Tyrosinase inhibitor and use thereof

Abstract

Provided are a tyrosinase inhibitor compound represented by formula (I), a composition, a preparation method and a use. The compound not only has excellent tyrosinase inhibitory activity, but also has good physical and chemical properties, can meet the use requirements of people with an extremely low concentration, and has no toxicity to melanocytes or skin.

Description

Tyrosinase inhibitors and their applications

[0001] This invention claims patent application number 202410353481.8 filed with the State Intellectual Property Office of China on March 26, 2024, patent application number 202410533155.5 filed with the State Intellectual Property Office of China on April 29, 2024, patent application number 202410711104.7 filed with the State Intellectual Property Office of China on June 03, 2024, patent application number 202410909706.3 filed with the State Intellectual Property Office of China on July 08, 2024, Patent application No. 202411025194.0 filed with the State Intellectual Property Office of China on July 29, 2024, patent application No. 202411775451.2 filed with the State Intellectual Property Office of China on December 4, 2024, and patent application No. 202510322654.4 filed with the State Intellectual Property Office of China on March 18, 2025, all of which have the priority of “Tyrosinase inhibitors and their applications”, the full text of the prior applications are incorporated into the present invention by reference. Technical Field

[0002] The present invention belongs to the field of compounds, and in particular relates to a tyrosinase inhibitor compound, a composition, a preparation method and an application thereof. Background Art

[0003] The number of melanocytes in human skin remains roughly the same, regardless of skin color. Skin color is primarily determined by the amount and type of melanin (black eumelanin or yellow to reddish-brown pheomelanin). Asians and people with light skin have lower eumelanin levels than darker skinned individuals and are less protected from sunlight. Melanin also varies in its distribution within the skin. In light-skinned individuals, the pigment is more abundant in the basal layer, while in darker skinned individuals, the melanin is diffused throughout the stratum corneum. Hyperpigmentation can occur due to various factors, including exposure to ultraviolet radiation (such as sun spots and freckles), genetic predisposition, abnormal pigmentation during wound healing (post-inflammatory hyperpigmentation), and abnormal pigmentation associated with aging (such as age spots). Post-inflammatory hyperpigmentation is a common problem in people of color. For example, pseudofolliculitis barbae, associated with abnormal pigmentation, can occur in men of color, as can melasma, which occurs particularly on the face and neck of Asian women.

[0004] Tyrosinase is a key enzyme in melanin production. It catalyzes three reactions: 1) hydroxylation of tyrosine to form 3,4-dihydroxyphenylalanine (DOPA); 2) oxidation of DOPA to form DOPAquinone; and 3) oxidation of DHI (5,6-dihydroxyindole) to form indolequinone. Tyrosinase belongs to the copper protein family and contains two copper ions in its active site. The binuclear copper ions have three main redox forms: 1) Cu + -Cu + - reduced form; 2) Cu that reversibly binds O2 as a peroxide 2+ -O2-Cu 2+ form; 3) Cu ions are bridged by small ligands such as H2O. 2+ -O2-Cu 2+ The redox state is key to tyrosinase activity. Tyrosinase catalyzes the reaction that introduces a second hydroxyl group into the ortho position of a monophenol (such as tyrosine), which is crucial for melanin biosynthesis. There are two main approaches to inhibiting melanin production: directly interacting with tyrosinase or indirectly inhibiting tyrosinase activity by complexing the catalytic center with a metallic copper ion.

[0005] Currently, substances commonly used for skin whitening include hydroquinone, hexadecene-1,16-dicarboxylic acid, kojic acid and its derivatives, arbutin, ascorbic acid and its derivatives, flavonoids, ellagic acid and its derivatives, tranexamic acid, and various resorcinol derivatives, 4-n-butylresorcinol, 4-n-hexylresorcinol, and 4-(1-phenylethyl)benzene-1,3-diol. Among them, hydroquinone was one of the earliest skin bleaching agents. For example, Albert Kligman et al. developed the so-called "Triformula," which is a combination of 0.1% retinoic acid, 5.0% hydroquinone, and 0.1% dexamethasone. However, long-term use of hydroquinone can cause irreversible changes in the skin's pigmentation system, become cytotoxic to melanocytes, and risk permanent skin discoloration. China has restricted the use of hydroquinone in skin care products, and it is only available by prescription.

[0006] Beiersdorf's research found that hydroquinone, arbutin, kojic acid, 4-n-butylresorcinol, 4-n-hexylresorcinol and 4-(1-phenylethyl)benzene-1,3-diol have weak inhibitory effects on human tyrosinase, or even have no inhibitory activity. They reported a class of resorcinol thiazole compounds that have relatively good inhibitory effects on human tyrosinase.

[0007] Resorcinol derivatives disclosed in the prior art suffer from insufficient inhibitory activity against human tyrosinase or unstable physicochemical properties, failing to meet the needs of patients with pigmentation. There is an urgent need to develop compounds that exhibit excellent reversible inhibition of human tyrosinase and favorable physicochemical properties, capable of being used at extremely low concentrations by patients while remaining non-toxic to melanocytes or skin. Summary of the Invention

[0008] To improve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:

[0009] Among them, each R a The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy;

[0010] L is absent or selected from unsubstituted or optionally substituted with one, two or more L a Substituted C 1-3 Alkylene; each L a The same or different, independently selected from H or C 1-6 alkyl;

[0011] R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -NR1R2 or -OR3; wherein R1, R2, R3 are the same or different and are independently selected from H, C 1-12 Alkyl, C 3-12 Cyclic hydrocarbon group, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0012] Each R b The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, NH2, -S(=O)2C 1-6 Alkyl, 3-8 membered heterocyclic group, -C 1-6 Alkylene-OC 1-6alkyl, -C(=O)-R5, -C(=O)OR6, -C(=O)NR7R8 or 5-14 membered heteroaryl; wherein R5, R6, R7, R8 are the same or different and are independently selected from H or C 1-6 alkyl;

[0013] Alternatively, two R attached to different carbon atoms b The carbon atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of one, two or more R b1 Substituted with the following groups: C 3-8 Carbocyclic or 3-8 membered heterocyclic ring;

[0014] Alternatively, two R attached to the same carbon atom b The carbon atoms to which it is attached together form an unsubstituted or optionally substituted group consisting of one, two or more R b2 Substituted with the following groups: C 3-8 Carbocyclic or 3-8 membered heterocyclic ring;

[0015] Each R b1 、R b2 The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkylene-OC 1-6 Alkyl or NH2;

[0016] Each R bb the same or different, independently selected from H, OH, CN, halogen, oxo (=O), C 1- 6 alkyl, C 1-6 Alkoxy or NH2;

[0017] R4 is selected from H; or, R4 is connected to the atoms on the R group to form a heterocyclic ring containing a lactam structure, wherein the heterocyclic ring is unsubstituted or optionally substituted by one, two or more R 4a substituted 5-8 membered heterocyclic ring; each R 4a the same or different, independently selected from OH, CN, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy;

[0018] n is selected from 0, 1, 2 or 3.

[0019] According to some embodiments, each R a The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy, and n is selected from 1, 2 or 3.

[0020] According to some embodiments, each R a are identical or different and are independently selected from OH, CN, F, Cl, Br, methyl, trifluoromethyl or methoxy.

[0021] According to some embodiments, n is selected from 1.

[0022] According to some embodiments, L is absent.

[0023] According to some embodiments, L is selected from -CH2-, -CH2CH2-, or -CH(CH3)-.

[0024] According to some embodiments, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -NR1R2 or -OR3.

[0025] According to some embodiments, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted from the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutan-2-yl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,4-dioxane, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-thiopyranyl, thiomorpholinyl, phenyl, pyridyl, pyrazolyl,

[0026] According to some embodiments, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups:

[0027] According to some embodiments, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups:

[0028] According to some embodiments, each R bThe same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, NH2, -S(=O)2C 1-3 Alkyl, 3-8 membered heterocyclic group, -C 1-3 Alkylene-OC 1-3 alkyl, -C(=O)-R5, -C(=O)OR6, -C(=O)NR7R8 or 5-6 membered heteroaryl.

[0029] According to some embodiments, R5, R6, R7, R8 are the same or different and are independently selected from H or methyl.

[0030] According to some embodiments, each R b The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-6 Alkyl (HO-C 1-6 alkyl), -C(=O)-C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, 3-6 membered heterocyclic group, -C 1-6 Alkyl-OC 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2, -C 1-6 Alkylene-O-halogenated C 1-6 Alkyl, 5-6 membered heteroaryl.

[0031] According to some embodiments, each R b The same or different, independently selected from H, OH, CN, F, Cl, Br, methyl, ethyl, methoxy, hydroxymethyl, hydroxyethyl (e.g. 1-hydroxyethyl, 2-hydroxyethyl), oxo (=O), difluoromethyl, acetyl, methylsulfonyl, oxetanyl (e.g. ), methoxyethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)N(CH3)2, -CH2CH2OCH2CF3, -CH2CH2OCH2CHF2, triazole (e.g. ), tetrazolyl or isoxazol-3(2H)-onyl.

[0032] According to some embodiments, R attached to two adjacent carbon atoms b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b1 Substituted with the following groups: C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic ring.

[0033] According to some embodiments, R attached to two adjacent carbon atoms b Together with the atoms to which it is attached, it forms a cyclopropane ring.

[0034] According to some embodiments, two R b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b2 Substituted with the following groups: C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic ring.

