methods and general steps described above in the route, as in the foregoing schemes and examples, with compound-3 replaced by an appropriate acyl chloride (Step 2). The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0193] Preparation route: Preparation of compound 39

[0194] Step 1: Preparation of N-(4-(2,4-bis-isopropoxycarbonyloxy-phenyl)selenozazole-2-yl)-3-methyloxetane-3-carboxamide(-2)

[0195] Compound-1 (55 mg, 0.47 mmol), triethylamine (71 mg, 0.70 mmol), EDCI (90 mg, 0.47 mmol), and HOBT (48 mg, 0.351 mmol) were added to anhydrous DCM (4 mL). The reaction mixture was stirred at room temperature for 0.5 h. Compound-2 (100 mg, 0.23 mmol) was then added to the system, and stirring continued for 16 h. TLC analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-2 (60 mg, yield 88.8%).

[0196] Step 2: Preparation of N-(4-(2,4-dihydroxyphenyl)selenozazole-2-yl)-3-methyloxetane-3-carboxamide (compound 39)

[0197] Compound-2 (60 mg, 0.11 mmol) was added to THF / MeOH (2 mL / 2 mL), followed by the addition of NaOH (4 N, 2 mL) aqueous solution. The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride (20 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 39 (23 mg, yield 57.1%), with a purity of 98.0%. LCMS ([M+H) + ):355.03. 1 H NMR (400MHz, DMSO) δ12.48(s,1H),11.11(s,1H),9.48(s,1H),7.90(d,J=22.7Hz,1H),7.66 -7.60(m,1H),6.33-6.25(m,2H),4.87(d,J=6.2Hz,2H),4.39(d,J=6.2Hz,2H),1.64(s,3H).

[0198] Compounds 40–48 were prepared by the methods and general steps described above in the route, as in the foregoing schemes and examples, with compound-1 replaced by a suitable carboxylic acid (Step 1). The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0199] Preparation route: Preparation of compound 49

[0200] Step 1: Preparation of (S)-4-(2-(3-(1-hydroxyisopropyl-2-yl)ureido)selenozol-4-yl)-1,3-phenylene diisopropyl dicarbonate (-2)

[0201] Compound-2 (300 mg, 0.70 mmol) and triethylamine (212 mg, 2.10 mmol) were added to DCM (10 mL), and the reaction was stirred at 0°C. A DCM solution of triphosgene (68 mg, 0.23 mmol) in 2 mL was added dropwise to the system, and the mixture was stirred for 5 minutes. Then, a DCM solution of compound-1 (79 mg, 1.10 mmol) in 2 mL was added dropwise to the system, and the mixture was stirred for another 0.5 hours. TLC analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-2 (110 mg, yield 29.6%).

[0202] Step 2: Preparation of (S)-diisopropyl(4-(2-((4-methyl-4,5-dihydrooxazol-2-yl)amino)selenozol-4-yl)-1,3-phenylene)dicarbonate (-3)

[0203] Compound-2 (110 mg, 0.21 mmol) was added to DCM (2 mL), followed by DAST (50 mg, 0.31 mmol). The reaction was stirred at room temperature for 15 min. TLC analysis showed that the starting material was almost completely consumed. The reaction was quenched with 1 mL of water and concentrated to obtain a crude product. The crude product was purified by pre-TLC to obtain compound-3 (50 mg, yield 47.2%).

[0204] Step 3: Preparation of (S)-4-(2-((4-methyl-4,5-dihydrooxazol-2-yl)amino)selenozol-4-yl)-1,3-benzenediol (compound 49)

[0205] Compound-3 (50 mg, 0.10 mmol) was added to methanol (2 mL), followed by 0.5 mL of 4 N aqueous solution. The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 49 (4 mg, yield 11.8%) with a purity of 99.6%. LCMS ([M+H) + ):340.03. 1 H NMR (400MHz, DMSO) δ11.10(s,1H),9.41(s,1H),7.98(s,1H),7.78(s,1H),7.62(d,J=8.9Hz,1H),6.30-6. 25(m,2H),4.26(t,J=9.5Hz,1H),3.95(dd,J=15.0,6.3Hz,1H),3.65(dd,J=10.1,6.0Hz,1H),1.26(s,3H).

[0206] Preparation route: Preparation of compound 50

[0207] Step 1: Preparation of diisopropyl(4-(2-(3-methylureo)selenozol-4-yl)-1,3-phenylene) dicarbonate (-2)

[0208] Compound-2 (100 mg, 0.23 mmol) and triethylamine (69 mg, 0.69 mmol) were added to DCM (5 mL), and the reaction was stirred at 0°C. A DCM solution of triphosgene (22 mg, 0.08 mmol) in 2 mL was added dropwise to the system, and the mixture was stirred for 5 minutes. Then, a DCM solution of compound-1 (23 mg, 0.35 mmol) in 2 mL was added dropwise to the system, and the mixture was stirred for another 0.5 hours. TLC analysis showed that the starting material was almost completely consumed. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-2 (30 mg, yield 26.8%).

[0209] Step 2: Preparation of 1-(4-(2,4-dihydroxyphenyl)selenozazole-2-yl)-3-methylurea (compound 50)

[0210] Compound-2 (30 mg, 0.06 mmol) was added to methanol (2 mL), followed by 0.5 mL of 4 N aqueous solution. The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 50 (6 mg, yield 31.1%) with a purity of 99.9%. LCMS ([M+H) + ):314.18. 1 H NMR(400MHz,DMSO)δ11.42(s,1H),11.08(s,1H),9.40(s,1H),7.65(s,1H),7 .54(d,J=8.4Hz,1H),6.48(s,1H),6.28-6.24(m,2H),2.73(t,J=6.7Hz,3H).

