Tyrosinase inhibitor and use thereof

Abstract

Provided are a tyrosinase inhibitor compound as shown in formula (I) or formula (II), a composition, a preparation method therefor, and a use thereof. The compound not only has excellent tyrosinase inhibition activity, but also has good physicochemical properties, can be used for a required population at very low concentrations, and has no melanocyte or skin toxicity.

Description

Tyrosinase inhibitors and uses thereof

[0001] This application claims priority to two applications filed with the China National Intellectual Property Office on August 14, 2024, Patent Application No. 202411131632.1, and September 13, 2024, Patent Application No. 202411287791.0, both entitled “Tyrosinase inhibitors and uses thereof”, the entire contents of the prior applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of compounds, and particularly relates to a tyrosinase inhibitor compound, a composition, and a preparation method and application thereof. BACKGROUND

[0003] The number of melanocytes in human skin is generally the same regardless of skin color. Skin color is mainly determined by the amount and type of melanin (black eumelanin or yellow to reddish-brown pheomelanin). Asians and light-skinned people have a relatively low level of eumelanin compared to dark-skinned people, and less protection against sunlight. The distribution of melanin in the skin is also different. In light-skinned people, a greater number of pigments are present in the basal layer, whereas in dark-skinned people, melanin is dispersed throughout the stratum corneum. There are many reasons for excessive pigmentation of the skin, such as ultraviolet radiation (e.g., sunburn, freckles), genetic predisposition, abnormal pigmentation of the skin when a wound heals or heals (post-inflammatory hyperpigmentation) or abnormal pigmentation of the skin when it ages (e.g., age spots). Among them, the problem of post-inflammatory hyperpigmentation often occurs in people of color. For example, the problem of pseudofolliculitis barbae in men of color is accompanied by abnormal pigmentation; the form of chloasma (especially on the face and chest and neck of Asian women).

[0004] Tyrosinase is a key enzyme for melanin production, which mainly catalyzes three reactions: 1) hydroxylation of tyrosine to produce 3,4-dihydroxyphenylalanine (DOPA); 2) oxidation of DOPA to DOPA quinone; 3) oxidation of DHI (5,6-dihydroxyindole) to indole quinone. Tyrosinase belongs to the copper protein family, and contains two copper ions in their active sites. The binuclear copper ion has three main redox forms: 1) Cu + -Cu + -reduced form; 2) Cu 2+ -O2-Cu 2+ form reversibly bound to O2as a peroxide; 3) Cu 2+ -O2-Cu 2+Oxidation-reduction state is the key to tyrosinase enzyme activity, and the reaction catalyzed by tyrosinase to introduce a second hydroxyl group into the ortho position of a monophenol (such as tyrosine) is the key to melanin biosynthesis. There are two methods to inhibit melanogenesis, such as directly acting on tyrosinase or indirectly inhibiting tyrosinase activity by complexing with the metal copper ion catalytic center.

[0005] Currently commonly used as skin whitening substances include hydroquinone, hexadecene-1, 16-dicarboxylic acid, kojic acid and its derivatives, arbutin, ascorbic acid and its derivatives, flavones, ellagic acid and its derivatives, condensate acid and different resorcinol derivatives, 4-n-butylresorcinol, 4-n-hexylresorcinol and 4-(1-phenylethyl)benzene-1, 3-diol. Among them, hydroquinone is one of the earliest skin bleaching agents, for example, Albert Kligman et al. developed the so-called "Triformula (three-in-one formula)", which is a combination of 0.1% tretinoin, 5.0% hydroquinone and 0.1% dexamethasone, but long-term use of hydroquinone can cause irreversible changes in the skin pigment system, has cytotoxicity to melanocytes, and has the risk of causing permanent depigmentation of the skin. China has restricted the addition of hydroquinone in skin care products, and it can only be obtained and used in the form of a prescription.

[0006] Bayer AG found that hydroquinone, arbutin, kojic acid, 4-n-butylresorcinol, 4-n-hexylresorcinol and 4-(1-phenylethyl)benzene-1, 3-diol have weak or even no inhibitory activity on human tyrosinase, and they reported a class of resorcinol thiazole compounds which have relatively good inhibition on human tyrosinase.

[0007] The resorcinol derivatives disclosed in the prior art have the problems of insufficient inhibition activity on human tyrosinase or unstable physical and chemical properties, and cannot meet the needs of patients with pigmentation. There is an urgent need to develop compounds with good reversible inhibition on human tyrosinase and good physical and chemical properties, so as to meet the needs of patients at very low concentrations, while having no toxicity to melanocytes or skin. SUMMARY

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

[0009] wherein each R a is the same or different, and is independently selected from H, OH, CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6alkoxy;

[0010] B is selected from an unsubstituted or optionally substituted 5-6 membered heteroaromatic ring with one, two or more R b substituted 5-6 membered heteroaromatic ring, and ring B is not an unsubstituted or substituted thiazole ring, pyrazole ring, triazole ring, isoxazole ring; each R b are the same or different, and are independently selected from H, OH, CN or halogen;

[0011] Y is selected from an unsubstituted or optionally substituted C y substituted C 1-12 alkyl, each R y are the same or different, and are independently selected from H, OH, CN, halogen, oxo (=0);

[0012] Alternatively, Y is selected from wherein ring D is selected from an unsubstituted or optionally substituted C d substituted C 3-14 cycloalkyl ring, 3-14 membered heterocyclic ring; ring E is selected from an unsubstituted or optionally substituted 5-12 membered heteroaromatic ring; e substituted 5-12 membered heteroaromatic ring;