[0035] According to some embodiments, two R b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b2 Substituted groups include: cyclopropane ring, cyclobutane ring, oxetane ring, azetidine ring or tetrahydro-2H-pyran ring.

[0036] According to some embodiments, two R b Together with the atoms to which they are connected, they form a cyclopropane ring, a cyclobutane ring, an oxetane ring (e.g. ),

[0037] According to some embodiments, R attached to two non-adjacent carbon atoms b Connected to its end group, together forming C 1-3 Alkylene (e.g., -CH2-, -CH2CH2-).

[0038] According to some embodiments, each R b1 、R b2 the same or different, independently selected from OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1- 3 alkyl, C 1-3 Alkoxy or NH2; each R bb The same or different, independently selected from H, OH, CN, C 1-6alkoxy (eg methoxy) or halogen (eg F, Cl, Br).

[0039] According to some embodiments, each R b2 The same or different groups are independently selected from methyl, ethyl, hydroxyethyl (eg 1-hydroxyethyl, 2-hydroxyethyl) or methoxyethyl.

[0040] According to some embodiments, R is selected from the following groups:

[0041] According to some embodiments, -LR is selected from the group consisting of:

[0042] According to some embodiments, R4 is connected to an atom on the R group to form

[0043] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0044] where R a , L, R, and n have the definitions as described herein.

[0045] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0046] Among them, R a , L, R, and n have the definitions as described herein.

[0047] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0048] Among them, R a , R have the definitions described herein.

[0049] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0050] wherein R has the definition as described herein, provided that R cannot be the following groups: unsubstituted C 3-8 Cycloalkyl,

[0051] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0052] According to some embodiments, the compound represented by formula (I) is selected from the following structures:

[0053] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0054] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0055] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0056] The present invention also provides a method for treating tyrosinase-mediated skin pigmentation, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compounds represented by formula (I), its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds.

[0057] The present invention also provides a method for treating tyrosinase-mediated skin pigmentation, comprising administering to a patient a preventive or therapeutically effective amount of the pharmaceutical composition.

[0058] The tyrosinase-mediated skin pigmentation symptoms are selected from chloasma, stretch marks, solar lentigo, café au lait spots, and freckles.

[0059] The tyrosinase-mediated skin pigmentation includes post-inflammatory pigmentation, wherein the inflammation is selected from acne, eczema, dermatitis, drug eruption, infection, sunburn, and trauma.

[0060] In some embodiments, the patient comprises a mammal, preferably a human.

[0061] The present invention also provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds, or a pharmaceutical composition thereof for treating tyrosinase-mediated diseases.

[0062] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a drug.

[0063] According to an embodiment of the present invention, the use can be for preparing a drug for treating tyrosinase-mediated skin pigmentation disorders and / or diseases, such as for preparing a tyrosinase inhibitor drug.

[0064] According to an embodiment of the present invention, the skin pigmentation disorder is chloasma, stretch marks, solar lentigo, café au lait spots, freckles, post-acne pigmentation, post-eczema pigmentation, post-dermatitis pigmentation, post-drug rash pigmentation, post-infectious pigmentation, post-sunburn pigmentation, and post-traumatic pigmentation.

[0065] The present invention also provides a cosmetic composition comprising an effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt or derivatives thereof.

[0066] According to an embodiment of the present invention, the cosmetic composition further comprises one or more adjuvants and / or additives, including thickeners, fillers, fragrances, colorants, emulsifiers, additional active ingredients such as vitamins or proteins, sunscreens, stabilizers, insect repellents, alcohol, water, salts, antibacterial agents, proteolytic or keratin-decomposing effective substances, etc.

[0067] The present invention also provides a non-therapeutic cosmetic method, which comprises administering to a mammal in need thereof an effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt, or derivative thereof, for improving / assisting in the treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening.

[0068] The present invention also provides a non-therapeutic cosmetic method, which comprises administering an effective amount of the cosmetic composition to a mammal in need thereof, for improving / assisting in the treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening.

[0069] The tyrosinase-mediated skin pigmentation symptoms are selected from chloasma, stretch marks, solar lentigo, café au lait spots, and freckles.

[0070] The tyrosinase-mediated skin pigmentation includes post-inflammatory pigmentation, wherein the inflammation is selected from acne, eczema, dermatitis, drug eruption, infection, sunburn, and trauma. Beneficial effects

[0071] The present invention obtains a class of novel structural compounds through structural optimization, which not only have excellent tyrosinase inhibitory activity, but also have good physical and chemical properties. They can be used by the required population at extremely low concentrations and have no toxicity to melanocytes or skin.

[0072] Definitions and Explanations of Terms

[0073] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0074] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to reciting each integer value in the numerical range "1-14", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0075] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0076] "More" means three or more.

[0077] The term "carbocycle" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, a monocyclic ring such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as a bicyclo[1.1.1]pentane ring, a bicyclo[2.2.1]heptane ring, a bicyclo[3.2.1]octane ring or a bicyclo[5.2.0]nonane ring, a decalin ring, etc.), which may be optionally substituted with one or more (such as one, two or three) suitable substituents. The term "3-6 membered carbocycle" refers to a carbocycle containing 3, 4, 5 or 6 ring-forming carbon atoms.

[0078] The term "C 1-12"Alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0079] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0080] The term "C 3-12 "Cycloalkenyl" is understood to mean a monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic olefin containing a carbon-carbon double bond, which has 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkenyl", more preferably "C 3-8 "cycloalkenyl", which may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12The cycloalkenyl group may be a monocyclic hydrocarbon group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, or a bicyclic hydrocarbon group such as spiro[2.5]oct-5-enyl, spiro[3.5]non-6-enyl, spiro[4.5]dec-7-enyl.

[0081] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or polyaromatic rings fused together, preferably "C 6-10 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0082] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzofused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4- 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6- , 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3

[0015] In some embodiments, the present invention further comprises carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5- to 14-membered heteroaryl group is linked to other groups to form a compound of the present invention, the carbon atoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups, or heteroatoms on the 5- to 14-membered heteroaryl ring may be linked to the other groups. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on a heteroaryl ring may be substituted, or a hydrogen atom connected to a heteroatom on a heteroaryl ring may be substituted.

[0083] The term "5-6 membered heteroaromatic ring" is understood to include monovalent monocyclic rings having 5 or 6 ring atoms and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S. Examples include, for example, pyrazole, thiophene, furan, imidazole, thiazole, oxazole, isoxazole, isoxazolone (e.g., isoxazol-3(2H)-one) rings. ) pyrimidine ring, pyridine ring, pyridone ring (such as ), pyrazine ring, pyridazine ring, etc. When the 5-6 membered heteroaromatic ring is connected to other groups to form the compound of the present invention, the carbon atom on the 5-6 membered heteroaromatic ring can be connected to the other group, or the heteroatom on the 5-6 membered heteroaromatic ring can be connected to the other group. When the 5-6 membered heteroaromatic ring is substituted, it can be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, a hydrogen atom connected to a carbon atom on the heteroaromatic ring can be substituted, or a hydrogen atom connected to a heteroatom on the heteroaromatic ring can be substituted.

[0084] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetane; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-14-membered heterocyclic group or to a heterocyclic atom on the 3-14-membered heterocyclic group ring. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to the other group. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0085] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0086] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0087] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0088] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0089] "Halo" means substituted with one or more halogens.

[0090] In the present invention, the compounds referred to also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 Substitution with hydrogen (H or D) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the present invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. Furthermore, the absence of separate listing of the term deuterium or tritium for hydrogen present in a substituent does not exclude deuterium or tritium, but rather may also include deuterium or tritium.

[0091] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0092] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0093] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures thereof, racemates, in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0094] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0095] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0096] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0097] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0098] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0099] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, and tetramethylsilane (TMS) as the internal standard.

[0100] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Ansett 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0101] Chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0102] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0103] Example 1

[0104] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide Cpd-01

[0105] The first step is the preparation of 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethane-1-one

[0106] 4-Fluorobenzene-1,3-diol Cpd-01a (500 mg, 3.90 mmol), bromoacetonitrile (515 mg, 4.29 mmol), and zinc chloride (266 mg, 1.95 mmol) were dissolved in hydrochloric acid / dioxane (4 M, 10 mL) and stirred at 45°C for 16 h. Water (10 mL) was then added, and the temperature was raised to 70°C and stirring continued for 3 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethane-1-one Cpd-01b (400 mg, light yellow solid) in a 45% yield.

[0107] MS m / z (ESI): 205.1 (M+1)

[0108] Step 2 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide

[0109] Dissolve 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one Cpd-01b (400 mg, 1.95 mmol) and 2-isopropylcarbonylthiourea (286 mg, 1.95 mmol) in ethanol (5 mL). Stir the reaction mixture at 85°C for 3 h. After completion of the reaction, concentrate the reaction mixture to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 18 min gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30 mL / min) and lyophilized to obtain the product N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide Cpd-01 (32 mg) in a yield of 5.5%.

[0110] MS m / z (ESI): 297.1 (M+1)

[0111] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),10.66(s,1H),9.96(s,1H),7.63(d,J=12.8Hz ,1H),7.52(s,1H),6.51(d,J=8.0Hz,1H),2.79-2.71(m,1H),1.13(d,J=6.9Hz,6H).