[0211] Compounds 51 to 55 were prepared by the methods and general steps described above in the route, as in the foregoing schemes and examples, with compound-1 replaced by a suitable amine or alcohol (Step 1). The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis from commercially available reagents using conventional reaction methods.

[0212] Preparation route: Preparation of compound 56

[0213] Step 1: Preparation of 5-(benzyloxy)valerate (-2)

[0214] Compound-1 (500 mg, 2.57 mmol) was added to acetone (10 mL), and the reaction was stirred at 0°C. Then, Jones reagent (2.57 mL, 6.70 mmol) was added dropwise to the system, and the reaction was stirred at room temperature for 16 h. TLC plate analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (20 mL) and extracted with DCM (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride (20 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude compound-2 (490 mg, yield 91.4%).

[0215] Step 2: Preparation of 4-(2-(5-(benzyloxy)pentanamide)selenozol-4-yl)-1,3-phenylene diisopropyl dicarbonate (-3)

[0216] Compound-2 (490 mg, 2.36 mmol), triethylamine (600 mg, 5.89 mmol), EDCI (727 mg, 3.77 mmol), and HOBT (382 mg, 2.83 mmol) were added to DCM (12 mL), and the reaction was stirred at room temperature for 0.5 h. Then, compound-2 (503 mg, 1.18 mmol) was added to the system, and stirring was continued for 16 h. TLC analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (50 mL) and extracted with DCM (50 mL * 3). The organic phases were combined, washed with saturated sodium chloride (50 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-3 (120 mg, yield 8.3%).

[0217] Step 3: Preparation of 5-(benzyloxy)-N-(4-(2,4-dihydroxyphenyl)selenozol-2-yl)-pentanamide (-4)

[0218] Compound-3 (120 mg, 0.19 mmol) was added to THF / MeOH (2 mL / 2 mL), followed by an aqueous solution of NaOH (4 N, 1 mL). The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The reaction mixture was poured into water (20 mL) and extracted with DCM (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride (20 mL * 1), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound-4 (14.5 mg, yield 16.8%).

[0219] Step 4: Preparation of N-(4-(2,4-dihydroxyphenyl)selenozazole-2-yl)-5-hydroxypentanamide (compound 56)

[0220] Compound-4 (80 mg, 0.180 mmol) was added to DCM (2 mL), followed by BBr3 (674 mg, 2.70 mmol). The reaction was stirred at room temperature for 1 h. TLC analysis showed that the starting material was almost completely consumed. The reaction was quenched by slow dropwise addition of methanol. The reaction solution was poured into water (20 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 56 (8 mg, yield 12.6%) with a purity of 99.03%. LCMS ([M+H) + ):356.98. 1 H NMR (400MHz, DMSO) δ12.45(s,1H),11.19(s,1H),9.47(s,1H),7.95-7.80(m,1H),7.67-7.59(m,1H),6.31-6.27(m,2 H),4.43(t,J=5.2Hz,1H),3.42(dd,J=11.7,6.4Hz,4H),2.48(d,J=7.5Hz,8H),1.70-1.62(m,2H),1.49-1.43(m,2H).

[0221] Preparation route IX: Preparation of compound 57

[0222] Step 1: Preparation of 4-(2-(2-chloroacetamido)thiazolyl-4-yl)-1,3-phenylene diisopropyl dicarbonate (IX-2)

[0223] Compound-5 (200 mg, 0.526 mmol) was added to DCM (8 mL), followed by Et3N (161 mg, 1.578 mmol). The reaction was stirred at 0 °C. Finally, a DCM solution of compound IX-1 (119 mg, 1.052 mmol) was added dropwise to the system at 0 °C and stirred for 1 h. TLC analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (100 mL) and extracted with DCM (50 mL x 3). The extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to give compound-2 (130 mg, 54% yield).

[0224] Step 2: Preparation of diisopropyl(4-(2-(2-(methylseleno)acetamido)thiazolyl-4-yl)-1,3-phenylene) dicarbonate (-3)

[0225] Compound-2 (22 mg, 0.114 mmol) was added to anhydrous ethanol (3 mL), and the reaction was stirred at 0 °C. Then, NaBH4 (13 mg, 0.341 mmol) was added to the system in portions, and stirring continued at 0 °C until clear. Finally, a solution of dimethyl diselenyl ether (130 mg, 0.284 mmol) in ethanol (2 mL) was added dropwise to the system, and the mixture was stirred at 0 °C for 1 hour. The reaction was confirmed by TLC. The reaction solution was poured into water (100 mL) and extracted with DCM (50 mL * 3). The solution was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to give compound-3 (40 mg, yield 27.5%). LCMS ([M+H]+): 516.76.