[0013] each R d are the same or different, and are independently selected from H, OH, CN, halogen, oxo (=0), unsubstituted or optionally substituted C dd substituted C 1-6 alkyl, C 1-6 alkoxy, NH2, -C(=0)-R1, -C(=0)OR2, -C(=0)NR3R4; wherein R1, R2, R3, R4 are the same or different, and are independently selected from H or C 1-6 alkyl;

[0014] Alternatively, two R d form, together with the carbon atom to which they are attached, an unsubstituted or optionally substituted C dd substituted C 3-8 cycloalkyl ring, 3-8 membered heterocyclic ring;

[0015] each R dd are the same or different, and are independently selected from H, OH, CN, halogen, oxo (=0), C 1- 6alkyl, C 1-6 alkoxy or NH2;

[0016] each R e are the same or different, and are independently selected from H, OH, CN, halogen, C 1-6 alkyl, halogenated C 1-6alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;

[0017] n is selected from 0, 1, 2 or 3;

[0018] wherein ring F is selected from a 3-10 membered heterocyclyl ring;

[0019] each R f are the same or different, independently of each other, selected from halogen, CN, oxo (=0), NH2, OH, COOH, C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, hydroxy C 1-10 alkyl, COOC 1-10 alkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl;

[0020] ring G is selected from a 5-10 membered heteroaryl ring, unsubstituted or optionally substituted with one, two or more R g substituted; each R g are the same or different, independently of each other, selected from halogen, CN, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkoxy;

[0021] each R 11 are the same or different, independently of each other, selected from OH, CN, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 1-10 alkoxy or halogenated C 1-10 alkoxy;

[0022] p is selected from 0, 1, 2 or 3;

[0023] q is selected from 0, 1, 2 or 3.

[0024] According to some embodiments, each R a are the same or different, independently of each other, selected from H, OH, CN, F, Cl, Br, methyl, trifluoromethyl or methoxy.

[0025] According to some embodiments, n is selected from 0 or 1.

[0026] According to some embodiments, ring B is selected from a thiophene ring, a pyridine ring, a pyridinone, a ring pyrimidine ring, a pyrimidinone ring, a pyridazine ring or a pyridazinone ring, unsubstituted or optionally substituted with one, two or more R b substituted.

[0027] According to some embodiments, ring B is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R b substituted with one, two or more R wherein the 1 -position is attached to the left-hand phenyl ring and the 2-position is attached to the right-hand N atom.

[0028] According to some embodiments, each R b are the same or different and are each independently selected from OH, CN, F, CI or Br.

[0029] According to some embodiments, ring B is selected from wherein the 1 -position is attached to the left-hand phenyl ring and the 2-position is attached to the right-hand N atom.

[0030] According to some embodiments, Y is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R y substituted with one, two or more R 1-6 alkyl.

[0031] According to some embodiments, each R y are the same or different and are each independently selected from H, OH, CN or halogen.

[0032] According to some embodiments, Y is selected from isopropyl.

[0033] According to some embodiments, Y is selected from wherein ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted with one, two or more R 3-8 cycloalkyl ring, 3-8 membered heterocyclic ring.

[0034] According to some embodiments, ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted with one, two or more R cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, azetidine ring, pyrrolidine ring, piperidine ring, tetrahydrofuran ring, tetrahydro-2H-pyran ring, spiro[3.3]heptane ring (e.g. ), 2-oxa-6-aza-spiro[3,3]heptane ring (e.g. ), or 2-oxa-spiro[3,3]heptane ring (e.g.

[0035] According to some embodiments, ring D is selected from the following groups, which are unsubstituted or optionally substituted with one, two or more R d substituted with one, two or more R wherein the “*” side is attached to the carbonyl group of the left-hand amide.

[0036] According to some embodiments, each R dthe same or different, are independently of each other selected from H, OH, CN, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl(HO-C 1-6 alkyl) or -C(=O)OH, -C(=O)OC 1-6 alkyl.

[0037] According to some embodiments, each R d the same or different, are independently of each other selected from H, -C(=O)OH or hydroxymethyl.

[0038] According to some embodiments, two R d form together with the carbon atom to which they are attached a 3-6 membered saturated or partially saturated ring, which is unsubstituted or optionally substituted by one, two or more R dd substituted with one, two or more R 3-6 cycloalkyl ring, 3-6 membered heterocyclic ring.

[0039] According to some embodiments, two R d form together with the carbon atom to which they are attached a cyclobutane ring or oxetane ring (e.g. ).

[0040] According to some embodiments, Y is selected from ring D has the definition as described herein, ring E is selected from a 5-6 membered heteroaromatic ring, which is unsubstituted or optionally substituted by one, two or more R e substituted with one, two or more R

[0041] According to some embodiments, is selected from ring E has the definition as described herein.

[0042] According to some embodiments, each R e the same or different, are independently of each other selected from H, OH, CN or halogen.

[0043] According to some embodiments, ring E is selected from a tetrazole ring (e.g. ).

[0044] According to some embodiments, Y is selected from

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

[0046] wherein ring B, ring D, ring E, Ra R b Y, n have the definitions as described herein; m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1 or 2.

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

[0048] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0049] According to embodiments of the present application, ring F in the compound of formula (II) is selected from 4-9 membered nitrogen containing heterocyclyl.

