Five-membered heterocyclic compound, and preparation method, intermediate, composition and application thereof

Abstract

The invention discloses a five-membered heterocyclic compound as well as a preparation method, an intermediate, a composition and application thereof. Specifically provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound provided by the invention has excellent biological activity; on one hand, free radicals can be removed, so that activation of tyrosinase is reduced; on the other hand, the activity of activated tyrosinase can be inhibited, and generation of melanin is reduced from multiple aspects; besides, the compound can reduce skin pigmentation induced by ultraviolet (UVB), has no obvious stimulation and inflammatory cell infiltration during administration, is safe and good in tolerance, has better solubility and preparation performance, is good in skin feeling, and is expected to be widely applied in the industries of medicine, cosmetics and beauty. # imgabs0 #

Description

[0001] This application claims the benefit of Chinese patent application No. 202410252232X filed on March 5, 2024. The entire content of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to five-membered heterocyclic compounds, preparation methods, intermediates, compositions and applications thereof Background Art

[0003] Tyrosinase (EC 1.14.18.1, also known as TYR) is a copper-containing oxidoreductase that is widely present in microorganisms, animals, plants, and humans. Tyrosinase is the rate-limiting enzyme in melanin production, possessing dual activities as tyrosine hydroxylase and dopa oxidase. It plays a crucial role in melanin production in melanocytes. During melanin synthesis, tyrosine is converted to dopa by tyrosinase, and then, through a series of steps, melanin is ultimately formed. This melanin imparts darker colors to animals, such as black and brown, and sometimes yellow.

[0004] The activation and activity of tyrosinase directly affect the rate and amount of melanin production, and reactive oxygen free radicals are important factors that promote tyrosinase activation. Recently, scientists have developed a variety of natural, semi-synthetic, and synthetic inhibitors to reduce melanin production, but they still suffer from problems such as a single mode of action, insufficient activity, significant side effects, and limitations. For example, while hydroquinone (hydroquinone) has a good whitening effect, it has strong side effects and irritation, and is significantly toxic to cells. Excessive use can cause severe corrosion to the skin and mucous membranes, and may even suppress the central nervous system or damage liver function. Therefore, the use of hydroquinone is generally limited to the pharmaceutical field worldwide. Although isobutylamidothiazolylresorcinol (Thiamidol), developed by the Beiersdorf Group, has shown strong tyrosinase inhibitory activity, there is still considerable room for improvement.

[0005] Summary of the Invention

[0006] To overcome the problems of inhibitors in the prior art, the present invention provides a novel five-membered heterocyclic compound, its preparation method, intermediates, composition, and application. The compound of the present invention exhibits excellent biological activity. It can scavenge free radicals, thereby reducing tyrosinase activation, and inhibit the activity of activated tyrosinase, thereby reducing melanin production in multiple ways. Furthermore, the compound of the present invention is safe, well-tolerated, exhibits excellent solubility and formulation properties, and has a good skin feel, and is expected to be widely used in the pharmaceutical, cosmetic, and beauty industries.

[0007] The present invention discloses a compound represented by formula I or a pharmaceutically acceptable salt thereof,

[0008]

[0009] R 1 C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0010] R 1-1 are each independently D (deuterium) or hydroxyl;

[0011] R 1-2 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more hydroxyl groups;

[0012] Y is H, D or halogen;

[0013] Z is S or Se;

[0014] K is 1, 2 or 3;

[0015] R 2 is hydroxyl group;

[0016] The compound represented by formula I satisfies one or more (e.g., one, two, or three) of the following conditions:

[0017] (1) Z is Se;

[0018] (2) Y is D or halogen;

[0019] (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0020] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments"): R 1 wherein the C1-C6 alkyl group is replaced by one or more R 1-1The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are each independently a straight-chain or branched C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further such as isopropyl or tert-butyl. Preferably, the C1-C6 alkyl groups are each independently a C3-C4 alkyl group, such as n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further such as isopropyl or tert-butyl. Further preferably, the C1-C6 alkyl groups are each independently a C3 alkyl group, such as isopropyl.