[0112] Example 2

[0113] Preparation of N-(4-(3-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide Cpd-02

[0114] The first step is the preparation of 2-chloro-1-(3-fluoro-2,4-dihydroxyphenyl)ethane-1-one

[0115] 2-Fluorobenzene-1,3-diol Cpd-02a (500 mg, 3.90 mmol), bromoacetonitrile (515 mg, 4.29 mmol), and zinc chloride (266 mg, 1.95 mmol) were dissolved in hydrochloric acid / dioxane (4 M, 10 mL) and stirred at 45°C for 16 h. Water (10 mL) was then added, and the temperature was raised to 70°C and stirring continued for 3 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude 2-chloro-1-(3-fluoro-2,4-dihydroxyphenyl)ethane-1-one Cpd-02b (500 mg, light yellow solid), which was used directly in the next step.

[0116] Step 2 Preparation of N-(4-(3-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide

[0117] Dissolve crude 2-chloro-1-(3-fluoro-2,4-dihydroxyphenyl)ethan-1-one Cpd-02b (500 mg) and 2-isopropylcarbonylthiourea (300 mg, 2.05 mmol) in ethanol (5 mL). Stir the reaction mixture at 85°C for 3 h. After completion of the reaction, concentrate the reaction mixture to obtain the crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 18 min gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30 mL / min) and lyophilized to obtain the product N-(4-(3-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)isobutyramide Cpd-02 (34 mg), with a two-step yield of 2.9%.

[0118] MS m / z (ESI): 297.1 (M+1)

[0119] 1H NMR (400MHz, CDCl3) δ9.56 (s, 1H), 7.27 (d, J = 2.0Hz, 0.5H), 7.25 (d, J = 2.0Hz, 0.5 H),7.06(s,1H),6.57(t,J=4.0Hz,1H),2.79-2.72(m,1H),1.34(d,J=6.9Hz,6H).

[0120] Example 3

[0121] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)pivalamide Cpd-03

[0122] Step 1 Preparation of 4-(2-aminothiazol-4-yl)-6-fluorobenzene-1,3-diol Cpd-01c

[0123] Cpd-01b (35 g crude product) and thiourea (6.6 g, 0.087 mol) were dissolved in a dioxane solution (100 mL). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filter cake was dissolved in a large amount of sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried, and concentrated to yield Cpd-01c (6.2 g, white solid).

[0124] MS m / z (ESI): 227.1 (M+1)

[0125] 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),9.88(s,1H),7.52–7.37(m,3H),7.40(s,1H),6.90(s,1H).

[0126] Step 2 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)pivalamide Cpd-03

[0127] Cpd-01c (60 mg, 0.26 mmol), pivalic acid (162.5 mg, 1.59 mmol), Carter's condensation agent (703.8 mg, 1.59 mmol), and N,N-diisopropylethylamine (274.2 mg, 2.1216 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 16 hours. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (8 mol / L, 1 mL) was added to the reaction solution. The reaction solution was stirred at 45°C for another 5 hours. After the reaction, dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by HPLC to obtain Cpd-03 (32.93 mg) in a yield of 40.01%.

[0128] MS m / z (ESI): 311.0 (M+1)

[0129] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),10.79(s,1H),9.95(s,1H),7.66(d,J=12.8Hz,1H),7.51(s,1H),6.49(d,J=7.9Hz,1H),1.26(s,9H).

[0130] Example 4

[0131] Preparation of (S)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-2-methylbutanamide Cpd-04A

[0132] Cpd-01c (60 mg, 0.26 mmol), (S)-2-methylbutyric acid (162.5 mg, 1.59 mmol), Carter condensation agent (703.8 mg, 1.59 mmol), and N,N-diisopropylethylamine (274.2 mg, 2.1216 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 16 hours. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (8 mol / L, 1 mL) was added to the reaction solution. The reaction solution was stirred at 45°C for another 5 hours. After the reaction, dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by HPLC to obtain Cpd-04A (35.47 mg) in a yield of 43.10%.

[0133] MS m / z (ESI): 311.1 (M+1)

[0134] 1H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.65(s,1H),9.96(s,1H),7.63(d,J=12.8Hz,1H),7.52(s,1H),6.51(d,J=7.9Hz,1H) ,2.58(dd,J=14.1,6.6Hz,1H),1.71–1.57(m,1H),1.46(dd,J=14.1,6.8Hz,1H),1.12(d,J=6.8Hz,3H),0.85(t,J=7.4Hz,3H).

[0135] Example 5

[0136] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)cyclopropanecarboxamide Cpd-09

[0137] Cpd-01c (100 mg, 0.44 mmol), cyclopropanecarboxylic acid (227 mg, 2.64 mmol), Carter condensation agent (1168 mg, 2.64 mmol), and N,N-diisopropylethylamine (1135 mg, 8.80 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 6 h. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (6 mol / L, 5 mL) was added to the reaction solution. The solution was stirred at 45°C for another 5 h. After the reaction, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPLC to obtain Cpd-09 (20 mg) in a 16% yield.

[0138] MS m / z (ESI): 295.1 (M+1)

[0139] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),10.63(s,1H),9.96(s,1H),7.63(d,J=12.4 Hz,1H),7.50(s,1H),6.51(d,J=8.0Hz,1H),1.99-1.91(m,1H),0.95-0.85(m,4H).

[0140] Example 6

[0141] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutanecarboxamide Cpd-11

[0142] Cpd-01c (100 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cyclobutanecarboxylic acid (265 mg, 2.65 mmol), Carter's condensation agent (1171 mg, 2.65 mmol), and N,N-diisopropylethylamine (568 mg, 4.4 mmol) were added. The reaction mixture was stirred at 55°C for 16 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated to dryness to obtain a crude brown oil. The crude product was dissolved in methanolic ammonia solution, and the reaction mixture was stirred at 25°C for 1 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) using a Waters MS-triggered Prep-LC with a QDA detector (WELCH Xtimate C18 21.2 x 250 mm 10 μm column; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 18-minute gradient (5% to 100% acetonitrile), flow rate: 30 mL / min) and lyophilized to afford Cpd-11 (54 mg) in a 40% yield.

[0143] MS m / z (ESI): 309.0 (M+1)

[0144] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),10.67(s,1H),9.95(s,1H),7.62(d,J=12.8Hz,1H),7 .52(s,1H),6.50(d,J=7.9Hz,1H),3.42–3.34(m,1H),2.33–2.10(m,4H),2.04–1.76(m,2H).

[0145] Example 7

[0146] Preparation of 2-cyclopropyl-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)propionamide Cpd-13

[0147] Cpd-01c (60 mg, 0.26 mmol), 2-cyclopropylpropionic acid (181.62 mg, 1.59 mmol), Carter condensation agent (703.8 mg, 1.59 mmol), and N,N-diisopropylethylamine (274.2 mg, 2.1216 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 16 hours. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (8 mol / L, 1 mL) was added to the reaction solution. The reaction solution was stirred at 45°C for another 5 hours. After the reaction, dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by HPLC to obtain Cpd-13 (29.15 mg, white solid) in a yield of 34.09%.

[0148] MS m / z (ESI): 323.1 (M+1)

[0149] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),10.62(s,1H),9.95(s,1H),7.63(d,J=12.8Hz,1H),7.53(s,1H),6.51(d,J=7.9Hz,1H),1 .92(dt,J=13.9,6.9Hz,1H),1.20(d,J=6.9Hz,3H),0.99–0.90(m,1H),0.55–0.47(m,1H),0.44–0.36(m,2H),0.19–0.11(m,1H).

[0150] Example 8

[0151] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-2-hydroxy-2-methylpropionamide Cpd-16

[0152] Cpd-01c (80 mg, 0.35 mmol), 2-hydroxy-2-methylpropionic acid (220.9 mg, 2.12 mmol), Carter condensation agent (938.3 mg, 2.12 mmol), and N,N-diisopropylethylamine (137.1 mg, 1.06 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 16 hours. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (6 mol / L, 5 mL) was added to the reaction solution. The reaction solution was stirred at 45°C for another 5 hours. After the reaction, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPLC to obtain Cpd-16 (20 mg) in an 18% yield.

[0153] MS m / z (ESI): 313.1 (M+1)

[0154] 1 H NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.90(s,1H),9.95(s,1H),7.62(d,J =12.6Hz,1H),7.53(s,1H),6.47(d,J=8.0Hz,1H),5.81(s,1H),1.39(s,6H).

[0155] Example 9

[0156] N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide Cpd-17

[0157] (1s,3s)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide

[0158] (1r,3r)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide

[0159] Step 1 Preparation of 3-(benzyloxy)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutane-1-carboxamide Cpd-17b

[0160] 4-(2-Aminothiazol-4-yl)-6-fluorobenzene-1,3-diol Cpd-01c (130 mg, 0.575 mmol) was dissolved in N,N-dimethylformamide (7 mL). 3-(Benzyloxy)cyclobutane-1-carboxylic acid Cpd-17a (711.03 mg, 3.45 mmol), Carter condensation agent (1.27 g, 2.87 mmol), and N,N-diisopropylethylamine (371 mg, 2.87 mmol) were added to the mixture. The mixture was heated to 55°C and stirred for 11 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Ammonia methanol solution (4 mol / L, 5 mL) was added to the crude product, heated to 50°C, and stirred for 1 hour. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:55) to give 3-(benzyloxy)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutane-1-carboxamide Cpd-17b (215 mg) in a 90% yield.

[0161] MS m / z (ESI): 415.1 (M+1)

[0162] Step 2 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide

[0163] 3-(Benzyloxy)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutane-1-carboxamide Cpd-17b (180 mg, 0.434 mmol) was dissolved in dichloromethane (8 mL). Boron tribromide (326 mg, 1.30 mmol) was added to the system under an ice bath. The ice bath was removed, the temperature was raised to 25°C, and the mixture was stirred for 1 hour. After completion of the reaction, methanol was added to quench the reaction and the crude product was obtained after concentration. The crude product was purified by HPLC and lyophilized to obtain the racemic N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide Cpd-17 (50 mg) in a 35% yield.