[0226] Step 3: Preparation of N-(4-(2,4-dihydroxyphenyl)thiazolyl)-2-(methylselenoacetamide) (compound 57)

[0227] Compound-3 (40 mg, 0.078 mmol) was added to methanol (4 mL) and dissolved by stirring at room temperature. Then, NaOH aqueous solution (4 N, 1 mL) was added to the system, and stirring was continued at room temperature for 2 h. TLC plate analysis showed that the starting material was almost completely consumed. The reaction solution was poured into water (100 mL) and the pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. Extraction was performed using DCM (50 mL * 3), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC and then by pre-HPLC to obtain compound 57 (16 mg, yield 54.1%) with a purity of 98.86%. LCMS ([M+H) + ):344.78. 1 H NMR (400MHz, DMSO) δ12.31(s,1H),10.80(s,1H),9.50(s,1H),7.67(d,J=8.4Hz,1H),7.44(s,1H),6.34-6.29(m,2H),3.37(s,2H),2.13(s,3H).

[0228] Preparation route: Preparation of compound 58

[0229] Step 1: Preparation of (2R,3S,4S,5R)-2-(acetoxymethyl)-6-(4-(tert-butoxycarbonyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (-3)

[0230] Compound-1 (1 g, 5.15 mmol), compound-2 (2.54 g, 6.18 mmol), and Ag₂O (2.84 g, 10.3 mmol) were added to CH₃CN (30 mL), and the reaction was stirred at room temperature for 12 h. The reaction mixture was completely consumed by TLC. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography to give compound-3 (2.3 g, 85% yield).

[0231] Step 2: Preparation of 4-(((3R,4S,5S,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)benzoic acid (-4)

[0232] Compound-3 (1 g, 1.91 mmol) was added to a TFA / DCM (10 mL / 20 mL) mixture, and the reaction was stirred at room temperature for 1 h. The reaction was confirmed by TLC. The reaction solution was concentrated, and the residue was poured into saturated NaHCO3 (100 mL) and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain crude compound-4, which was used directly in the next step.

[0233] Step 3: Preparation of (2R,3S,4S,5R)-2-(acetoxymethyl)-6-(4-(chloroformyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (-5)

[0234] Compound-4 (800 mg, 1.7 mmol) was added to SOCl2 (10.0 mL), stirred at 80 °C for 2 h, and the reaction solution was concentrated to obtain crude compound 5, which was used directly in the next step.

[0235] Step 4: Preparation of (2R,3S,4S,5R)-2-(acetoxymethyl)-6-(4-((4-(2,4-bis((isopropoxycarbonyl)oxy)phenyl)thiazolyl-2-yl)carbamoyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (-6)

[0236] Compounds -5 (400 mg, 1.05 mmol), -5 (770 mg, 1.58 mmol), and Et3N (0.59 mL, 4.21 mmol) were added to DCM (20 mL), and the reaction was stirred at room temperature for 12 h. The reaction was confirmed to be complete by TLC. The reaction solution was poured into water (100 mL) and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by pre-TLC to obtain compound -6 (600 mg, yield 68.7%).

[0237] Step 5: Preparation of N-(4-(2,4-dihydroxyphenyl)thiazolyl)-4-(((3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)benzamide (compound 58)

[0238] Compound-6 (600 mg, 0.72 mmol) was added to methanol (8.0 mL) and dissolved by stirring at room temperature. Then, 2 mL of 4 N NaOH aqueous solution was added to the system, and stirring was continued at room temperature for 2 h. The reaction was confirmed by TLC. The reaction solution was poured into water (100 mL) and the pH was adjusted to approximately 5–6 with 2 N hydrochloric acid. The mixture was concentrated, and the crude product was purified by pre-HPLC to obtain compound 58 (23.0 mg, yield 54.1%) with a purity of 97.4%. LCMS ([M+H) + ):491.19.1H NMR (400MHz, DMSO) δ12.55(s,1H),11.13(s,1H),9.51(s,1H),8.09(d,J=8.7Hz,2H),7.68 (d,J=9.2Hz,1H),7.46(s,1H),7.18(d,J=8.7Hz,2H),6.32-6.31(m,2H),5.23-5.21(m,1H) ,4.99(d,J=7.6Hz,1H),4.90-4.88(m,1H),4.69-4.66(m,1H),4.53(d,J=4.3Hz,1H),3.73 -3.71(m,1H),3.67-3.64(m,1H),3.62-3.59(m,1H),3.56-3.50(m,2H),3.45-3.42(m,1H).

[0239] Preparation route XI: Preparation of compound 59

[0240] Step 1: Preparation of ethyl 4-(diethoxyphosphoryl)benzoate (XI-3)

[0241] Compound-1 (1 g, 4.37 mmol), compound-2 (723 mg, 5.24 mmol), Pd(OAc)2 (98 mg, 0.44 mmol), PPh3 (229 mg, 0.88 mmol), and Et3N (1.84 mL, 13.10 mmol) were added to EtOH (20 mL), and the reaction was carried out under a nitrogen atmosphere at 90 °C with stirring for 12 h. TLC analysis showed that the starting materials were almost completely consumed. The reaction solution was concentrated, poured into water (50 mL), and extracted with DCM (50 mL * 3). After drying with anhydrous Na2SO4, the solution was filtered, concentrated, and the crude product was obtained. The crude product was purified by column chromatography to obtain compound-3 (1.0 g, 80% yield).

[0242] Step 2: Preparation of 4-(diethoxyphosphoryl)benzoic acid (-4)

[0243] Compound-3 (1 g, 3.49 mmol) and LiOH (84 mg, 3.49 mmol) were added to EtOH / water (8 mL / 2 mL). The reaction was stirred at room temperature for 12 h, and the reaction was confirmed by TLC. The reaction solution was poured into water, and the pH was adjusted to acidic with HCl (4N). The solution was extracted with DCM (50 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound-4 (500 mg, yield 55.4%).