[0021] In some embodiments, R 1 In the embodiment, the C3-C8 cycloalkyl group is a monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclohexyl.

[0022] In some embodiments, R 1 In the embodiment, the 3-8 membered heterocyclic group is a monocyclic heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; preferably, the 3-8 membered heterocyclic group is a 4-6 membered heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; further preferably, the 3-8 membered heterocyclic group is a 6 membered heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; for example, the 3-8 membered heterocyclic group is

[0023] In some embodiments, R 1 In the embodiment, the 3-8 membered heterocyclic group (for example, a 6 membered heterocyclic group) is a monocyclic heterocyclic group, for example, a 6 membered monocyclic heterocyclic group.

[0024] In some embodiments, R 1 In the above-mentioned 3-8 membered heterocyclic group, the number of heteroatoms is 1.

[0025] In some embodiments, R 1 wherein the heteroatom in the 3-8 membered heterocyclic group is O.

[0026] In some embodiments, R 1 In the embodiment, the 3-8 membered heterocyclic group is a 4-6 membered monocyclic heterocyclic group, for example, the 3-8 membered heterocyclic group is

[0027] In some embodiments, R 1 In the C6-C 14 Aryl and one or more R 1-2 Substituted C6-C 14 C6-C 14 Aryl groups are each independently phenyl or naphthyl, for example phenyl.

[0028] In some embodiments, R 1 In the above, one or more R1-1 Substituted C1-C6 alkyl is substituted by 6 R 1-1 Substituted C3-C4 alkyl groups, such as

[0029] In some embodiments, R 1 In the above, one or more R 1-2 Substituted C6-C 14 Aryl is substituted by 1 R 1-2 Substituted C6-C 14 Aryl, preferably substituted with 1 R 1-2 Substituted phenyl groups, such as

[0030] In some embodiments, R 1-2 In the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more hydroxyl groups, the C1-C6 alkyl group is independently a straight chain or branched C1-C6 alkyl group, preferably a straight chain or branched C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and another example is methyl.

[0031] In some embodiments, R 1-2 In the embodiment, the C1-C6 alkyl group substituted by one or more hydroxyl groups is a C1-C6 alkyl group substituted by one hydroxyl group, for example

[0032] In some embodiments, in Y, the halogen is fluorine, chlorine or bromine, such as fluorine.

[0033] In some embodiments, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0034] In some embodiments, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0035] In some embodiments, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0036] In some embodiments, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 The substituted C1-C6 alkyl group has 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0037] In some embodiments, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0038] In some embodiments, R 1 It is a C1-C6 alkyl group (for example, a C3-C4 alkyl group).

[0039] In some embodiments, R 1 is a C3 alkyl group (eg, isopropyl).

[0040] In some embodiments, R 1 is a 6-membered monocyclic heterocyclic group having 1 heteroatom, wherein the heteroatom is O (e.g. ).

[0041] In some embodiments, R 1-1 is D (deuterium).

[0042] In some embodiments, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0043] In some embodiments, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0044] In some embodiments, R 1-2 It is a C1-C6 alkyl group substituted by one or more hydroxy groups.

[0045] In some embodiments, R 1-2 It is a C1-C3 alkyl group substituted by one or more hydroxy groups.

[0046] In some embodiments, the plurality is 2, 3, 4, 5, 6, 7, 8 or 9, preferably, R 1 In the above, one or more R 1-1 The number of substituted C1-C6 alkyl groups is 6.

[0047] In some embodiments, K is 1 or 2, for example, K is 2.

[0048] In some embodiments, K is 2, and two R 2 In meta position, e.g. for

[0049] In some embodiments, Y is H or D, such as D.

[0050] In some embodiments, Z is Se.

[0051] In some embodiments, Z is Se, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 The substituted C1-C6 alkyl group has 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0052] In some embodiments, Z is Se, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a 6-membered monocyclic heterocyclic group 1-1 The substituted C3-C4 alkyl group, wherein the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0053] In some embodiments, Y is H, R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D (deuterium).

[0054] In some embodiments, Y is H, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0055] In some embodiments, Y is H, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0056] In some embodiments, Y is D, R 1 It is a C1-C6 alkyl group.