[0164] MS m / z (ESI): 325.0 (M+1)

[0165] Step 3

[0166] Preparation of (1s,3s)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide and (1r,3r)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide

[0167] N-(4-(5-Fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide Cpd-17 (50 mg) was purified by chiral separation (SFC 150, column: Daicel CHIRALCEL OZ, 250 mm × 30 mm ID, 10 μm; mobile phase 1: CO2; mobile phase 2: MeOH [0.2% NH3 (7 M solution in MeOH)]; gradient: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 75 / 35, flow rate: 120 g / min) and lyophilized to afford Cpd-17A (30.07 mg, yield: 21%) and Cpd-17B (3.58 mg, yield: 2%).

[0168] Cpd-17A:

[0169] MS m / z (ESI): 325.0 (M+1)

[0170] 1H NMR (400MHz, DMSO-d6) δ12.12(s,1H),10.71(s,1H),10.00(s,1H),7.61(d,J=12.7Hz,1H),7.50(s,1H),6.50(d,J=7.9Hz ,1H),5.21(s,1H),4.07–3.96(m,1H),2.75(p,J=9.8Hz,1H),2.41(dd,J=13.0,4.9Hz,2H),2.03(dd,J=14.7,6.2Hz,2H).

[0171] Cpd-17B:

[0172] MS m / z (ESI): 325.0 (M+1)

[0173] 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.71(s,1H),9.97(s,1H),7.61(d,J=12.8Hz,1H),7.50(s,1H),6.49(d,J=7.9Hz ,1H),5.16(d,J=6.0Hz,1H),4.30(dd,J=13.1,6.7Hz,1H),3.19(t,J=9.8Hz,1H),2.44–2.39(m,2H),2.15–2.07(m,2H).

[0174] Example 10

[0175] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)oxetane-3-carboxamide Cpd-18

[0176] Cpd-01c (100 mg, 0.44 mmol), oxetane-3-carboxylic acid (270 mg, 2.64 mmol), carter condensation agent (1168 mg, 2.64 mmol), and N,N-diisopropylethylamine (1135 mg, 8.80 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 55°C for 6 h. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (6 mol / L, 5 mL) was added to the reaction solution. The reaction solution was stirred at 45°C for another 5 h. After the reaction, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPLC to obtain Cpd-18 (21 mg) in a 15% yield.

[0177] MS m / z (ESI): 311.0 (M+1)

[0178] 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),10.56(s,1H),9.93(s,1H),7.62(d,J=12 .8Hz,1H),7.56(s,1H),6.51(d,J=7.6Hz,1H),4.77–4.66(m,4H),4.09(s,1H).

[0179] Example 11

[0180] Preparation of cis-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-methoxycyclobutane-1-carboxamide Cpd-19A

[0181] Cpd-01c (50 mg, 0.22 mmol), cis-3-methoxycyclobutane-1-carboxylic acid (172 mg, 1.32 mmol), Carter's condensation agent (584 mg, 1.32 mmol), and N,N-diisopropylethylamine (568 mg, 4.40 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 55°C for 6 h. After the reaction, the temperature was lowered to 45°C, and aqueous sodium hydroxide (6 mol / L, 2.5 mL) was added to the reaction solution. The solution was stirred at 45°C for another 5 h. After the reaction, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by HPLC to obtain Cpd-19A (15 mg) in a 20% yield.

[0182] MS m / z (ESI): 339.0 (M+1)

[0183] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),10.62(s,1H),9.95(s,1H),7.62(d,J=12.8Hz,1H),7.53(s,1H),6.51 (d,J=8.0Hz,1H),3.87–3.78(m,1H),3.14(s,3H),2.93–2.84(m,1H),2.46–2.41(m,2H),2.11–2.02(m,2H).

[0184] Example 12

[0185] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)azetidine-3-carboxamide Cpd-22

[0186] Step 1 Preparation of tert-butyl 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate Cpd-22a

[0187] Cpd-01c (150 mg, 0.663 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (801 mg, 3.98 mmol) were dissolved in N,N-dimethylformamide (7 mL). N,N-diisopropylethylamine (429 mg, 3.32 mmol) and Carter condensation agent (880 mg, 1.99 mmol) were added to the mixture and stirred at 55°C for 11 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Ammonia methanol solution (4 mol / L, 5 mL) was added to the crude product, heated to 50°C, and stirred for 1 h. After completion of the reaction, the mixture was concentrated to obtain the crude product Cpd-22a (260 mg, yellow solid) in a yield of 76.6%.

[0188] MS m / z (ESI): 410.1 (M+1)

[0189] Step 2 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)azetidine-3-carboxamide Cpd-22

[0190] Cpd-22a (260 mg, 0.635 mmol) was dissolved in dichloromethane (7 mL). Hydrochloric acid / 1,4-dioxane (4 mmol / L, 6.35 mmol) was added to the reaction mixture under an ice bath. The reaction mixture was removed from the ice bath, warmed to 25°C, and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated to yield the crude product. The crude product was purified by preparative HPLC (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150*19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile 12% to 100%, flow rate: 20 mL / min) and lyophilized to yield Cpd-22 (11.9 mg) in a 6% yield.

[0191] MS m / z(ESI):310.0(M+1).

[0192] 1H NMR(400MHz,DMSO-d6)δ7.60(d,J=12.8Hz,1H),7.51(s,1H),6.51(d,J=8.0H z,1H),4.01-3.95(m,2H),3.89(t,J=8.9Hz,2H),3.79(dd,J=16.5,8.0Hz,1H)

[0193] Example 13

[0194] Preparation of (R)-N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)tetrahydrofuran-3-carboxamide Cpd-36A

[0195] Cpd-01c (60 mg, 0.26 mmol) and (R)-tetrahydrofuran-3-carboxylic acid (184.76 mg, 1.59 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (102.63 mg, 0.79 mmol) and Carter condensation agent (703.77 mg, 1.59 mmol) were added and stirred at 55°C for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Ammonia methanol solution (4 mol / L, 5 mL) was added to the crude product and stirred at 25°C for 1 h. After completion of the reaction, the methanol was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150*19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 42%-52%, flow rate: 20 mL / min) and lyophilized to obtain the product Cpd-36A (20.92 mg) in a 23% yield.

[0196] MS m / z(ESI):325.0(M+1).

[0197] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),10.61(s,1H),9.96(s,1H),7.63(d,J=12.8Hz,1H),7.54(s,1H), 6.51(d,J=7.9Hz,1H),3.93(t,J=8.3Hz,1H),3.83–3.68(m,3H),3.32–3.26(m,1H),2.19–2.05(m,2H).

[0198] Example 14

[0199] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)morpholine-4-carboxamide Cpd-44

[0200] Step 1 Preparation of tert-butyl (4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamate Cpd-01d

[0201] Cpd-01b (22 g crude product), N-Boc thiourea (7.5 g, 0.042 mol), and pyridine (5.5 g, 0.070 mol) were dissolved in a dioxane solution (100 mL). The reaction mixture was stirred at 90°C for 6 h. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with citric acid solution and saturated brine, dried, and concentrated to obtain the crude product. The crude product was slurried with dichloromethane and diethyl ether to afford Cpd-01d (3.2 g, white solid) in a 22.5% yield (based on thiourea).

[0202] MS m / z (ESI): 327.1 (M+1)

[0203] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.80(s,1H),9.94(s,1H),7.59(d,J=12.7Hz,1H),7.47(s,1H),6.46(d,J=7.9Hz,1H),1.50(s,9H).

[0204] Step 2 Preparation of 4-(2-((tert-butyloxycarbonyl)amino)thiazol-4-yl)-6-fluoro-1,3-phenylene diacetate Cpd-01e

[0205] Cpd-01d (3.2 g, 10 mmol) was dissolved in 30 mL of tetrahydrofuran, triethylamine (4.04 g, 40 mmol) was added, and the mixture was cooled to 0°C. Acetyl chloride (1.72 g, 22 mmol) was slowly added dropwise. The reaction was stirred at 0°C for 2 h. After completion of the reaction, the reaction mixture was separated into water and ethyl acetate. The organic phase was dried and concentrated to obtain crude Cpd-01e, which was used directly in the next reaction (4.10 g, 100% crude yield).

[0206] MS m / z (ESI): 205.1 (M+1)

[0207] Step 3 Preparation of 4-(2-aminothiazol-4-yl)-6-fluoro-1,3-phenylene diacetate Cpd-01f

[0208] Cpd-01e (4.10 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, dried, and concentrated to afford Cpd-01f (2.5 g) in an 80% yield.

[0209] MS m / z (ESI): 311.1 (M+1)

[0210] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=11.8Hz,1H),7.22(d,J=7.0Hz,1H),7.10(s,2H),6.97(s,1H),2.34(d,J=5.5Hz,6H).

[0211] Step 4 Preparation of 4-(2-(bis(phenoxycarbonyl)amino)thiazol-4-yl)-6-fluoro-1,3-phenyl diacetate Cpd-01g

[0212] Cpd-01f (150 mg, 0.48 mmol) and N,N-diisopropylethylamine (187 mg, 1.45 mmol) were dissolved in dichloromethane (5 mL), and phenyl chloroformate (150 mg, 0.96 mmol) was added and stirred at 25°C for 1 h. After the reaction was completed, the mixture was concentrated to give Cpd-01g (200 mg, brown solid).