[0050] According to embodiments of the present application, ring F is selected from azetidinyl, pyrrolidinyl, piperidinyl,

[0051] According to embodiments of the present application, ring F is selected from wherein denotes that ring F is covalently connected to ring G at the position indicated.

[0052] According to embodiments of the present application, each R f are the same or different, independently from each other, selected from OH, COOH, hydroxymethyl, COOCH3, 1-6 alkyl, COOC 1-6 alkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl.

[0053] According to embodiments of the present application, each R f are the same or different, independently from each other, selected from OH, COOH, hydroxymethyl, COOCH3, 1-6 alkyl, COOC 1-6 alkyl, triazolyl, tetrazolyl.

[0054] According to embodiments of the present application, each R f are the same or different, independently from each other, selected from OH, COOH, hydroxymethyl, COOCH3,

[0055] According to embodiments of the present application, ring G is selected from 5-6 membered heteroaryl.

[0056] According to embodiments of the present application, ring G is selected from thiazolyl, pyridinyl, thienyl.

[0057] According to embodiments of the present application, ring G is selected from

[0058] According to embodiments of the present application, ring G is selected from wherein 1 is attached to ring F and 2 is attached to the phenyl ring.

[0059] According to embodiments of the present application, R 11 is selected from halogen, preferably F.

[0060] According to embodiments of the present application, the compound of formula (II) is selected from the following structures:

[0061] wherein ring F, R 11 , R f , p and q independently of each other have the definitions as described above.

[0062] According to embodiments of the present application, the compound of formula (II) is selected from the following structures:

[0063] wherein ring F, R 11 , R f and q independently of each other have the definitions as described above.

[0064] According to some embodiments, the compound of formula (II) is selected from the following compounds:

[0065] The present application also provides a method for preparing the compound of formula (II), comprising the following steps: reacting compound a and compound b to obtain the compound of formula (II);

[0066] wherein ring F, R 11 , R f , p and q independently of each other have the definitions as described above; X is selected from halogen, such as Cl or Br; ring G is selected from

[0067] According to embodiments of the present application, the reaction can be carried out in the presence of a solvent such as an organic solvent or a mixed solvent of an organic solvent and water. For example, the organic solvent can be selected from at least one of alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenyl ethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl glycol dimethyl ether, diphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, and hydrocarbons that can be substituted with fluorine and / or chlorine atoms such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, or ethylene carbonate.

[0068] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds represented by Formula (I) or Formula (II), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

[0069] According to embodiments of the present application, the pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients.

[0070] According to embodiments of the present application, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0071] The present application also provides a method of treating tyrosinase-mediated skin pigmentation, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds represented by Formula (I) or Formula (II), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

[0072] The present application also provides a method of treating tyrosinase-mediated skin pigmentation, comprising administering to a patient a prophylactically or therapeutically effective amount of the above pharmaceutical composition.

[0073] The tyrosinase-mediated skin pigmentation symptoms are selected from melasma, stretch marks, solar lentigo, cafe-au-lait spots, freckles.

[0074] The tyrosinase-mediated skin pigmentation comprises post-inflammatory hyperpigmentation, wherein the inflammation is selected from acne, eczema, dermatitis, drug eruptions, infections, sunburn, trauma.

[0075] In some embodiments, the patient comprises a mammal, preferably a human.

[0076] The present application also provides at least one of the compound of Formula (I) or Formula (II), racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, for use in treating a tyrosinase-mediated disease.

[0077] The present application also provides use of at least one of the compound of Formula (I) or Formula (II), racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament.

[0078] According to an embodiment of the present application, the use can be use in the manufacture of a medicament for treating a tyrosinase-mediated skin pigmentation disorder and / or disease, such as use in the manufacture of a tyrosinase inhibitor medicament.

[0079] According to an embodiment of the present application, the skin pigmentation disorder is melasma, stretch marks, solar lentigo, cafe-au-lait spots, freckles, post-acne hyperpigmentation, post-eczema hyperpigmentation, post-dermatitis hyperpigmentation, post-drug eruption hyperpigmentation, post-infection hyperpigmentation, post-sunburn hyperpigmentation, post-trauma hyperpigmentation.

[0080] The present application also provides a cosmetic composition comprising an effective amount of at least one of the compound of Formula (I) or Formula (II), racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt or derivative thereof.

[0081] According to an embodiment of the present application, the cosmetic composition further comprises one or more auxiliary agents and / or additives, including thickening agents, fillers, fragrances, colorants, emulsifiers, additional active ingredients such as vitamins or proteins, photoprotective agents, stabilizers, insect repellents, alcohols, water, salts, antibacterial agents, protein- or keratin-decomposing active substances, etc.

[0082] The present application also provides a non-therapeutic cosmetic method, the method comprising administering to a mammal in need thereof an effective amount of at least one of the compound of Formula (I) or Formula (II), racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt or derivative thereof, for ameliorating / assisting in the treatment of a tyrosinase-mediated skin pigmentation symptom or for skin whitening.

[0083] The present application also provides a non-therapeutic cosmetic method, the method comprising administering to a mammal in need thereof an effective amount of a cosmetic composition, for ameliorating / assisting in the treatment of a tyrosinase-mediated skin pigmentation symptom or for skin whitening.

[0084] The tyrosinase-mediated skin pigmentation symptoms are selected from the group consisting of chloasma, stretch marks, solar lentigo, cafe-au-lait spots, freckles.