[0057] In some embodiments, Y is D, R 1 C3- C4 alkyl.

[0058] In some embodiments, Y is F, R 1 It is a C1-C6 alkyl group.

[0059] In some embodiments, Y is F, R 1 It is a C3-C4 alkyl group.

[0060] In some embodiments, the compound represented by Formula I is a compound represented by Formula I-1 or I-2;

[0061]

[0062] Among them, R 1 , Y, K and R 2 Each independently as described in any one of the present invention.

[0063] In some embodiments, in the compound represented by formula I-1, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0064] In some embodiments, in the compound represented by formula I-1, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0065] In some embodiments, in the compound represented by formula I-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0066] In some embodiments, in the compound represented by formula I-1, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1The substituted C1-C6 alkyl group has 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0067] In some embodiments, in the compound represented by formula I-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0068] In some embodiments, in the compound represented by formula I-1, R 1 It is a C1-C6 alkyl group (for example, a C3-C4 alkyl group).

[0069] In some embodiments, in the compound represented by formula I-1, R 1 is a C3 alkyl group (eg, isopropyl).

[0070] In some embodiments, in the compound represented by formula I-1, R 1 is a 6-membered monocyclic heterocyclic group having 1 heteroatom, wherein the heteroatom is O (e.g. ).

[0071] In some embodiments, in the compound represented by formula I-1, R 1-1 is D (deuterium).

[0072] In some embodiments, in the compound represented by formula I-1, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0073] In some embodiments, in the compound represented by formula I-1, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0074] In some embodiments, in the compound represented by formula I-1, R 1-2 It is a C1-C6 alkyl group substituted by one or more hydroxy groups.

[0075] In some embodiments, in the compound represented by formula I-1, R 1-2 It is a C1-C3 alkyl group substituted by one or more hydroxy groups.

[0076] In some embodiments, in the compound represented by formula I-1, K is 1 or 2, for example, 2.

[0077] In some embodiments, in the compound represented by formula I-1, K is 2, and two R 2 In the meta position (e.g. for ).

[0078] In some embodiments, in the compound represented by formula I-1,

[0079] R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0080] R 1-1 is D (deuterium);

[0081] R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups;

[0082] K is 1 or 2;

[0083] R 2 It is a hydroxyl group.

[0084] In some embodiments, in the compound represented by formula I-1,

[0085] R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl; the 3-8 membered heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0086] R 1-1 is D (deuterium);

[0087] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for

[0088]

[0089] R 2 It is a hydroxyl group.

[0090] In some embodiments, in the compound represented by formula I-1,

[0091] R1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O;

[0092] R 1-1 is D (deuterium);

[0093] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for

[0094]

[0095] R 2 It is a hydroxyl group.

[0096] In some embodiments, in the compound represented by formula I-1,

[0097] R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl; for example, the C3 alkyl is isopropyl;

[0098] R 1-1 is D (deuterium);

[0099] K is 2, two R 2 In meta position, e.g. for

[0100] R 2 It is a hydroxyl group.

[0101] In some embodiments, in the compound represented by formula I-2, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0102] In some embodiments, in the compound represented by formula I-2, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0103] In some embodiments, in the compound represented by formula I-2, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0104] In some embodiments, in the compound represented by formula I-2, R 1 is C1-C6 alkyl or is replaced by one or more R 1-1 Substituted C1-C6 alkyl.

[0105] In some embodiments, in the compound represented by formula I-2, R 1 is C3-C4 alkyl or is replaced by one or more R 1-1 Substituted C3-C4 alkyl.

[0106] In some embodiments, in the compound represented by formula I-2, R 1-1 is D (deuterium).

[0107] In some embodiments, in the compound represented by formula I-2, R 1-2 is a C1-C6 alkyl group substituted by one or more hydroxyl groups, preferably, R 1-2 It is a C1-C3 alkyl group substituted by one or more hydroxy groups.

[0108] In some embodiments, in the compound represented by formula I-2, R 1 is a C3 alkyl group (eg, isopropyl).