[0244] Step 3: Preparation of 4-(diethoxyphosphoryl)benzoyl chloride (-5)

[0245] Compound-4 (500 mg, 1.94 mmol) was added to SOCl2 (4.0 mL), and the reaction was stirred at 80 °C for 2 h. The reaction solution was concentrated to obtain crude compound-5, which was used directly in the next step.

[0246] Step 4: Preparation of (4-(2-(4-(diethoxyphosphoryl)benzamido)thiazolyl-4-yl)-1,3-phenylene)diisopropyl dicarbonate (-6)

[0247] Compound II-5 (500 mg, 1.3 mmol), compound-5 (436 mg, 1.6 mmol), and Et3N (665 mg, 6.6 mmol) were added to DCM (20 mL), and the reaction was stirred at room temperature for 12 h. The reaction was confirmed by TLC. The reaction solution was poured into water (100 mL) and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound-6 (0.5 g, yield 61.3%).

[0248] Step 5: Preparation of diethyl (4-((4-(2,4-dihydroxyphenyl)thiazolyl-2-yl)carbamoyl)phenyl)phosphonate (-7)

[0249] Compound-6 (200 mg, 0.32 mmol) was added to EtOH (4.0 mL), and the reaction was stirred at room temperature. Then, a solution of NaOH (103 mg, 2.6 mmol) in water (1.0 mL) was added to the system, and the mixture was stirred at room temperature for another 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was poured into water (100 mL), and the pH was adjusted to 5 with HCl (4N). The mixture was concentrated to obtain a crude product, which was purified by pre-HPLC to obtain compound-7 (870 mg, yield 48.3%).

[0250] Step 6: Preparation of (4-((4-(2,4-dihydroxyphenyl)thiazolyl-2-yl)carbamoyl)phenyl)phosphonic acid (compound 59)

[0251] Compound-7 (70 mg, 0.16 mmol) and TMSBr (240 mg, 1.6 mmol) were added to DCM / CH3CN (4 mL / 4 mL). The reaction was stirred at room temperature for 12 h, and the reaction was confirmed by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by pre-HPLC to obtain compound 59 (8.5 mg, yield 13.9%) with a purity of 96.5%. LCMS ([MH)) - ):391.00.1H NMR(400MHz,DMSO)δ12.66(s,1H),11.10(s,1H),9.50(s,1H),8.04-8.03(m,2 H),7.97-7.83(m,2H),7.68(d,J=8.0Hz,1H),7.43(s,1H),6.33-6.31(m,2H).

[0252] Compound 60 was prepared by the method and general steps (Steps 1-5) described in Route XI, with compound-2 replaced by dimethylphosphine oxide (Step 1) as described in the foregoing schemes and examples. The required starting materials were commercially available, or obtained by following the procedures described in the literature, or synthesized by a person skilled in the art of organic synthesis using commercially available reagents and conventional reaction methods.

[0253] Preparation route XII: Preparation of compound 61

[0254] Step 1: Preparation of tert-butyl 4-((diethoxyphosphoryl)methyl)benzoate (XII-3)

[0255] Compounds -1 (2 g, 7.38 mmol) and -2 (6.13 g, 36.88 mmol) were placed in a microwave-safe tube and reacted under microwave conditions at 130 °C with stirring for 1 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated, and the crude product was purified by column chromatography to give compound -3 (1.0 g, yield 41.3%).

[0256] Step 2: Preparation of 4-((diethoxyphosphoryl)methyl)benzoic acid (-4)

[0257] Compound-3 (1 g, 3.05 mmol) was added to TFA / DCM (10 mL / 20 mL), and the reaction was stirred at room temperature for 11 h. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated, and the residue was poured into water and extracted with DCM (100 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product, which was used directly in the next step.

[0258] Step 3: Preparation of 4-((diethoxyphosphoryl)methyl)benzoyl chloride (-5)

[0259] Compound-4 (500 mg, 1.8 mmol) was added to SOCl2 (4.0 mL), and the reaction was stirred at 80 °C for 2 h. The reaction solution was concentrated to obtain crude compound-5, which was used directly in the next step.

[0260] Step 4: Preparation of (4-(2-(4-((diethoxyphosphoryl)methyl)benzamido)thiazolyl-4-yl)-1,3-phenylene)diisopropyl dicarbonate (-6)

[0261] Compound-5 (500 mg, 1.3 mmol), compound-5 (458 mg, 1.6 mmol), and Et3N (1.0 mL, 6.6 mmol) were added to DCM (10 mL), and the reaction was stirred at room temperature for 12 h. The reaction was confirmed to be complete by TLC. The reaction solution was poured into water (100 mL) and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound-6 (30 mg, yield 3.5%).

[0262] Step 5: Preparation of diethyl (4-((4-(2,4-dihydroxyphenyl)thiazolyl-2-yl)carbamoyl)benzyl)phosphonate (compound 61)

[0263] Compound-6 (30 mg, 0.047 mmol) was added to EtOH (4.0 mL), and the reaction was stirred at room temperature. Then, a solution of NaOH (15 mg, 0.47 mmol) in water (1.0 mL) was added to the system, and the mixture was stirred at room temperature for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was poured into water (50 mL), and the pH was adjusted to 5 with HCl (4N). The mixture was concentrated, and the crude product was purified by pre-HPLC to give compound 61 (3.0 mg, yield 13.6%) with a purity of 99.3%. LCMS ([MH)) - ):461.1.1H NMR (400MHz, DMSO) δ11.64(s,1H),9.65(s,1H),8.05(d,J=8.0Hz,2H),7.65(d,J=8.8Hz,1H),7.43(d, J=6.7Hz,2H),7.36(s,1H),6.31-6.29(m,2H),4.01-3.93(m,4H),3.32(s,2H),1.18(t,J=7.0Hz,6H).