[0085] The tyrosinase-mediated skin pigmentation comprises post-inflammatory hyperpigmentation, wherein the inflammation is selected from the group consisting of acne, eczema, dermatitis, drug eruptions, infections, sunburn, trauma. Beneficial effects

[0086] The present application obtains a class of novel compounds with structural optimization, which not only has excellent tyrosinase inhibitory activity, but also has good physical and chemical properties, can meet the needs of the target population at very low concentration, and has no toxicity to melanocytes or skin.

[0087] Definitions and explanations of terms

[0088] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims of this application, including the definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other. Such groups and compound structures after combination should be understood as within the scope recited in the specification and / or claims.

[0089] Unless otherwise indicated, the numerical range recited in the specification and claims of this application corresponds to at least each specific integer value recited in the numerical range. For example, the numerical range "1-14" corresponds to each integer value in the numerical range "1-14", i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

[0090] The term "optional" (or "optionally", "option") in the general formula definition of this application means the case of being substituted by zero, one or more substituents, for example "optionally substituted by one, two or more R" means that it can not be substituted by R (no substitution) or can be selected to be substituted by one, two or more R.

[0091] "More" means three or more.

[0092] The term "carbocyclo" means a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[l. l. l]pentane ring, bicyclo[2.2. l]heptane ring, bicyclo[3.2. l]octane ring or bicyclo[5.2.0]nonane ring, decahydronaphthalene ring, and the like), which can be optionally substituted with 1 or more (such as 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclo" means a carbocyclo ring containing 3, 4, 5, or 6 ring-forming carbon atoms.

[0093] The term "C 1-12 "alkyl" is understood to mean a straight and branched chain alkyl group having from 1 to 12 carbon atoms, "C 1-8 "alkyl" means a straight and branched chain alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 "alkyl" means a straight and branched chain alkyl group 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, t-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, and the like or isomers thereof.

[0094] The term "C 3-12 "Cycloalkyl" is understood to mean a saturated, monovalent monocyclic, bicyclic (e.g., bridged, spiro) hydrocarbon ring or tricyclic alkane having from 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 (e.g., bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C 3-12Cycloalkyl can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as norbornyl, indyl, 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]nonanyl, 2,6-diazaspiro[3.4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0095] The term "C 3-12 Cycloalkenyl" is to be understood as meaning a monovalent, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic olefin which contains a carbon-carbon double bond and has 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkenyl", more preferably "C 3-8 Cycloalkenyl", which can have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Said C 3-12 Cycloalkenyl" can 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.

[0096] The term "C 6-14 Aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which can be a single aromatic ring or multiple aromatic rings which are fused together, preferably "C 6-10 Aryl". The term "C 6-14 Aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 Aryl"), in particular a ring having 6 carbon atoms ("C6 aryl"), for example phenyl; or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 Aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C 13 Aryl"), for example fluorenyl; or a ring having 14 carbon atoms ("C 14 Aryl"), for example anthryl. When the C 6-20 Aryl" is substituted, it can be mono- or polysubstituted. Furthermore, there is no restriction on the substitution site, for example ortho, para or meta substitution.

[0097] The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring system having 5 to 14 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, e.g. "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system 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 comprising 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, additionally in each case, can be benzo-fused. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the 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-quinolizyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 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-oxazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 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]-ortho-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-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiophenyl, 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]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 5-14 membered heteroaryl ring or through a heteroatom on the 5-14 membered heteroaryl ring. When the 5-14 membered heteroaryl is substituted, it can be mono- or poly-substituted. Also, there is no limitation on the substitution site, for example, the hydrogen attached to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom on the heteroaryl ring can be substituted.

[0098] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spirocyclic) or 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5 or more heteroatoms selected from O, S, and N, wherein N and S can also be optionally oxidized into various oxidation states to form nitroso, -S(O)-, or -S(O)2- states. Preferably, the heterocyclyl group can 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 heterocyclyl group can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolanyl, 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 heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, such as, but not limited to, 5,5 membered rings such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or 5,6 membered bicyclic rings such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e., it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[l,4]thiazinyl, or it can be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14 membered heterocyclyl group is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 3-14 membered heterocyclyl group or through a heteroatom on the 3-14 membered heterocyclyl ring. For example, when the 3-14 membered heterocyclyl group is selected from piperazinyl, it can be attached to other groups through a nitrogen atom on the piperazinyl group. Or when the 3-14 membered heterocyclyl group is selected from piperidinyl, it can be attached to other groups through a nitrogen atom on the piperidinyl ring and a carbon atom para to the nitrogen atom.

[0099] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0100] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0101] The term "bridged ring" refers to ring systems in which two rings share 3 or more ring-forming atoms.

[0102] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0103] "Halo" means substituted with one or more halogens.

[0104] In the present application, the compounds involved also include isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom 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 a compound of the application 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 present application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H or D, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. The present application includes compounds of the formula as set forth in the claims wherein deuterium or tritium is substituted for hydrogen. Moreover, the presence of deuterium or tritium in a substituent group is not excluded by the absence of the term deuterium or tritium from the name of the substituent group.

[0105] It will be appreciated by one skilled in the art that the compounds of Formula (I) or Formula (II) can exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., carboxyl) and a basic center (e.g., amino), they can also form inner salts.