[0213] MS m / z (ESI): 551.2 (M+1)

[0214] Step 5 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)morpholine-4-carboxamide Cpd-44

[0215] Crude Cpd-01g (200 mg) and morpholine (200 mg, 2.29 mmol) were dissolved in pyridine (5 mL). The reaction mixture was stirred at 90°C for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was dissolved in ammonia in methanol, and the reaction mixture was stirred at 25°C for 1 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10μm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile phase 5% to 100%, flow rate: 30 mL / min) and lyophilized to obtain the product Cpd-44 (50 mg) with a two-step yield of 31%.

[0216] MS m / z (ESI): 340.1 (M+1)

[0217] 1 H NMR (400MHz, DMSO-d6) δ10.99(d,2H),9.92(s,1H),7.60(d,J=12.7Hz,1H),7.39(s,1H),6.46(d,J=8.0Hz,1H),3.66–3.58(m,4H),3.55–3.47(m,4H).

[0218] Example 15

[0219] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carboxamide Cpd-45

[0220] Cpd-01c (80 mg, 0.3536 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (276.11 mg, 2.1216 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (136.84 mg, 1.0608 mmol) and Carter condensation agent (938.36 mg, 2.1216 mmol) were added and stirred at 55°C for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Ammonia methanol solution (4 mol / L, 5 mL) was added to the crude product and stirred at 25°C for 1 h. After completion of the reaction, the methanol was removed by rotary evaporation, and the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 150*19mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 42%-52%, flow rate: 20 mL / min) and lyophilized to obtain the product Cpd-45 (37.57 mg) in a 30% yield.

[0221] MS m / z(ESI):339.0(M+1).

[0222] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.67(s,1H),9.96(s,1H),7.63(d,J=12.8Hz,1H),7.53(s,1H),6.5 1(d,J=7.9Hz,1H),3.95–3.87(m,2H),3.35(td,J=11.5,2.1Hz,2H),2.82–2.71(m,1H),1.80–1.60(m,4H).

[0223] Example 16

[0224] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-8-azabicyclo[3.2.1]octane-3-carboxamide Cpd-46

[0225] Step 1 Preparation of 4-(2-(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxamido)thiazol-4-yl)-6-fluoro-1,3-phenylenebis(8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylate) Cpd-46a

[0226] Cpd-01c (100 mg, 0.44 mmol), N,N-diisopropylethylamine (285 mg, 2.21 mmol), 8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (277 mg, 2.65 mmol), and Carter condensation agent (977 mg, 2.21 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 16 h. After the reaction, water was added to quench the reaction. The reaction solution was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product Cpd-46a (500 mg, yellow oil) with a yield of 96.47%.

[0227] MS m / z (ESI): 938.3 (M+1)

[0228] Step 2 Preparation of tert-butyl 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)-8-azabicyclo[3.2.1]octane-8-carboxylate Cpd-46b

[0229] Cpd-46a (450 mg, 0.47 mmol) was dissolved in methanol (3 mL) and sodium hydroxide solution (12 M, 2 mL) was added and stirred at room temperature for 4 h. After the reaction, the solvent was concentrated and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product Cpd-46b (200 mg, yellow oil) with a yield of 80.95%.

[0230] MS m / z (ESI): 464.2 (M+1)

[0231] Step 3 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-8-azabicyclo[3.2.1]octane-3-carboxamide Cpd-46

[0232] Cpd-46b (200 mg, 0.43 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of trifluoroacetic acid (98 mg, 0.86 mmol). The reaction mixture was stirred at 20°C for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by HPLC (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10 μm; mobile phase 1: water (containing 0.1% 0.1FA); mobile phase 2: acetonitrile; 18-minute gradient, gradient ratio: acetonitrile 5% to 100%, flow rate: 30 mL / min) and lyophilized to obtain Cpd-46 (150 mg) in an 86.0% yield.

[0233] MS m / z (ESI): 364.1 (M+1)

[0234] 1 H NMR (400MHz, DMSO-d6) δ10.69 (s, 2H), 7.61 (d, J = 12.8Hz, 1H), 7.51 (s, 1H), 6.52 (d,J=8.0Hz,1H),3.85(s,2H),3.08–2.93(m,1H),1.88(dd,J=28.1,16.4Hz,8H).

[0235] Example 17

[0236] N-(4-(5-Fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[0237] Step 1 Preparation of 4-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-carboxamide)thiazol-4-yl)-6-fluoro-1,3-phenylenebis(tetrahydro-2H-thiopyran-4-carboxylate 1,1-dioxide) Cpd-47a

[0238] Cpd-01c (60 mg, 0.26 mmol) and tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (189 mg, 1.06 mmol) were dissolved in N,N-dimethylformamide (3 mL). Carter condensation agent (586 mg, 1.32 mmol) and N,N-diisopropylethylamine (342 mg, 2.65 mmol) were then added and stirred at room temperature for 16 h. After the reaction was completed, water was added to quench the reaction. The reaction solution was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford the crude product Cpd-47a (110 mg, black oil) in a yield of 46.95%.

[0239] MS m / z (ESI): 707.0 (M+1)

[0240] Step 2 Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide Cpd-47

[0241] Cpd-47a (120 mg, 0.16 mmol) was dissolved in a methanol / water solution (1 mL / 1 mL), followed by the addition of sodium hydroxide (13 mg, 0.33 mmol). The reaction mixture was stirred at 20°C for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) using a Waters MS-triggered Prep-LC with a QDA detector (WELCH Xtimate C18 21.2 x 250 mm 10 μm column; mobile phase 1: water (containing 0.1% 0.1% FA); mobile phase 2: acetonitrile; 18-minute gradient from 5% to 100% acetonitrile; flow rate: 30 mL / min) and lyophilized to obtain Cpd-47 (51.47 mg) in a yield of 78.15%.

[0242] MS m / z (ESI): 387.0 (M+1)

[0243] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),10.66(s,1H),9.96(s,1H),7.63(d,J=12.8Hz,1H),7.55(s,1H),6.51(d,J=8.0 Hz,1H),3.28–3.10(m,4H),2.86(ddd,J=10.8,7.6,3.5Hz,1H),2.25(d,J=11.2Hz,2H),2.11(dd,J=19.2,8.0Hz,2H).

[0244] Example 18

[0245] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide Cpd-54

[0246] 4-(2-Aminothiazol-4-yl)-6-fluorobenzene-1,3-diol Cpd-01c (1 g, 4.4 mmol), 4-methyltetrahydro-2H-pyran-4-carboxylic acid Cpd-54a (3.91 g, 26.4 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11.68 g, 26.4 mmol) and N,N-diisopropylethylamine (3.42 g, 26.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and stirred at 55 °C for 16 h. After the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude compound was added with ammonia-methanol solution (10 mL, 4 M), and the reaction solution was reacted at room temperature for 2 h. After the reaction, the reaction solution was spin-dried, added with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate / petroleum ether = 40%) to obtain the product N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide Cpd-54 (870 mg) in a yield of 56%.

[0247] MS m / z (ESI): 353.0 (M+1)

[0248] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.74(s,1H),9.95(s,1H),7.66(d,J=12.8Hz,1H),7.53(s,1H),6.50(d, J=7.9Hz,1H),3.74–3.64(m,2H),3.44(t,J=9.0Hz,2H),2.12(d,J=14.1Hz,2H),1.59–1.50(m,2H),1.30(s,3H).

[0249] Example 19

[0250] Preparation of N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-methoxyazetidine-1-carboxamide Cpd-107

[0251] Under nitrogen, pyridine (61 mg, 0.774 mmol) and phenyl chloroformate (61 mg, 0.387 mmol) were added to a solution of 4-(2-aminothiazol-4-yl)-6-fluoro-1,3-phenylene diacetate Cpd-01f (60 mg, 0.193 mmol) in dichloromethane (0.5 mL) and the reaction solution was stirred at room temperature for 1 hour. After the reaction, the reaction solution was dried and slurried twice with petroleum ether. The solid was collected and dried to give a crude product. The crude product was then dissolved in pyridine (0.5 mL), and 3-methoxyazetidine hydrochloride Cpd-107a (60 mg, 0.484 mmol) was added. The reaction solution was stirred at 90 °C for 1.5 hours. After the reaction, the reaction solution was dried to obtain a crude product, which was then dissolved in ammonia methanol solution (4 mol / L, 1 mL). The reaction solution was stirred at 50 °C for 1 hour and dried to obtain a crude product that was purified by HPLC to obtain N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-methoxyazetidine-1-carboxamide Cpd-107 (30.54 mg) in a yield of 46%.

[0252] MS m / z(ESI):340.1(M+1).

[0253] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.93(s,1H),9.91(s,1H),7.59(d,J=12.7Hz,1H ),7.38(s,1H),6.46(d,J=8.0Hz,1H),4.22(s,3H),3.83(d,J=6.4Hz,2H),3.22(s,3H).