[0264] Preparation route XIII: Preparation of compound 62:

[0265] Step 1: Preparation of tert-butyl 4-((diethoxyphosphoryl)oxy)benzoate (XIII-3)

[0266] Compound-1 (3 g, 15.45 mmol), compound-2 (4.22 g, 23.17 mmol), and pyridine (3.6 mL, 46.34 mmol) were added to DCM (50 mL). Tf₂O (8.7 g, 30.89 mmol) was added dropwise to the system at -20 °C, and the mixture was stirred for 12 h at -20 °C. The reaction was confirmed to be complete by TLC. The reaction mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3). The extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound-3 (0.5 g, yield 9.8%).

[0267] Steps 2-5: Preparation of diethyl phosphate (4-((4-(2,4-dihydroxyphenyl)thiazolyl-2-yl)carbamoyl)phenyl)phosphate (compound 62)

[0268] Compound 62 was prepared via the general steps of the above-described route, with compound-3 substituted for compound-3 in the preparation scheme and examples described above (Step 2). The required starting materials are commercially available, or obtained according to the procedures described in the literature, or synthesized by an experienced person in the field of organic synthesis using commercially available reagents and conventional reaction methods. LCMS([MH)) - ):463.33. 1 H NMR (400MHz, DMSO) δ11.53(s,1H),9.55(s,1H),8.16(d,J=8.7Hz,2H),7.65(d,J=9.1Hz,1H) ,7.36-7.34(m,3H),6.33-6.26(m,2H),4.19(dq,J=14.3,7.1Hz,4H),1.28(t,J=7.1Hz,6H).

[0269] Preparation of control A:

[0270] Step 1: Preparation of 1-(4-(2,4-dimethoxyphenyl)thiazolyl-2-yl)-3-methylurea (A-2)

[0271] Compound-3 (250 mg, 1.06 mmol), compound A-1 (218 mg, 1.27 mmol), and DIEA (409 mg, 3.17 mmol) were added to DMF (8 mL). The reaction mixture was stirred at 100 °C for 1 hour, and TLC analysis showed that the starting materials were almost completely consumed. The reaction mixture was concentrated to a minimum volume, poured into water (100 mL), and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was purified by pre-TLC to obtain compound A-2 (220 mg, yield 71.0%).

[0272] Step 2: Preparation of 1-(4-(2,4-dihydroxyphenyl)thiazolyl)-3-methylurea (Control A)

[0273] Compound A-2 (100 mg, 0.34 mmol) was added to anhydrous DCM (8 ml), and the reaction was stirred at room temperature. Then, BBr3 (0.3 ml) was added dropwise to the system, and stirring was continued at room temperature for 1 hour. TLC plate analysis showed that the starting material was almost completely consumed. The reaction was quenched by adding methanol dropwise to the system under ice bath conditions. The residue was concentrated to obtain a crude product, which was purified by pre-TLC plate and then by pre-HPLC to obtain compound control A (14 mg, yield 15.6%) with a purity of 99.30%. LCMS ([M+H) +):266.13.1H NMR(400MHz,DMSO)δ11.10(s,1H),10.83(s,1H),9.47(s,1H),7.63-7.54( m,1H),7.23(s,1H),6.44(s,1H),6.31-6.24(m,2H),2.70(d,J=4.6Hz,3H).

[0274] Preparation of control B:

[0275] Step 1: Preparation of 3-(4-(2,4-dimethoxyphenyl)thiazolyl-2-yl)-1,1-dimethylurea (B-2)

[0276] Compound-3 (100 mg, 0.42 mmol), compound B-1 (90 mg, 0.85 mmol), and Cs₂CO₃ (400 mg, 1.27 mmol) were added to CH₃CN (8 mL). The reaction mixture was stirred at 80 °C for 1 hour, and TLC analysis showed that the starting materials were almost completely consumed. The reaction mixture was poured into water (100 mL) and extracted with DCM (50 mL * 3). The extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a crude product. The crude product was purified by pre-TLC to obtain compound B-2 (80 mg, yield 61.5%).

[0277] Step 2: Preparation of 3-(4-(2,4-dihydroxyphenyl)thiazolyl)-1,1-dimethylurea (Control B)

[0278] Compound B-2 (70 mg, 0.22 mmol) was added to anhydrous DCM (5 ml), and the reaction was stirred at room temperature. Then, BBr3 (0.3 ml) was added dropwise to the system, and stirring was continued at room temperature for 1 hour. TLC plate analysis showed that the starting material was almost completely consumed. The reaction was quenched by adding methanol dropwise to the system under ice bath conditions. The residue was concentrated to obtain a crude product, which was purified by pre-TLC plate and then by pre-HPLC to obtain compound control B (5.4 mg, yield 8.4%). Purity 99.18%. LCMS ([M+H) + ): 280.13.1H NMR (400MHz, DMSO) δ11.34(s,1H),10.78(s,1H),9.46(s,1H),7.62-7.55(m,1H),7.24(s,1H),6.31-6.25(m,2H),2.98(s,6H).