[0106] The compounds of the present application can exist in the form of solvates (e.g. hydrates), wherein the compound of the present application contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of said compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0107] Depending on their molecular structure, the compounds of the present application can be chiral and, therefore, various enantiomeric forms can exist. The compounds can thus exist in racemic or optically active form. The compounds of the present application encompass the isomers with R or S configuration at each chiral carbon or mixtures thereof, racemates. The compounds of the present application or intermediates thereof can be separated into the enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art, or used as such in the synthesis. In the case of racemic amines, the diastereomeric amines are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as, for example, the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acids, for example N-benzoylproline or N-benzenesulfonylproline, or the various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution with the aid of optically active stationary phases, for example, dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing agents, is also advantageously possible. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0108] The corresponding stable isomers can be isolated according to known methods, for example, by extraction, filtration or column chromatography.

[0109] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0110] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed pathology or symptoms of the disease.(2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., retarding the further development of the pathology and / or symptoms).(3) relieving the disease: for example, causing the regression of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms). DETAILED DESCRIPTION

[0111] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology achieved based on the above description of the present application is covered within the scope intended to be protected by the present application.

[0112] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0113] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR determination is made with a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0114] The determination of liquid chromatography-mass spectrometry LC-MS is made with an Agilent 1200 Infinity Series mass spectrometer. The determination of HPLC is made with an Agilent 1200 DAD high-pressure liquid chromatograph (Sunfire C18 150x4.6mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150x4.6mm column).

[0115] Chromatographic silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification of products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0116] Unless otherwise specified, all reactions of the present application are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, and the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

[0117] Example 1

[0118] Preparation of 1-((5-(5-fluoro-2,4-dihydroxyphenyl)pyridin-3-yl)carbamoyl)azetidine-3-carboxylic acid Cpd-05

[0119] Preparation of 5-(5-fluoro-2,4-dimethoxyphenyl)pyridin-3-amine Cpd-05b

[0120] To a solution of 1-bromo-5-fluoro-2,4-dimethoxybenzene Cpd-05a (300 mg, 1.28 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (561.8 mg, 2.55 mmol) in 1,4-dioxane / water (v / v = 5 mL / 1 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (94 mg, 0.13 mmol) and potassium carbonate (529 mg, 3.83 mmol) under nitrogen protection. Stirring at 90 °C for 16 h. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium chloride solution, and the reaction solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column (petroleum ether / ethyl acetate = 0-50%) to give 5-(5-fluoro-2,4-dimethoxyphenyl)pyridin-3-amine Cpd-05b (568 mg), yield: 89.63%. MS m / z (ESI): 249.1 (M+1)

[0121] Preparation of the second step 4-(5-aminopyridin-3-yl)-6-fluorobenzene-1,3-diol Cpd-05c

[0122] To a solution of 5-(5-fluoro-2,4-dimethoxyphenyl)pyridin-3-amine Cpd-05b (568 mg, 2.29 mmol) in dichloromethane (15 mL) was added boron tribromide (2.86 g, 11.44 mmol, 2 M in dichloromethane) at 0 °C. Stirring at room temperature for 2 h. After the reaction was completed, the reaction was quenched by adding ice water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product 4-(5-aminopyridin-3-yl)-6-fluorobenzene-1,3-diol Cpd-05c (478.6 mg), yield: 95%. MS m / z (ESI): 221.1 (M+1)

[0123] Preparation of the third step 1-((5-(5-fluoro-2,4-dihydroxyphenyl)pyridin-3- yl)carbamoyl)azetidine-3-carboxylic acid Cpd-05

[0124] To a solution of 4-(5-amino-pyridin-3-yl)-6-fluoro-benzene-1,3-diol Cpd 05c (200 mg, 0.9083 mmol) in dichloromethane (5 mL) was added pyridine (287.39 mg, 3.6332 mmol) and phenyl chloroformate 2 (711.04 mg, 4.5415 mmol) was added drop wise slowly and stirred at 25 degree for 1 h. After completion of the reaction, petroleum ether was added drop wise to the solution until no more precipitate was formed, filtered and the filtrate was the crude product (200 mg). The crude product (200 mg) was dissolved in pyridine (5 mL) and azetidine-3-carboxylic acid (275.21 mg, 2.725 mol) was added and stirred at 90 degree for 4 h. After completion of the reaction, it was evaporated to dryness. 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 10um; Mobile phase 1 : Water (with 0.1% TFA); Mobile phase 2: Acetonitrile; 10 min gradient, Gradient ratio: Acetonitrile phase 15-25%, Flow rate: 30 mL / min) to give the title compound 1-((5-(5-fluoro-2,4-dihydroxyphenyl)pyridin-3-yl)carbamoyl)azetidine-3-carboxylic acid Cpd-05 (30.82 mg) in 9.78% yield. MS m / z (ESI): 348.0 (M+1)

[0125] 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.18 (s, 1H), 9.91 (s, 1H), 9.14 (s, 1H), 8.82 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.20 (d, J = 12.0 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.19 (t, J = 8.7 Hz, 2H), 4.08 - 4.03 (m, 2H), 3.47 - 3.40 (m, 1H).

[0126] Example 2

[0127] Preparation of N-(5-(5-fluoro-2,4-dihydroxyphenyl)-pyridin-3-yl)-2-oxaspiro[3.3]heptane-6- carboxamide Cpd-14

[0128] Sodium 2-oxaspiro[3.3]heptane-6-carboxylate (102 mg, 0.614 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 4-(5-aminopyridin-3-yl)-6- fluorobenzene-1,3-diol (45 mg, 0.204 mmol), Carter's condensing reagent (361 mg, 0.818 mmol) and N,N-diisopropylethylamine (396 mg, 3.07 mmol) were added to the system. The system was warmed to 25 °C and stirred for 11 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL) and heated to 50 °C for 2 h. After the reaction was completed, the system was concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5u C18 250*21.2 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 5%-35%, flow rate: 30 mL / min) to obtain the product N-(5-(5-fluoro-2,4-dihydroxyphenyl)pyridin-3-yl)-2-oxaspiro[3.3]heptane-6- carboxamide Cpd-14 (2.46 mg), with a yield of 4.9%. MS m / z (ESI): 345.1 (M+H).