[0109] In some embodiments, in the compound represented by formula I-2, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0110] In some embodiments, in the compound represented by formula I-2, K is 1 or 2, for example, K is 2; preferably, K is 2, and the two R 2 In the meta position (e.g. for ).

[0111] In some embodiments, in the compound represented by formula I-2, Y is D or halogen, for example, D.

[0112] In some embodiments, in the compound represented by formula I-2,

[0113] R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0114] R 1-1 is D (deuterium);

[0115] R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups;

[0116] Y is H, D or halogen;

[0117] K is 1 or 2;

[0118] R 2 is hydroxyl group;

[0119] At the same time, one or more (for example, one or two) of the following conditions are met:

[0120] (1) Y is D or halogen (e.g., D);

[0121] (2)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0122] In some embodiments, in the compound represented by formula I-2,

[0123] R 1 is C1-C6 alkyl or is replaced by one or more R 1-1 Substituted C1-C6 alkyl;

[0124] R 1-1 is D (deuterium);

[0125] Y is H, D or halogen;

[0126] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for

[0127]

[0128] R 2 is hydroxyl group;

[0129] At the same time, one or more (for example, one or two) of the following conditions are met:

[0130] (1) Y is D or halogen (e.g., D);

[0131] (2)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0132] In some embodiments, in the compound represented by formula I-2,

[0133] R 1 is C3-C4 alkyl or is replaced by one or more R 1-1 Substituted C3-C4 alkyl;

[0134] R 1-1 is D (deuterium);

[0135] Y is H, D or halogen;

[0136] K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group;

[0137] At the same time, one or more (for example, one or two) of the following conditions are met:

[0138] (1) Y is D or halogen (e.g., D);

[0139] (2)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 It is D.

[0140] In some embodiments, in the compound represented by formula I-2,

[0141] R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl; for example, the C3 alkyl is isopropyl;

[0142] R 1-1 is D (deuterium);

[0143] Y is H, D or halogen;

[0144] K is 2, two R 2 In meta position, e.g. for

[0145] R2 is hydroxyl group;

[0146] At the same time, one or more (for example, one or two) of the following conditions are met:

[0147] (1) Y is D or halogen (e.g., D);

[0148] (2)R 1 For one or more R 1-1 Substituted C3 alkyl, R 1-1 It is D.

[0149] In some embodiments, the compound represented by formula I-1 is a compound represented by formula I-1-1;

[0150]

[0151] Among them, R 1 As described in any one of the present invention.

[0152] In some embodiments, in the compound represented by formula I-1-1, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0153] In some embodiments, in the compound represented by formula I-1-1, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0154] In some embodiments, in the compound represented by formula I-1-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0155] In some embodiments, in the compound represented by formula I-1-1, R 1is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 The substituted C1-C6 alkyl group has 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0156] In some embodiments, in the compound represented by formula I-1-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0157] In some embodiments, in the compound represented by formula I-1-1, R 1 It is a C1-C6 alkyl group (for example, a C3-C4 alkyl group).

[0158] In some embodiments, in the compound represented by formula I-1-1, R 1 is a C3 alkyl group (eg, isopropyl).

[0159] In some embodiments, in the compound represented by formula I-1-1, R 1 is a 6-membered monocyclic heterocyclic group having 1 heteroatom, wherein the heteroatom is O (e.g. ).

[0160] In some embodiments, in the compound represented by formula I-1-1, R 1-1 is D (deuterium).

[0161] In some embodiments, in the compound represented by formula I-1-1, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0162] In some embodiments, in the compound represented by formula I-1-1, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0163] In some embodiments, in the compound represented by formula I-1-1, R 1-2 It is a C1-C6 alkyl group substituted by one or more hydroxy groups.

[0164] In some embodiments, in the compound represented by formula I-1-1, R 1-2 It is a C1-C6 alkyl group substituted by one hydroxyl group.

[0165] In some embodiments, the compound represented by formula I-2 is a compound represented by formula I-2-1;

[0166]

[0167] Among them, R 1 As described in any one of the present invention.