[0279] Biological tests:

[0280] 1. Inhibitory activity of the compound against tyrosinase (Tyr)

[0281] To verify the inhibitory activity of the compound of the present invention on tyrosinase (Tyr) in mammals, particularly on human tyrosinase (hTyr), the applicant used MNT-1 cells (human melanoma cells) to evaluate and detect the inhibitory activity of the compound on tyrosinase (Tyr). The specific methods are as follows:

[0282] Collect MNT-1 cells in the logarithmic growth phase, wash three times with PBS buffer, add a certain amount of PBS buffer and sonicate to disrupt the cells, then incubate on ice for 3-5 minutes, centrifuge at 13000 rpm for 15 minutes, collect the supernatant as crude tyrosinase enzyme solution, and store on ice for later use. Perform 3-fold serial dilutions of the test compounds, setting 7-9 concentration points for each compound. Take a 96-well plate (Costar 3599), add 20 μL of crude enzyme solution and 80 μL of sodium phosphate buffer to each well, centrifuge at 1000 rpm for 30 seconds. Then add 2 μL of different concentrations of the test compound, centrifuge at 1000 rpm for 30 seconds. After shaking at room temperature for 1 minute, incubate for 5 minutes. Add 100 μL of L-DOPA (MCE, HY-N0304) to each well to a final concentration of 4 mM, shake at room temperature for 1 minute, and set the microplate reader (BioTek, Synerray H1 Hybrid Reader) to kinetic mode, temperature 26°C, absorbance mode, 475 nm, and read continuously for 59 minutes, with one reading every 1 minute. Based on the absorbance values, perform IC50 analysis of tyrosinase activity using GraphPad software. 50 calculate.

[0283] Experimental results:

[0284] The inhibitory activity test data of the compounds of this invention and the control compounds against human tyrosinase are shown in Table 1.

[0285] Table 1: Test data on the inhibitory activity of the compounds of the present invention and control compounds against human tyrosinase Note: "-" indicates that no test was performed.

[0286] The experimental results show that the compounds of the present invention have good inhibitory activity against human tyrosinase (hTyr), and are significantly better than phenylethyl resorcinol; when the compounds of the present invention have the structure of formula III, specifically compounds 18 to 23, their inhibitory activity against human tyrosinase is better than that of controls A and B.

[0287] 2. Tests on the inhibitory activity of the compound on melanin production

[0288] Test method:

[0289] MNT-1 cells in the logarithmic growth phase were divided into 3 × 10⁻⁶ cells per well. 5 Cells were seeded into 6-well plates, and the test compounds were added to final concentrations of 0 and 10 μM, respectively. After culturing for 3 days, the cell pellet was collected. 120 μL of RIPA lysis buffer (Solepro, R0010) was added to the cell pellet, and the plates were placed on ice for low-temperature lysis for 15-30 minutes. After centrifugation at 13000 rpm for 10 minutes, the supernatant was collected, and the protein concentration was determined using the BCA method to calculate the total protein content. The melanin precipitate obtained after centrifugation was added to 300 μL of NaOH lysis buffer to a final concentration of 1 M, and lysed at 85°C for 3 hours. After heat treatment, the plates were centrifuged at 13000 rpm for 10 minutes, and the supernatant was collected and the absorbance at 405 nm was measured using a microplate reader (BioTek, Synerray H1 Hybrid Reader). Based on the standard curve of melanin (Sigma, M8631) (maximum concentration 50 μg / mL, 2-fold serial dilution, 8 concentration points), the melanin content in the sample was calculated, and the melanin content per mg of protein was finally calculated based on the total protein content. Using the untreated group as 100%, the percentage of melanin content at different concentrations of the test compound was calculated. The experimental results are shown in Table 2:

[0290] Table 2: Inhibitory activity of the compound of the present invention (10 μM) on melanin production Note that "-" indicates that no test was performed.