[0129] 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.60 (s, 1H), 8.64 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 7.07 (d, J = 12 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 4.59 (s, 2H), 4.51 (s, 2H), 3.04 (t, J = 8 Hz, 1H), 2.43-2.35 (m, 4H).

[0130] Using similar conditions as described in the above examples, the following compounds in Table 1 were prepared. The structural characterization data of these compounds are listed in Table 1

[0131] Table 1

[0132] Example 3

[0133] Preparation of 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one

[0134] To a solution of 4-fluorobenzene-1,3-diol Cpd-1001a (500 mg, 3.90 mmol), bromoacetonitrile (515 mg, 4.29 mmol), zinc chloride (266 mg, 1.95 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 45 °C for 16 h. Then added water (10 mL), the temperature was raised to 70 °C and continued to stir for 3 h, after the reaction was completed, cooled to room temperature, the reaction was extracted with ethyl acetate, saturated brine was washed, the organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one Cpd-1001b (400 mg, light yellow solid), yield: 45%.

[0135] MS m / z (ESI): 205.1 (M+1)

[0136] Example 4

[0137] Preparation of 4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-4-yl)-6- fluorobenzene-1,3-diol

[0138] Preparation of 2-oxa-6-azaspiro[3.3]heptane-6-carbomethic acid in the first step

[0139] To a solution of 2-oxa-6-azaspiro[3.3]heptane Cpd-1001c (300 mg, 3.03 mmol), bis(1H-imidazol-1-yl)methanethione (620 mg, 3.5 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 2 h, then transferred to 55 °C for 1 h. The solvent was removed, added to the amine methanol solution (7 M, 3 mL), after stirring at room temperature for 1 h, the temperature was raised to 55 °C and continued to stir overnight, after the reaction was completed, cooled to room temperature, the solvent was removed and concentrated to give the crude 2-oxa-6-azaspiro[3.3]heptane-6-carbomethic acid Cpd-1001d (160 mg), yield: 33%.

[0140] MS m / z (ESI): 159.1 (M+1)

[0141] Preparation of 4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-4-yl)-6- fluorobenzene-1,3-diol in the second step

[0142] 2-Oxa-6-azaspiro[3.3]heptane-6-carbathioamide Cpd-1001d (160 mg, 1.01 mmol) and 2-chloro-1-(5-fluoro-2,4-dihydroxyphenyl)ethan-1-one Cpd-1001b (206.87 mg, 1.01 mmol) were dissolved in dimethyl sulfoxide solution (5 mL). The reaction was stirred at 80 °C for 3 h. After the reaction was completed, the reaction was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography, and the product 4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazol-4-yl)-6-fluorobenzene-1,3-diol Cpd-1001 (115.13 mg) was obtained by lyophilization, with a yield of 37%.

[0143] MS m / z (ESI): 309.1 (M+1)

[0144] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.92 (s, 1H), 7.54 (d, J = 12.8 Hz, 1H), 7.17 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.73 (s, 4H), 4.24 (s, 4H).

[0145] The following compounds in Table 2 were prepared according to the similar conditions described in Example 4 above, and their structure characterization data are shown in Table 2.

[0146] Table 2

[0147] Biological evaluation

[0148] Test Example 1 Inhibitory activity of the compound of the present application on human tyrosinase

[0149] 1.1 Experimental materials

[0150] 1.2 Experimental apparatus and instruments

[0151] 1.3 Experimental procedure

[0152] First step, preparation of compound DMSO stock solution, all compounds were reconstituted with DMSO to 60 Mm stock solution, stored in a desiccator for use, short-term storage (up to 3 months) at room temperature.

[0153] Second step, compound screening procedure

[0154] 1) Thiamidol from 20Mm continuous dilution 3 times, prepare 10 concentrations (6.667Mm, 2.222Mm, 0.741Mm, 0.247Mm, 0.082Mm, 0.027Mm, 0.009Mm, 0.003Mm, 0.001Mm, 0.3Μm respectively) of Thiamidol DMSO solution and DMSO blank solution;

[0155] 2) Use Echo 665.3 to transfer 100nl compound dilution solution to each well of the assay plate, and centrifuge the compound plate at 1000rpm for 1min.

[0156] 3) Add 10Μl 2X tyrosinase (TYR) working solution on the detection plate, incubate at room temperature for 30min, add 10Μl 2X L-DOPA working solution on the detection plate, incubate at 37℃ for 2h;

[0157] 4) Read the absorbance 475nm signal on the BMG plate reader.

[0158] Step 3, data processing

[0159] The percentage of inhibition rate is calculated as follows:

[0160] %inhibition = 100-(Signal cmpd -Signal Ave_PC ) / (Signal Ave-VC -Signal Ave_PC )×100

[0161] Signal cmpd : The average absorbance value of the test compound on the reaction plate.

[0162] Signal ave_pc : The average absorbance value of the positive control on the reaction plate.

[0163] Signal ave_vc : The average absorbance value of the negative control on the reaction plate.