[0254] Example 20

[0255] N-(4-(5-Fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-(2H-tetrazol-5-yl)azetidine-1-carboxamide

[0256] Cpd-01c (3 g, 13.26 mmol) was dissolved in dichloromethane (20 mL), pyridine (4.19 g, 53 mmol) was added, and phenyl chloroformate (10.38 g, 66.3 mmol) was slowly added dropwise. The mixture was stirred at 25°C for 1 hour. After the reaction, petroleum ether was added dropwise until no more precipitate formed. The residue was filtered to obtain a crude product (9 g). The crude product (4.2 g) was dissolved in pyridine (20 mL), and 5-(azetidin-3-yl)-2H-tetrazole hydrochloride Cpd-114a (2.14 g, 13.3 mmol) was added. The mixture was stirred at 90°C for 2 hours. After the reaction, the mixture was dried by evaporation. The crude product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10um; mobile phase 1: water (containing 0.1% NH4HCO3); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 10%-35%, flow rate: 15 mL / min) to obtain compound N-(4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)-3-(2H-tetrazol-5-yl)azetidine-1-carboxamide Cpd-114 (364.21 mg) in a yield of 15.6%.

[0257] MS m / z (ESI): 378.0 (M+1)

[0258] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.60(d,J=12.7Hz,1H),7.38(s,1H),6.46(d, J=7.9Hz,1H),4.39(t,J=7.8Hz,2H),4.22–4.09(m,2H),4.02(dt,J=8.8,7.5Hz,1H).

[0259] Example 21

[0260] 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid Cpd-117

[0261] (1R,3S)-3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid

[0262] (1S,3R)-3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid

[0263] (1S,3S)-3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid

[0264] (1R,3R)-3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid

[0265] Step 1 Preparation of 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid Cpd-117

[0266] Cpd-01c (1.50 g, 6.63 mmol) was dissolved in N,N-dimethylformamide (40 mL). 3-(Methoxycarbonyl)cyclopentane-1-carboxylic acid Cpd-117a (5.13 g, 29.84 mmol), Carter condensation agent (13.19 g, 29.84 mmol), and N,N-diisopropylethylamine (7.70 g, 59.67 mmol) were added. The reaction mixture was stirred at 55°C for 16 h. After completion of the reaction, the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated to dryness to obtain a crude brown oil. The crude product was dissolved in methanol (20 mL) and sodium hydroxide (4 M, 20 mL) was added. The reaction mixture was stirred at 25°C for 1 h. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid Cpd-117 (1.3 g, white solid) in a 54% yield.

[0267] MS m / z (ESI): 367.0 (M+1)

[0268] Step 2

[0269] Compound 3-((4-(5-fluoro-2,4-dihydroxyphenyl)thiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid (1.3 g, 3.55 mmol) was purified by SFC (Apparatus: SFC 150, Column: Daicel CHIRALCEL AD, 250 mm × 30 mm ID, 10 μm, Mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 65 / 35, Flow rate: 120 g / min, Wavelength: UV 214 nm, Temperature: 35°C) to obtain Cpd-117A, Cpd-117B, Cpd-117C and Cpd-117D, and their characterization information is as follows.

[0270] Cpd-117A (330 mg), yield: 25%

[0271] MS m / z (ESI): 367.0 (M+1)

[0272] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,2H),7.62(d,J=12.7Hz,1H),7.51(s,1H),6.50(d,J=8 .0Hz,1H),3.05–2.92(m,1H),2.82–2.69(m,1H),2.24–2.12(m,1H),2.04–1.76(m,5H).

[0273] Cpd-117B (310 mg), yield: 24%

[0274] MS m / z (ESI): 367.0 (M+1)

[0275] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,2H),7.62(d,J=12.7Hz,1H),7.51(s,1H),6.50(d,J=8 .0Hz,1H),3.04–2.93(m,1H),2.84–2.70(m,1H),2.23–2.11(m,1H),2.01–1.80(m,5H).

[0276] Cpd-117C (33 mg), yield: 2.5%

[0277] MS m / z (ESI): 367.0 (M+1)

[0278] 1H NMR (400MHz, DMSO-d6) δ12.24(s,1H),7.62(d,J=12.8Hz,1H),7.52(s,1H),6.50(d,J=7 .7Hz,1H),3.13–3.02(m,1H),2.91–2.82(m,1H),2.13–1.94(m,4H),1.83–1.71(m,2H).

[0279] Cpd-117D (31 mg), yield: 2.4%

[0280] MS m / z (ESI): 367.0 (M+1)

[0281] 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),12.13(s,1H),10.68(s,1H),9.95(s,1H),7.62(d,J=12.8Hz,1H),7.5 2(s,1H),6.50(d,J=8.0Hz,1H),3.15–3.00(m,1H),2.92–2.78(m,1H),2.16–1.93(m,4H),1.85–1.68(m,2H).

[0282] Example 22

[0283] Preparation of N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide Cpd-131

[0284] The first step is the preparation of 2-chloro-1-(2,4-dihydroxyphenyl)ethane-1-one

[0285] Resorcinol Cpd-131a (35 g, 0.31 mol) was dissolved in 300 ml of dioxane hydrochloride, followed by the addition of zinc chloride (21.7 g, 0.17 mol). Bromoacetonitrile (37.0 g, 0.35 mol) was then slowly added at 0°C. The reaction solution was stirred at 20°C for 16 h. The reaction was monitored for the disappearance of the starting material. 100 ml of water was then added to the reaction solution, and the temperature was raised to 80°C. Stirring was continued for 3 h. After the reaction was complete, the temperature was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed once with saturated sodium bicarbonate and twice with saturated brine. The organic phase was concentrated and purified by slurrying with ethyl acetate to obtain 2-chloro-1-(2,4-dihydroxyphenyl)ethane-1-one Cpd-131b (48 g) in an 83% yield.

[0286] MS m / z (ESI): 187.0 (M+1)

[0287] Step 2 Preparation of 4-(2-aminothiazol-4-yl)benzene-1,3-diol

[0288] 2-Chloro-1-(2,4-dihydroxyphenyl)ethane-1-one Cpd-131b (10 g, 0.053 mol) was dissolved in 100 mL of dioxane, followed by the addition of thiourea (4.13 g, 0.053 mmol) and stirring at 80°C for 3 h. After completion of the reaction, the mixture was filtered to obtain a filter cake, which was then washed with saturated sodium bicarbonate solution, filtered, and dried to afford 4-(2-aminothiazol-4-yl)benzene-1,3-diol Cpd-131c (9 g) in an 81% yield.

[0289] MS m / z (ESI): 209.0 (M+1)

[0290] Step 3 Preparation of 4-(2-(4-methyltetrahydro-2H-pyran-4-carboxamido)thiazol-4-yl)-1,3-phenylenebis(4-methyltetrahydro-2H-pyran-4-carboxylate)

[0291] 4-(2-Aminothiazol-4-yl)benzene-1,3-diol Cpd-131c (100 mg, 0.48 mmol), 4-methyltetrahydro-2H-pyran-4-carboxylic acid (346 mg, 2.4 mmol), Carter's condensation agent (1.06 g, 2.4 mmol), and N,N-diisopropylethylamine (619 mg, 4.8 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 55°C for 16 hours. After the reaction, the reaction solution was poured into water and extracted twice with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 4-(2-(4-methyltetrahydro-2H-pyran-4-carboxamido)thiazol-4-yl)-1,3-phenylenebis(4-methyltetrahydro-2H-pyran-4-carboxylate Cpd-131d (110 mg), which was used directly in the next step.

[0292] Step 4 Preparation of N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide Cpd-131

[0293] To a methanol solution of 4-(2-(4-methyltetrahydro-2H-pyran-4-carboxamido)thiazol-4-yl)-1,3-phenylenebis(4-methyltetrahydro-2H-pyran-4-carboxylate) Cpd-131d (110 mg crude product) was added aqueous sodium hydroxide (8 mol / L, 2 mL), and the reaction mixture was stirred at 50°C for 1 hour. After completion of the reaction, dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by HPLC to obtain N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-methyltetrahydro-2H-pyran-4-carboxamide Cpd-131 (43 mg) in a combined yield of 26% for the two steps.

[0294] MS m / z (ESI): 335.0 (M+1)

[0295] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),10.95(s,1H),9.47(s,1H),7.68(d,J=8.4Hz,1H),7.42(s,1H),6.3 1-6.28(m,2H),3.70-3.66(m,2H),3.46-3.41(m,2H),2.17-2.06(m,2H),1.55-1.51(m,2H),1.30(s,3H).

[0296] Example 23

[0297] Preparation of (1s,3s)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide Cpd-144A

[0298] Step 1 Preparation of (1s, 3s)-3-(benzyloxy)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutane-1-carboxamide Cpd-144b

[0299] 4-(2-Aminothiazol-4-yl)benzene-1,3-diol Cpd-131c (130 mg, 0.625 mmol) was dissolved in N,N-dimethylformamide (10 mL). (1s,3s)-3-(benzoyloxy)cyclobutane-1-carboxylic acid Cpd-144a (644.5 mg, 3.125 mmol), Carter condensation agent (1.10 g, 2.5 mmol), and N,N-diisopropylethylamine (323 mg, 2.5 mmol) were added to the mixture. The mixture was heated to 55°C and stirred overnight. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Ammonia methanol solution (4 mol / L, 5 mL) was added to the crude product, heated to 50°C, and stirred for 1 hour. After the reaction, the system was concentrated to obtain a crude product, which was purified by beating with ethyl acetate to obtain the product (1s, 3s)-3-(benzyloxy)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclobutane-1-carboxamide Cpd-144b (390 mg) in a yield of 86%.

[0300] MS m / z (ESI): 397.0 (M+1)

[0301] Step 2 Preparation of (1s,3s)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclobutane-1-carboxamide Cpd-144A

[0302] Cpd-144b (390 mg, 0.0984 mmol) was dissolved in 2 ml of dichloromethane, and then 1 ml of boron tribromide was added. The reaction solution was stirred at 20 degrees Celsius for 1 hour. After the reaction was completed, methanol was added dropwise to quench the reaction.