Claims

1. A heterocyclic compound having the structure of Formula (I), Formula (II), Formula (III), or Formula (IV): or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof: in: R1are the same or different, independently optionally selected from: H, D, halogen, CN, -N(R 1a )2, -OR 1a , R 1a , -NHR 1b , -OR 1b ; R 1a the same or different, are independently optionally selected from: H, C 1-6 alkyl; when R 1a is C 1-6 alkyl, two adjacent R1may form a 4-8 membered ring with the carbon atom, nitrogen atom or oxygen atom to which they are attached; R 1b the same or different, independently are optionally selected from: a monosaccharide residue, an oligosaccharide residue, a polysaccharide residue, -P(=0)(OM)2, -P(=0)R 5a R 5b ; M is the same or different, independently optionally selected from: H, C 1-6 alkyl; R 5a , R 5b is selected from: C 1-6 alkyl; m is selected from: 1, 2, 3, 4, 5; W is a partially saturated C4-C10cycloalkylene, C4-C10heterocycloalkylene, or C4-C10heterocycloalkenylene ring having at least one ring atom independently optionally selected from N, O, or S(O) 14 heterocycloalkenylene ring having at least one ring atom independently optionally selected from N, O, or S(O) p ; R a the same or different, are independently selected from H, D, halogen, C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-6 alkoxy, C 6-14 aryl, C 5-14 heteroaryl, when R a is C 1-6 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, R a may form, together with the W ring atom adjacent thereto, a ring of 3-10 ring members; R a The optional elements are F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, and -(CH2). r R a1 -(CH2) r OR a1 -(CH2) r SR a1 -(CH2) r C(O)R a1 -(CH2) r C(O)OR a1 -(CH2) r OC(O)R a1 -(CH2) r NR a1 R a1 -(CH2) r C(O)NR a1 R a1 -(CH2) r NR a1 C(O)R a1 -(CH2) r NR a1 C(O)OR a1 -NR a1 C(O)NR a1 R a1 -S(O) p NR a1 R a1 -NR a1 S(O) p R a1 -O(CH2) r OR a1 -S(O) p R a1 C 1-6 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -C 3-8 Heterocyclic alkyl substitution; R a1 the same or different, are independently optionally selected from H, D, C 1-6 alkyl, C 2-10 alkenyl, -(CH2) q OH, C 1-6 haloalkyl, -(CH2) q -C 3-10 cycloalkyl, -(CH2) q -C 3-10 heterocycloalkyl, -(CH2) q -phenyl; X is selected from: -C(R) a )3;-C(O)R a ;-C(O)NR a R a ;-C(O)OR a ;-NR a R a ;-NR a C(O)R a ;-NR a C(O)NR a R a ;-NR a C(O)OR a ;-OR a ;-S(O) p R a ;Optionally used by R a Replacement C 6-14 Aryl, C 5-14 heteroaryl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl groups; R2is selected from: -NR a R a , -OR a , -C(O)R a , -C(O)OR a , -S(O) p R a ; R3is selected from: H, D, C 1-6 alkyl, C 3-10 cycloalkyl, -NR a R a , -OR a , -C(O)R a , -C(O)OR a , -S(O) p R a ; T is selected from CH or N; Z is selected from: O, S, Se; L1is selected from the group consisting of a bond, -C(R b )2NR b -, -C(O)-, -C(O)C(R b )2C(O)-, -C(O)NR b -, C(O)NR b NR b -, -C(O)NR b C(O)-, -C(O)O-, -NR b -, -NR b C(O)-, -NR b C(O)C(O)-, -NR b C(O)NR b -, -NR b C(O)O-, -NR b C= N-, -NR b N=CH-, -NR b C(S)-, -NR b C(S)NR b , -O-, -OC(O)-, -OC(O)NR b -, -S-, -S(O) p -, -S(O) p NR b -; R b the same or different, are independently optionally selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl; R4 is C 1-6 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 3-10 heterocycloalkylene, C 6-14 arylene or C 5-14 heteroarylene; R4 may optionally be substituted with the following substituents: F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, -(CH2) r R a1 -(CH2) r OR a1 -(CH2) r SR a1 -(CH2) r C(O)R a1 -(CH2) r C(O)OR a1 -(CH2) r OC(O)R a1 -(CH2) r NR a1 R a1 -(CH2) r C(O)NR a1 R a1 -(CH2) r NR a1 C(O)R a1 -(CH2) r NR a1 C(O)OR a1 -NR a1 C(O)NR a1 R a1 -S(O) p NR a1 R a1 -NR a1 S(O) p R a1 -O(CH2) r OR a1 -S(O) p R a1 C 1-6 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -C 3-8 Heterocyclic alkyl groups; L2is selected from a bond, -(CH2) t - -(CH2) r O- -(CH2) r NH-; n is selected from: 0, 1, 2, 3, 4, 5; p is selected from 0, 1, and 2; r is selected from 0, 1, 2, 3, and 4; q is selected from 0, 1, 2, 3, and 4; t is selected from 1, 2, 3, and 4.

2. The heterocyclic compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein, R1is the same or different, independently selected from -OH, -OR 1b m is selected from: 1, 2, 3; Preferably, selected from the group consisting of R 1b are the same or different, independently selected from the group consisting of monosaccharide residues, oligosaccharide residues, -P(=0)(OM)2, -P(=0)R 5a R 5b ; M is the same or different, independently selected from the group consisting of: H, C 1-4 alkyl.

3. The heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates according to claim 1 or 2, having the structure of formula (I), wherein: For The W ring is a C4-C8 heterocyclic alkyl group containing a double bond, and at least two ring atoms in the W ring are independently selected from N, O or S; preferably, two ring atoms in the W ring are selected from N and O or N and S respectively; R a Whether the two are the same or different, choose C independently. 1-6 Alkyl, or R a C 1-6 Alkyl groups, together with their adjacent ring atoms, form 3-5 membered rings; R a Optional F, OCF3, CF3, -OR a1 -NR a1 R a1 Replace; R a1 For H, C 1-6 alkyl; n is selected from 0, 1, 2; Preferably, the W ring is Y represents O and S; R a the same or different, are independently optionally selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl; or, R a together with the W ring atom to which they are attached form a 3-5 membered ring; R a optionally substituted with -OH; n is selected from 0, 1, 2; Further preferably, the W ring is R a the same or different, are independently optionally selected from methyl, or R a is n-propyl and together with the W ring atom adjacent thereto forms a 5-membered ring; n is selected from 1 and 2.