[0164] IC50fitting calculation:

[0165] The percentage of inhibition and the logarithm of compound concentration are fitted to nonlinear regression with Graphpad 8.0 to calculate IC 50 .

[0166] 1.4 Experimental results

[0167] The specific experimental results are shown in Table 3.

[0168] Table 3 Inhibitory activity of compounds of the present application on human tyrosinase

[0169] The results show that the compound disclosed by the application has good inhibitory activity on human tyrosinase.

Claims

1. A compound of formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: wherein Each R a They may be the same or different, and are independently selected from H, OH, CN, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy; ring B is selected from the group consisting of an unsubstituted or optionally substituted 5-6 membered heteroaromatic ring, and ring B is not a substituted or unsubstituted thiazole ring, pyrazole ring, triazole ring, isoxazole ring; each R b substituted 5-6 membered heteroaromatic ring, and ring B is not a substituted or unsubstituted thiazole ring, pyrazole ring, triazole ring, isoxazole ring; each R b are the same or different, independently of one another, selected from the group consisting of H, OH, CN or halogen; Y is selected from the group consisting of no substitution or optionally substituted with one, two or more R y substituted C 1-12 alkyl, each R y the same or different, are independently selected from the group consisting of H, OH, CN, halogen, oxo (=0); Alternatively, Y is selected from wherein ring D is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R d substituted C 3-14 cycloalkyl ring, 3-14 membered heterocyclic ring; ring E is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R e substituted 5-12 membered heteroaromatic ring; Each R d They may be the same or different, and are independently selected from H, OH, CN, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R atoms. dd The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkyl group, NH2, -C(=O)-R1, -C(=O)OR2, -C(=O)NR3R4; wherein R1, R2, R3, and R4 are the same or different, and are independently selected from H or C. 1-6 alkyl; or, two R groups attached to the same carbon atom are taken together to form a substituted or unsubstituted d with the carbon atom to which it is attached to form a substituted or unsubstituted dd substituted or unsubstituted C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 3- to 8- membered 3-8 heterocycle; or, two R groups attached to the same carbon atom are taken together to form a substituted or unsubstituted Each R dd They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), and C. 1- 6-alkyl, C 1-6 alkoxy or NH2; each R is independently selected from H, OH, CN, halogen, C e the same or different, independently of one another, are selected from H, OH, CN, halogen, C 1-6 alkyl, haloC 1- 6alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy; n is selected from 0, 1, 2 or 3.

2. The compound of claim 1, wherein each R is independently selected from H, OH, CN, F, Cl, Br, methyl, trifluoromethyl, or methoxy, and n is selected from 0 or 1. a are the same or different, and are independently selected from H, OH, CN, F, Cl, Br, methyl, trifluoromethyl, or methoxy, and n is selected from 0 or 1. Preferably, ring B is selected from unsubstituted or optionally substituted with one, two or more R b substituted thiophene ring, pyridine ring, pyridinone, cyclopyrimidine ring, pyrimidinone ring, pyridazine ring or pyridazinone ring; Preferably, ring B is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R b substituted with one, two or more R wherein 1 is connected to the left benzene ring and 2 is connected to the right N atom; Preferably, each R b are the same or different, independently of each other, selected from OH, CN, F, Cl or Br; More preferably, ring B is selected from wherein 1 is connected to the left benzene ring and 2 is connected to the right N atom.

3. The compound of any one of claims 1-2, wherein, Y is selected from unsubstituted or optionally substituted by one, two or more R y substituted C 1-6 alkyl, each R y are the same or different, independently of one another, selected from H, OH, CN or halogen; Preferably, Y is selected from isopropyl; Alternatively, Y is selected from wherein ring D is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R d substituted C 3-8 cycloalkyl ring, 3-8 membered heterocyclic ring; ring E is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R e substituted 5-6 membered heteroaromatic ring; Preferably, ring D is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R d substituted cyclopropane ring, substituted cyclobutane ring, substituted cyclopentane ring, substituted cyclohexane ring, substituted azetidine ring, substituted pyrrolidine ring, substituted piperidine ring, substituted tetrahydrofuran ring, substituted tetrahydro-2H-pyran ring, substituted spiro[3.3]heptane ring (e.g. ), 2-oxa-6-aza-spiro[3.3]heptane ring (e.g. ) or 2-oxa-spiro[3,3]heptane ring (e.g. )； Preferably, ring D is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R d substituted with one, two or more R wherein 1 is connected to the left benzene ring and 2 is connected to the right N atom; Preferably, each R d identically or differently, independently of one another, selected from H, OH, CN, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl(HO-C 1-6 alkyl) or -C(=O)OH, -C(=O)OC 1- 6alkyl; Preferably, each R d are the same or different, independently of each other, selected from H, -C(=0)OH or hydroxymethyl; Preferably, two R d with the carbon atom to which they are attached to form a substituted or unsubstituted 3-6 membered cycloalkyl ring, 3-6 membered heterocyclyl ring, 5-6 membered heteroaryl ring, or 6-membered aryl ring dd substituted with one, two, or more R 3-6 substituted with one, two, or more R substituted with one, two, or more R substituted with one, two, or more R substituted with one, two, or more R Preferably, two R groups attached to the same carbon atom d with the carbon atom to which it is attached forming a cyclobutane or oxetane ring (e.g. )； Preferably, selected from the group consisting of wherein ring E is selected from an unsubstituted or optionally substituted 5-6 membered heteroaromatic ring with one, two or more R e substituted 5-6 membered heteroaromatic ring; Preferably, each R e are the same or different, independently of each other, selected from H, OH, CN or halogen; Preferably, ring E is selected from a tetrazole ring (e.g. )； More preferably, Y is selected from 4. The compound according to any one of claims 1 to 3, characterized in that, The compound of formula (I) is selected from the following structures: wherein ring B, ring D, ring E, R a , R b , Y, n have the definitions as described in any one of claims 1 to 3; m1 is selected from 0, 1, 2 or 3; m2 is selected from 0, 1 or 2.