[0168] In some embodiments, in the compound represented by formula I-2-1, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0169] In some embodiments, in the compound represented by formula I-2-1, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0170] In some embodiments, in the compound represented by formula I-2-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O.

[0171] In some embodiments, in the compound represented by formula I-2-1, R 1 is C1-C6 alkyl or is replaced by one or more R 1 -1 Substituted C1-C6 alkyl.

[0172] In some embodiments, in the compound represented by formula I-2-1, R 1 is C3-C4 alkyl or is replaced by one or more R 1 -1 Substituted C3-C4 alkyl.

[0173] In some embodiments, in the compound represented by formula I-2-1, R1-1 is D (deuterium).

[0174] In some embodiments, in the compound represented by formula I-2-1, R 1 is a C3 alkyl group (eg, isopropyl).

[0175] In some embodiments, in the compound represented by formula I-2-1, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0176] In some embodiments, the compound represented by formula I-2 is a compound represented by formula I-2-2;

[0177]

[0178] Among them, R 1 As described in any one of the present invention.

[0179] In some embodiments, R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D (deuterium).

[0180] In some embodiments, in the compound represented by formula I-2-2, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0181] In some embodiments, in the compound represented by formula I-2-2, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0182] In some embodiments, the compound represented by formula I-2 is a compound represented by formula I-2-3;

[0183]

[0184] Among them, R 1 As described in any one of the present invention.

[0185] In some embodiments, in the compound represented by formula I-2-3, R 1 is C1-C6 alkyl or is replaced by one or more R 1 -1 Substituted C1-C6 alkyl, R1-1 is D (deuterium).

[0186] In some embodiments, in the compound represented by formula I-2-3, R 1 is C3-C4 alkyl or is replaced by one or more R 1 -1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0187] In some embodiments, in the compound represented by formula I-2-3, R 1 It is a C1-C6 alkyl group.

[0188] In some embodiments, in the compound represented by formula I-2-3, R 1 It is a C3-C4 alkyl group.

[0189] In some embodiments, in the compound represented by formula I-2-3, R 1 is a C3 alkyl group (eg, isopropyl).

[0190] In some embodiments, in the compound represented by formula I-2-3, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium).

[0191] In some embodiments, in the compound represented by formula I-2-3, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D (deuterium) (e.g. ).

[0192] In some embodiments, in the compound represented by Formula I,

[0193] R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0194] R 1-1 are each independently D (deuterium);

[0195] R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups;

[0196] Y is H, D or halogen;

[0197] Z is S or Se;

[0198] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for );

[0199] R 2 is hydroxyl group;

[0200] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0201] (1) Z is Se;

[0202] (2) Y is D or halogen;

[0203] (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D (deuterium).

[0204] In some embodiments, in the compound represented by Formula I,

[0205] R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0206] R 1-1 are each independently D (deuterium);

[0207] R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups;

[0208] Y is H or D;

[0209] Z is S or Se;

[0210] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for

[0211]

[0212] R2 is hydroxyl group;

[0213] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0214] (1) Z is Se;

[0215] (2) Y is D;

[0216] (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0217] In some embodiments, in the compound represented by Formula I,

[0218] R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O;

[0219] R 1-1 are each independently D (deuterium);

[0220] R 1-2 are each independently a C1-C6 alkyl group (e.g., a C1-C3 alkyl group) substituted with one or more hydroxyl groups;

[0221] Y is H, D or halogen;

[0222] Z is S or Se;

[0223] K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for

[0224]

[0225] R 2 is hydroxyl group;

[0226] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0227] (1) Z is Se;

[0228] (2) Y is D or halogen;

[0229] (3)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1It is D.

[0230] In some embodiments, in the compound represented by Formula I,

[0231] R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C1-C6 alkyl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0232] R 1-1 is D (deuterium);

[0233] Y is H or D;

[0234] Z is S or Se (e.g., Se);

[0235] K is 2, two R 2 In meta position, e.g. for

[0236] R 2 is hydroxyl group;

[0237] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0238] (1) Z is Se;

[0239] (2) Y is D;

[0240] (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0241] In some embodiments, in the compound represented by Formula I,

[0242] R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O;

[0243] R 1-1 is D (deuterium);

[0244] Y is H or D;

[0245] Z is S or Se (e.g., Se);

[0246] K is 2, two R 2 In meta position, e.g. for

[0247] R 2 is hydroxyl group;

[0248] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0249] (1) Z is Se;

[0250] (2) Y is D;

[0251] (3)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 It is D.