[0303] The reaction solution was concentrated and purified using a silica gel preparation plate (petroleum ether / ethyl acetate = 1 / 1) to obtain the product Cpd-144A (250 mg) with a yield of 83.4%.

[0304] MS m / z (ESI): 307.0 (M+1)

[0305] 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.85(s,1H),9.48(s,1H),7.65(d,J=8.3Hz,1H),7.41(s,1H),6.30(dt,J=8.3,2.3Hz,2H),5. 21(d,J=7.0Hz,1H),4.02(dd,J=15.1,8.1Hz,1H),2.75(td,J=9.7,4.9Hz,1H),2.40(ddd,J=15.2,7.4,2.8Hz,2H),2.11–2.00(m,2H)

[0306] Example 24

[0307] N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide Cpd-153

[0308] (1R,3S)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide

[0309] (1S,3R)-N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide

[0310] (1R,3R)-N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide

[0311] (1S,3S)-N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide

[0312] Step 1 Preparation of 3-(benzyloxy)cyclopentane-1-carboxylic acid Cpd-153b

[0313] Methyl 3-hydroxycyclopentane-1-carboxylate Cpd-153a (1 g, 6.9 mmol) and benzyl bromide (1.54 g, 8.97 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). Sodium hydride (330 mg, 13.8 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, aqueous solution was added to quench the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude compound was dissolved in methanol (5 mL), and sodium hydroxide (276 mg, 6.9 mmol) was added. The reaction mixture was reacted at 55°C for 1 hour. After completion of the reaction, the reaction mixture was spin-dried, the pH was adjusted to 2-3 with concentrated hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford the crude product, 3-(benzyloxy)cyclopentane-1-carboxylic acid Cpd-153b (1.45 g), in a yield of 95%.

[0314] MS m / z (ESI): 221.2 (M+1)

[0315] Step 2 Preparation of 3-(benzyloxy)cyclopentane-1-carbonyl chloride Cpd-153c

[0316] 3-(Benzyloxy)cyclopentane-1-carboxylic acid Cpd-153b (1.45 g, 6.9 mmol) was dissolved in anhydrous dichloromethane (20 mL). N,N-dimethylformamide (96 mg, 1.38 mmol) was added, and oxalyl chloride (1.25 g, 9.88 mmol) was slowly added dropwise at 0°C. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to afford the crude product, 3-(benzyloxy)cyclopentane-1-carbonyl chloride Cpd-153c (1.32 g), in an 84% yield.

[0317] Step 3 Preparation of 3-(benzyloxy)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclopentane-1-carboxamide Cpd-153d

[0318] Dissolve 4-(2-aminothiazol-4-yl)benzene-1,3-diol (Cpd-131c) (191 mg, 0.92 mmol) in dichloromethane (20 mL). Slowly add triethylamine (750 mg, 7.36 mmol) and 3-(benzyloxy)cyclopentane-1-carbonyl chloride (Cpd-153c) (1.64 g, 5.5 mmol) dissolved in anhydrous dichloromethane (2 mL). After stirring the reaction mixture at room temperature for 1 hour, sodium hydroxide (110 mg, 2.76 mmol) was added. The reaction mixture was stirred at 55°C for 1 hour. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 3-(benzyloxy)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclopentane-1-carboxamide Cpd-153d (80 mg) in a yield of 21%.

[0319] MS m / z(ESI):411.1(M+1)

[0320] Step 4 Preparation of N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide Cpd-153

[0321] 3-(Benzyloxy)-N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclopentane-1-carboxamide Cpd-153d (80 mg, 0.19 mmol) was dissolved in dichloromethane, and boron tribromide (3 drops) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 1 hour. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) afforded crude N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-3-hydroxycyclopentane-1-carboxamide Cpd-153 (30 mg, 0.09 mmol).

[0322] Step 5: SFC chiral separation

[0323] Cpd-153A (1.02 mg, t R =1.943 min, yield: 1.6%)

[0324] MS m / z (ESI): 321.1 (M+1)

[0325] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),10.90(s,1H),9.48(s,1H),7.65(d,J=8.4Hz,1H),7.40(s,1H),6.31(s,2H),4.57(d,J=4.0Hz,1H), 4.24(d,J=4.0Hz,1H),3.17(dt,J=16.6,8.4Hz,2H),1.84(m,2H),1.81(d,J=4.0Hz,1H),1.72(ddd,J=16.0,8.0,4.0Hz,2H),1.51(m,2H).

[0326] Using conditions similar to those in the above examples, the compounds listed in Table 1 were prepared. The structural characterization data of these compounds are listed in Table 1.

[0327] Table 1

[0328] Biological evaluation

[0329] Test Example 1 Inhibitory activity of the compounds of the present invention on human tyrosinase

[0330] 1.1 Experimental Materials

[0331] 1.2 Experimental setup and instruments

[0332] 1.3 Experimental steps

[0333] In the first step, DMSO stock solutions of the compounds were prepared. All compounds were reconstituted with DMSO to 60 mM stock solutions, stored in a desiccator until use, and stored at room temperature for a short period of time (up to 3 months).

[0334] Step 2: Compound Screening Process

[0335] 1) Thiamidol was serially diluted 3-fold from 20 mM to prepare 10 concentrations (6.667 mM, 2.222 mM, 0.741 mM, 0.247 mM, 0.082 mM, 0.027 mM, 0.009 mM, 0.003 mM, 0.001 mM, and 0.3 μM) of DMSO solution of Yangshen and a DMSO blank solution;

[0336] 2) Using Echo 665.3, transfer 100 nl of compound dilution to each well of the assay plate and centrifuge the compound plate at 1000 rpm for 1 min.

[0337] 3) Add 10 μL of 2X tyrosinase (TYR) working solution to the assay plate and incubate at room temperature for 30 minutes. Add 10 μL of 2X L-DOPA working solution to the assay plate and incubate at 37°C for 2 hours.

[0338] 4) Read the absorbance signal at 475 nm on a BMG plate reader.

[0339] Step 3: Data processing

[0340] The percentage inhibition rate was calculated as follows:

[0341] %inhibition=100-(Signal cmpd -Signal Ave_PC ) / (Signal Ave-VC -Signal Ave_PC )×100

[0342] Signal cmpd : The average absorbance value of the test compound on the reaction plate.

[0343] Signal ave_pc : Average absorbance of the positive control on the reaction plate.

[0344] Signal ave_vc : Average absorbance of negative control on the reaction plate.

[0345] Fitting calculation of IC50:

[0346] The IC was calculated by fitting the inhibition percentage values ​​and the logarithm of compound concentration to a nonlinear regression using Graphpad 8.0. 50 .

[0347] 1.4 Experimental Results

[0348] The specific experimental results are shown in Table 2.

[0349] Table 2 Inhibitory activity of the compounds of the present invention on human tyrosinase

[0350] The results show that the compounds disclosed in the present invention have good inhibitory activity on human tyrosinase.

[0351] Test Example 2: Detecting the ability of compounds to inhibit B16F10A spontaneous and α-MSH-stimulated melanin production

[0352] 2.1 Cell lines

[0353] B16F10A (mouse melanoma cell line), culture medium: RPMI1640 + 10% fetal bovine serum + 1% penicillin-streptomycin

[0354] 2.2 Main reagents and consumables:

[0355] 2.3 Main instruments:

[0356] 2.4 Experimental methods:

[0357] 1) Rinse the cells once with DPBS and then digest them with 0.25% trypsin solution and centrifuge at 300g for 4 minutes.

[0358] 2) Wash the cells once with phenol red-free culture medium (phenol red-free DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin)

[0359] 3) Resuspend the cells in phenol red-free culture medium and inoculate 10,000 cells / 200 μl / well into a 96-well flat-bottom plate. Incubate at 37°C with 5% CO2 for 24 hours.

[0360] 4) Add 2 μl of each test compound to the cells and incubate at 37°C 5% CO2 for 30 minutes

[0361] 5) Add 1 μl α-MSH (final concentration 200 μm) to the cells and stimulate for 96 hours

[0362] 6) Observe the color change of the culture medium and take photos

[0363] 7) Transfer the cell supernatant to a new 96-well flat-bottom plate and read the absorbance at 470 nm on a microplate reader.

[0364] 1) The positive control group was DMSO, and the negative control group was cell-free (pure culture medium);

[0365] 2) The formula for calculating the % inhibition rate is as follows:

[0366] Inhibition rate (%inhibition) = 100 - (absorbance value of compound - average absorbance value of negative control) / (average absorbance value of positive control - average absorbance value of negative control) × 100;

[0367] 3) Effect-dose curve of the compound: Graphpad 10.0 was used to fit the inhibition percentage values ​​and the logarithm of the compound concentration to a nonlinear regression (dose response-variable slope) to calculate the IC50.

[0368] 2.6 Experimental Results

[0369] The results of the inhibition of melanin synthesis in B16F10 cells by the compounds disclosed in the present invention are shown in Table 3.

[0370] Table 3 Inhibitory activity of the compounds of the present invention on melanin synthesis in B16F10 cells

[0371] The results show that the compounds disclosed in the present invention have good inhibitory activity on melanin synthesis in B16F10 cells.