5. A compound of formula (II), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: wherein, Ring F is selected from 3-10 membered heterocyclyl; Each R f They may be the same or different, and are independently selected from halogens, CN, oxo (=O), NH2, OH, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, hydroxy C 1-10 Alkyl, COOC 1-10 Alkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl; Ring G is selected from the group consisting of unsubstituted or optionally substituted with one, two, or more R g substituted 5-10 membered heteroaryl; each R g are the same or different, each being independently selected from the group consisting of halogen, CN, C 1-10 alkyl, haloC 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkoxy; Each R 11 They are either the same or different, and are independently selected from OH, CN, halogens, and C. 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 1-10 alkoxy or halogenated C 1-10 Alkoxy; p is selected from 0, 1, 2 or 3; q is selected from 0, 1, 2 or 3.

6. The compound of claim 5, and racemates, stereoisomers, tautomers, nitroso derivatives, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, characterized in that, Ring F is selected from 4-9 membered nitrogen-containing heterocyclyl; Preferably, ring F is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, Preferably, ring F is selected from wherein represents that ring F is covalently connected to ring G at the position; Preferably, each R f are the same or different, independently of each other, selected from OH, COOH, hydroxy C 1-6 alkyl, COOC 1-6 alkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl; Preferably, each R f identically or differently, independently of one another, selected from OH, COOH, hydroxy C 1-6 alkyl, COOC 1-6 alkyl, triazolyl, tetrazolyl; Preferably, each R f are the same or different, independently of each other, selected from OH, COOH, hydroxymethyl, COOCH3, Preferably, ring G is selected from 5-6 membered heteroaryl; Preferably, ring G is selected from thiazolyl, pyridyl, thienyl; Preferably, ring G is selected from Preferably, ring G is selected from wherein 1 is connected to ring F and 2 is connected to the benzene ring; Preferably, R 11 is selected from halogen, preferably F.

7. The compound according to claim 5 or 6, and its racemate, stereoisomer, tautomer, nitroxide, solvate, polymorph, metabolite, ester, prodrug, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (II) is selected from the following structures: wherein ring F, R 11 , R f , p and q independently of one another have the definitions given in claim 5 or 6; Preferably, the compound of formula (II) is selected from the following structures: Among them, rings F and R 11 R f Both q and q have the definition as described in claim 5 or 6 independently of each other.

8. A compound characterized in that, and its racemates, stereoisomers, tautomers, nitroso compounds, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, wherein the structure of said compound is as shown below:

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-8. Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

10. 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, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-8 or the pharmaceutical composition of claim 9. Preferably, the tyrosinase-mediated disease is tyrosinase-mediated skin pigmentation. Preferably, the skin pigmentation symptoms are selected from melasma, stretch marks, solar lentigines, cafe-au-lait spots, freckles. Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory hyperpigmentation, wherein, The inflammation is selected from acne, eczema, dermatitis, drug eruption, infection, sunburn, trauma.

11. Use of at least one of the compound, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-8 or the pharmaceutical composition of claim 9 in the manufacture of a medicament. Preferably, the tyrosinase-mediated disease is tyrosinase-mediated skin pigmentation. Preferably, the skin pigmentation symptoms are selected from melasma, stretch marks, solar lentigines, cafe-au-lait spots, freckles. Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory hyperpigmentation, wherein, The inflammation is selected from acne, eczema, dermatitis, drug eruption, infection, sunburn, trauma.

12. A cosmetic composition comprising an effective amount of at least one of the compound, its racemate, stereoisomer, tautomer, solvate, polymorph, acceptable salt or derivative thereof represented by formula (I) or formula (II). Preferably, the cosmetic composition further comprises one or more auxiliary agents and / or additives, including thickening agents, fillers, fragrances, colorants, emulsifiers, additional active ingredients such as vitamins or proteins, light protection agents, stabilizers, insect repellents, alcohols, water, salts, antibacterial agents, protein-decomposing or keratin-decomposing effective substances, etc.

13. A cosmetic method for non-therapeutic purposes, the method comprising administering to a mammal in need thereof an effective amount of at least one of the compounds represented by Formula (I) or Formula (II), racemates, stereoisomers, tautomers, solvates, polymorphs, acceptable salts or derivatives thereof, or the cosmetic composition of claim 12 for ameliorating / assisting the treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening; Preferably, the method comprises administering to a mammal in need thereof an effective amount of the cosmetic composition for ameliorating / assisting the treatment of tyrosinase-mediated skin pigmentation symptoms or for skin whitening; Preferably, the tyrosinase-mediated skin pigmentation symptoms are selected from the group consisting of chloasma, stretch marks, solar lentigo, cafe-au-lait spots, freckles; Preferably, the tyrosinase-mediated skin pigmentation comprises post-inflammatory hyperpigmentation, wherein, The inflammation is selected from the group consisting of acne, eczema, dermatitis, drug eruption, infection, sunburn, trauma.

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