[0252] In some embodiments, in the compound represented by Formula I,

[0253] R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl; R 1-1 is D (deuterium);

[0254] Y is H or D;

[0255] Z is S or Se (e.g., Se);

[0256] K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group;

[0257] The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions:

[0258] (1) Z is Se;

[0259] (2) Y is D;

[0260] (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

[0261] In some embodiments, R 1 for (For example, ).

[0262] In some embodiments, for (For example, ).

[0263] In some embodiments, Y is H, D, or F (eg, is H or D).

[0264] In some embodiments, Z is S or Se (eg, is Se).

[0265] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0266]

[0267]

[0268] In another aspect, the present invention further provides a composition comprising (i) a compound represented by Formula I or a pharmaceutically acceptable salt thereof; and (ii) an excipient. Preferably, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is the active ingredient.

[0269] In some embodiments, the composition is used as a medicine or a cosmetic.

[0270] In some embodiments, the composition is a pharmaceutical composition or a cosmetic composition.

[0271] In some embodiments, the excipient is a pharmaceutically acceptable excipient.

[0272] On the other hand, the present invention also provides a compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for use as a medicine or cosmetic.

[0273] On the other hand, the present invention also provides a compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for use as a medicine or cosmetic.

[0274] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition in the preparation of medicines and cosmetics.

[0275] On the other hand, the present invention also provides a use of the compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above composition as a tyrosinase inhibitor.

[0276] On the other hand, the present invention also provides a compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition as a tyrosinase inhibitor.

[0277] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition in the preparation of a tyrosinase inhibitor.

[0278] On the other hand, the present invention also provides a compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for use in treating and / or preventing diseases.

[0279] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0280] On the other hand, the present invention also provides a compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for treating and / or preventing a disease.

[0281] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0282] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition in the preparation of a drug for treating and / or preventing a disease.

[0283] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0284] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition as a drug for treating and / or preventing diseases related to tyrosinase.

[0285] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0286] On the other hand, the present invention also provides a compound of the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for treating and / or preventing diseases associated with tyrosinase.

[0287] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0288] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition in the preparation of a drug for treating and / or preventing tyrosinase-related diseases.

[0289] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0290] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition as a drug for treating and / or preventing pigmentation.

[0291] In some embodiments, the pigmentation is chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0292] On the other hand, the present invention also provides a compound of the above formula I or a pharmaceutically acceptable salt thereof, or the above composition for treating and / or preventing pigmentation.

[0293] In some embodiments, the pigmentation is chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0294] On the other hand, the present invention also provides a use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition in the preparation of a drug for treating and / or preventing pigmentation.

[0295] In some embodiments, the pigmentation is chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0296] On the other hand, the present invention also provides a method for treating and / or preventing diseases related to tyrosinase, which comprises administering the compound represented by the above formula I or a pharmaceutically acceptable salt thereof, or the above composition to a subject in need of such treatment and / or prevention.

[0297] In some embodiments, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots, dark circles, etc.

[0298] The present invention discloses a compound represented by formula II or a pharmaceutically acceptable salt thereof;

[0299]

[0300] R 3 are independently a hydroxyl protecting group, preferably, the hydroxyl protecting group is a C1-C6 alkyl-O-carbonyl or a benzyl group;

[0301] K, Y, Z, and R 1 Each independently as described in any one of the present invention.

[0302] In some embodiments, R 3 In the C 1- C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example isopropyl.

[0303] The present invention discloses a compound represented by formula II, which is any of the following compounds:

[0304]

[0305] The present invention discloses a compound represented by formula III or a pharmaceutically acceptable salt thereof;

[0306]

[0307] Among them, R 3 , K, Y, and Z are independently as described in any one of the present invention.