[0372] Test Example 3 In vitro skin penetration behavior

[0373] 3.1 Formula ratio

[0374] Table 4 Recipe

[0375] 3.2 Transdermal experimental conditions

[0376] Skin: Miniature pig back skin

[0377] Temperature: 32±0.5℃

[0378] Receiving solution: 20% ethanol-normal saline

[0379] Receiving liquid volume: 12ml

[0380] Sampling volume: 1ml

[0381] Effective area: 1.76cm 2

[0382] Sample volume: Quantitative loop, unlimited sample loading, about 400 mg

[0383] Speed: 600rpm

[0384] Sampling points: 0.5, 4, 8, 12, 16, 20, 24h

[0385] 3.3 Experimental procedures

[0386] Before testing, thaw the pigskin, rinse with saline, and dry with filter paper. Secure the pigskin between the upper and lower chambers of a Franz diffusion cell, with the stratum corneum facing upward. Add the sample to the quantitative loop and secure the device. Fill the receiving chamber with a receiving medium maintained at a constant temperature of 32 ± 1°C. Place the diffusion cell in a constant-temperature water bath with electromagnetic stirring. Samples were taken at various sampling times, and the same volume of receiving medium was replenished simultaneously at the same temperature.

[0387] 3.4 Experimental Results

[0388] Table 5 Results of permeation at different times

[0389] The results show that the compounds disclosed in the present invention have good transdermal properties. For example, the transdermal properties of the compound Cpd-131 of the present invention are better than those of the compound Cpd-d3.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound: in, Each R a The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy; L is absent or selected from unsubstituted or optionally substituted with one, two or more L a Substituted C 1-3 Alkylene; each L a The same or different, independently selected from H or C 1-6 alkyl; R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -NR1R2 or -OR3; Wherein, R1, R2, and R3 are the same or different and are independently selected from H, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; Each R b The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, NH2, -S(=O)2C 1-6 Alkyl, 3-8 membered heterocyclic group, -C 1-6 Alkylene-OC 1-6 alkyl, -C(=O)-R5, -C(=O)OR6, -C(=O)NR7R8 or 5-14 membered heteroaryl; wherein R5, R6, R7, R8 are the same or different and are independently selected from H or C 1-6 alkyl; Alternatively, two R attached to different carbon atoms b The carbon atoms to which it is attached together form an unsubstituted or optionally substituted R b1 Substituted with the following groups: C 3-8 Carbocyclic or 3-8 membered heterocyclic ring; Alternatively, two R attached to the same carbon atom b The carbon atoms to which it is attached together form an unsubstituted or optionally substituted R b2 Substituted with the following groups: C 3-8 Carbocyclic or 3-8 membered heterocyclic ring; Each R b1 、R b2 The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkylene-OC 1-6 Alkyl or NH2; Each R bb The same or different, independently selected from H, OH, CN, halogen, oxo (=O), C 1- 6 alkyl, C 1-6 Alkoxy or NH2; R4 is selected from H; or, R4 is connected to the atoms on the R group to form a heterocyclic ring containing a lactam structure, wherein the heterocyclic ring is unsubstituted or optionally substituted by one, two or more R 4a substituted 5-8 membered heterocyclic ring; each R 4a the same or different, independently selected from OH, CN, halogen, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 alkoxy; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, characterized in that Each R a The same or different, independently selected from OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy, and n is selected from 1, 2 or 3; Or, each R a are the same or different and are independently selected from OH, CN, F, Cl, Br, methyl, trifluoromethyl or methoxy; Preferably, n is selected from 1; Preferably, L is absent or selected from -CH2-, -CH2CH2- or -CH(CH3)-.

3. The compound according to claim 1 or 2, characterized in that R4 is selected from H, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NR1R2 or -OR3; Preferably, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted from the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutan-2-yl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,4-dioxane, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-thiopyranyl, thiomorpholinyl, phenyl, pyridyl, pyrazolyl, isopropyloxy or Preferably, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: Preferably, R is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: Alternatively, R4 is connected to an atom on the R group to form 4. The compound according to any one of claims 1 to 3, wherein each R b The same or different, independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkoxy, NH2, -S(=O)2C 1-3 Alkyl, 3-8 membered heterocyclic group, -C 1-3 Alkylene-OC 1-3 Alkyl, -C(=O)-R5, -C(=O)OR6, -C(=O)NR7R8 or 5-6 membered heteroaryl; Preferably, R5, R6, R7, and R8 are the same or different and are independently selected from H or methyl; Preferably, each R b The same or different, independently selected from H, OH, CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy-C 1-6 Alkyl (HO-C 1-6 alkyl), -C(=O)-C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-OC 1-6 Alkyl, -C(=O)OH, -C(=O)OC 1-6 Alkyl, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2, -C 1-6 Alkylene-O-halogenated C 1-6 Alkyl, 5-6 membered heteroaryl; Preferably, each R b The same or different, independently selected from H, OH, CN, F, Cl, Br, methyl, ethyl, methoxy, hydroxymethyl, hydroxyethyl (e.g. 1-hydroxyethyl, 2-hydroxyethyl), oxo (=O), difluoromethyl, acetyl, methylsulfonyl, oxetanyl (e.g. ), methoxyethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, -C(=O)OH, -C(=O)OCH3, -C(=O)NH2, -C(=O)N(CH3)2, -CH2CH2OCH2CF3 or -CH2CH2OCH2CHF2, triazole (e.g. ), tetrazolyl or isoxazol-3(2H)-onyl; Alternatively, R attached to two adjacent carbon atoms b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b1 Substituted with the following groups: C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic ring; Alternatively, R attached to two non-adjacent carbon atoms b Connected to its end group, together forming C 1-3 Alkylene (e.g., -CH2-, -CH2CH2-); Alternatively, two R attached to the same carbon atom b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b2 Substituted with the following groups: C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl or 3-8 membered heterocyclic ring; Preferably, R connected to two adjacent carbon atoms b Together with the atoms to which they are attached, they form a cyclopropane ring; Preferably, two R b Together with the atoms to which they are attached, they form an unsubstituted or optionally substituted group consisting of one, two or more R b2 Substituted groups of the following: cyclopropane ring, cyclobutane ring, oxetane ring, azetidine ring or tetrahydro-2H-pyran ring; Preferably, two R b Together with the atoms to which they are connected, they form a cyclopropane ring, a cyclobutane ring, an oxetane ring (e.g. )、 Preferably, each R b1 、R b2 the same or different, independently selected from OH, CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R bb Substituted with the following groups: C 1-3 Alkyl, C 1- 3 alkoxy or NH2; Preferably, each R bb The same or different, independently selected from H, OH, CN, C 1-6 Alkoxy (e.g., methoxy) or halogen (e.g., F, Cl, Br); More preferably, each R b2 are the same or different and are independently selected from methyl, ethyl, hydroxyethyl (e.g. 1-hydroxyethyl, 2-hydroxyethyl) or methoxyethyl; Preferably, R is selected from the following groups: Preferably, -LR is selected from the following groups:

5. The compound according to any one of claims 1 to 4, characterized in that The compound represented by formula (I) is selected from the following structures: where R a , L, R, n have the definitions as described in any one of claims 1-4; Preferably, the compound represented by formula (I) is selected from the following structures: Among them, R a , L, R, n have the definitions as described in any one of claims 1-4; Preferably, the compound represented by formula (I) is selected from the following structures: Among them, R a , R has the definition as described in any one of claims 1-4; Preferably, the compound represented by formula (I) is selected from the following structures: wherein R has the definition as defined in any one of claims 1 to 4, provided that R cannot be the following groups: unsubstituted C 3-8 Cycloalkyl, 6. The compound according to any one of claims 1 to 5, characterized in that The compound has the following structure: Preferably, the compound represented by formula (I) is selected from the following structures:

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of any one of claims 1 to 6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof; Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

8. A method for treating a tyrosinase-mediated disease, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compound of any one of claims 1 to 6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, or the pharmaceutical composition of claim 7; Preferably, the tyrosinase-mediated disease is tyrosinase-mediated skin pigmentation; Preferably, the skin pigmentation symptoms are selected from chloasma, stretch marks, solar lentigo, café au lait spots, and freckles; Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory pigmentation, wherein The inflammation is selected from acne, eczema, dermatitis, drug rash, infection, sunburn, and trauma.

9. Use of the compound according to any one of claims 1 to 6, at least one of its racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament; Preferably, the tyrosinase-mediated disease is tyrosinase-mediated skin pigmentation; Preferably, the skin pigmentation symptoms are selected from chloasma, stretch marks, solar lentigo, café au lait spots, and freckles; Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory pigmentation, wherein The inflammation is selected from acne, eczema, dermatitis, drug rash, infection, sunburn, and trauma.

10. A cosmetic composition comprising an effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt or derivative thereof; Preferably, the cosmetic composition further comprises one or more auxiliary agents and / or additives, including thickeners, fillers, fragrances, colorants, emulsifiers, additional active ingredients such as vitamins or proteins, sunscreens, stabilizers, insect repellents, alcohol, water, salts, antibacterial agents, proteolytic or keratinogenic active substances, etc.

11. A non-therapeutic cosmetic method, comprising administering to a mammal in need thereof an effective amount of at least one of the compound of formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt, or derivative thereof, or the composition of claim 10 for improving / assistive treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening; Preferably, the method comprises administering an effective amount of the cosmetic composition to a mammal in need thereof, for improving / assisting in the treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening; Preferably, the tyrosinase-mediated skin pigmentation symptoms are selected from chloasma, stretch marks, solar lentigo, café au lait spots, and freckles; Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory pigmentation, wherein The inflammation is selected from acne, eczema, dermatitis, drug rash, infection, sunburn, and trauma.

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