4. The heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, and solvates according to claim 1 or 2, wherein the structure is of formula (II), wherein: For X is -NR a R a , -NR a C(O)R a , -NR a C(O)NR a R a , -NR a C(O)OR a ; R a the same or different, independently are optionally selected from H, C 1-6 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl; R a optionally substituted by F, CN, -(CH2) r R a1 , -(CH2) r OR a1 , -O(CH2) r OR a1 , C 1-6 alkyl, C 2-8 alkenyl; R a1 is H, C 1-6 alkyl, C 2-10 alkenyl, -(CH2) q OH; r is selected from 0, 1, 2, 3, and 4; q is selected from 0, 1, 2, 3, and 4; Preferably, R a the same or different, are independently optionally selected from H, methyl, ethyl, propyl, butyl, pentyl, isopropyl, tert-butyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, propenyl, allyl, phenyl, pyridyl, methoxy, morpholinyl, wherein: Y is O, S; R a1 the same or different, are independently optionally selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or R a1 may form, together with the W ring atom adjacent thereto, a 3-5 membered ring; n is selected from 0, 1, 2; Further preferably, X is -NR a C(O)R a ; R a are the same or different, independently optionally selected from H, methyl, ethyl, n-propyl, cyclopropanyl, cyclobutanyl, isopropyl, t-butyl, pyridyl, propenyl, 5. The heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates according to claim 1 or 2, having a structure of formula (III), wherein: For R2is -OR a , -SR a ; R3is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, -NR a R a , -OR a , -SR a ; R a the same or different, are independently optionally selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 2-6 alkenyl, C 2-6 alkynyl; R a optionally substituted with F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; Preferably, R2is -OR a ; R3is hydrogen, C 1-6 alkyl; R a is independently selected from hydrogen, C 1-6 alkyl; Further preferably, R2is -OR a ; R3is hydrogen, methyl, ethyl; R a are independently optionally selected from hydrogen, methyl, ethyl, isopropyl.

6. The heterocyclic compound or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates according to claim 1 or 2, wherein it has the structure of formula (IV), wherein: selected from the group consisting of T is N; Z is S; L1 is selected from the group consisting of bonds, -CH2NH-, -C(O)-, -C(O)NH-, C(O)NHNH-, -C(O)NHC(O)-, -C(O)O-, -NH-, -NHC(O)-, -NHC(O)C(O)-, -NHC(O)NH-, -NHC(O)O-, -NHC=N-, -NHC(S)-; R4is selected from C 1-6 alkylene, C 2-10 alkenylene, C 3-10 cycloalkylene, C 3-10 heterocycloalkylene, C 6-14 aryl, C 5- 14 heteroaryl; R4is optionally substituted with F, CI, Br, OCF3, CF3, CH2F, CHF2, CN, NH2, NO2, -CH2OH, -OH, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, substituted with 0-2 groups independently selected from F, CI, Br, OCF3, CF3, CH2F, CHF2, CN, NH2, NO2, -CH2OH, -OH, C L2is selected from the group consisting of a bond, -(CH2) t - -(CH2) r O-; r is selected from 0, 1, 2, 3, 4; t is selected from 1, 2, 3, 4; R 1b the same or different, are independently optionally selected from the group consisting of monosaccharide residues, oligosaccharide residues, -P(=0)(OM)2, -P(=0)R 5a R 5b ; M are the same or different, independently optionally selected from: H, C 1-4 alkyl; R 5a , R 5b are independently optionally selected from: methyl, ethyl; Preferably, the monosaccharide residues are selected from glucosyl, mannose, galactosyl, xylose, lythose, fucose, arabinose, rhamnose, fructose, sorbitol, and tagatose. Preferably, the oligosaccharide residue is a disaccharide residue; more preferably, the disaccharide residue is selected from lactosyl, maltulose, palaginose, lactulose, amygdalinose, menobiose, cellobiose, isomaltose, rutinose, and maltose. More preferably, L1 is selected from -C(O)-, -C(O)NH-, C(O)O-, -NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)O-; R4 is selected from methylene, ethylene, propylene, isopropylene, morpholino, piperidinyl, piperazine, phenylene, naphthyl, pyridinyl, pyridazine, pyrimidinyl, furanyl, oxazolyl, dihydrooxazolyl, thiophene, pyrazolyl, thiazolyl, dihydrothiazolyl, pyrrolyl, and imidazolyl; R4 may optionally be substituted with F, Cl, Br, OCF3, CF3, CH2F, CHF2, CN, NH2, NO2, -OH, methyl, ethyl, vinyl, or ethynyl. L2is selected from the group consisting of a bond, -0-, -CH2-, -CH2O-, -CH2CH2O-; R 1b selected from glucosyl, mannosyl, galactosyl, rhamnosyl, fucosyl, fructosyl, arabinosyl, xylosyl, ribosyl, sucrosyl, lactosyl, trehalosyl, -P(=O)(OH)2, -P(=O)(OH)(OCH3), -P(=O)(OCH3)2, -P(=O)(OH)(OCH2CH3), -P(=O)(OCH2CH3)2, -P(=O)(CH3)2.

7. The heterocyclic compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, which is selected from the following compounds or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof:

8. A composition comprising: The heterocyclic compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier or a skin care carrier.

9. Use of the heterocyclic compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, or the composition according to claim 8, for inhibiting the activity of tyrosinase in a mammal.

10. Use of the heterocyclic compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, or the composition according to claim 8, for the manufacture of a medicament or a skin care product for treating a hyperpigmentation disease, for the manufacture of a medicament for pest control, for the manufacture of an antifungal medicament or for the manufacture of an anti-browning food product. Preferably, the hyperpigmentation disease is selected from the group consisting of freckles, age spots, chloasma, nevi, post-inflammatory hyperpigmentation or solar lentigines.

11. The heterocyclic compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof, or the composition according to claim 8, for use in the manufacture of a skin care product having a whitening, anti-aging, moisturizing, lightening and / or lightening function.

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