[0308] The present invention discloses a compound represented by formula III, which is any of the following compounds:

[0309]

[0310] The present invention also provides a method for preparing the compound of formula I, which comprises the following method 1, method 2 or method 3;

[0311] Method 1 comprises the following steps: hydrolyzing the compound represented by Formula II in an organic solvent (e.g., an alcohol solvent or a mixed solvent of an alcohol solvent and water, such as ethanol or a mixed solvent of ethanol and water) in the presence of a base (e.g., an inorganic base, such as NaOH) to obtain the compound represented by Formula I;

[0312]

[0313] Among them, R 3 are each independently C1-C6 alkyl-O-carbonyl;

[0314] K, Y, Z, R 1 and R 2 Each independently as described in any one of the present invention;

[0315] Method 2 comprises the following steps: in an organic solvent (e.g., an alcohol solvent, such as ethanol), in the presence of a palladium catalyst (e.g., palladium hydroxide), hydrogenating the compound represented by Formula II with hydrogen to obtain the compound represented by Formula I;

[0316]

[0317] Among them, R 3 are each independently benzyl;

[0318] K, Y, Z, R 1 and R 2 Each independently as described in any one of the present invention;

[0319] Method 3 comprises the following steps: hydrolyzing the compound represented by Formula II in an organic solvent (e.g., a halogenated hydrocarbon solvent, e.g., dichloromethane) at (e.g., -60°C to -80°C, e.g., -78°C) in the presence of a catalyst (e.g., boron tribromide) to obtain the compound represented by Formula I;

[0320]

[0321] Among them, R 3 are each independently benzyl;

[0322] K, Y, Z, R 1 and R 2 Each independently as described in any one of the present invention.

[0323] The present invention also provides a method for preparing the compound shown in Formula II, which comprises Method 1 or Method 2;

[0324] Method 1 comprises the following steps: amidating a compound represented by Formula III with a compound represented by Formula III-1 in an organic solvent (e.g., a halogenated hydrocarbon solvent, e.g., dichloromethane) under the action of a base (e.g., an organic base, e.g., triethylamine) to obtain a compound represented by Formula II;

[0325]

[0326] Among them, R 4 is a halogen (e.g., chlorine);

[0327] R 3 , K, Y, Z and R 1 Each independently as described in any one of the present invention;

[0328] Method 2 comprises the following steps: in an organic solvent (e.g., a halogenated hydrocarbon solvent, such as dichloromethane), in the presence of an acylating agent (e.g., 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide), amidating the compound represented by Formula III with the compound represented by Formula III-1 to obtain the compound represented by Formula II;

[0329]

[0330] Among them, R 4 is hydroxyl group;

[0331] R 3 , K, Y, Z and R 1 Each independently as described in any one of the present invention.

[0332] Definition of terms:

[0333] Unless otherwise specified, the terms used in this application have the following definitions. Definitions of terms not mentioned below are as commonly understood by those skilled in the art to which the present invention belongs.

[0334] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0335] As used herein, the term "excipient" refers to excipients and additives used in the production and formulation of a prescription. Excipients are substances, other than the active ingredient, contained in a composition that are non-toxic, safe, and suitable for administration. For more information, see the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009, Sixth Edition).

[0336] In the present invention, the term "plurality" refers to a natural number greater than 1, such as 2, 3, 4, 5, 6, 7, 8 or 9.

[0337] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0338] In the present invention, the term "hydroxyl group" means -OH.

[0339] In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having a certain number of carbon atoms. 1–6 Alkyl refers to an alkyl group having 1–6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms, including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0340] In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, a monocyclic cycloalkyl group, a spirocyclic alkyl group, a fused cycloalkyl group, and a bridged cycloalkyl group. The term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring carbon atoms. For example, a C3-C8 cycloalkyl group specifically refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms, and another example is a C3, C4, C5 or C6 monocyclic cycloalkyl group. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0341] As used herein, the term "heterocyclyl" refers to a saturated heterocyclic substituent having a specified number of ring atoms (e.g., 3 to 12 members), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatom (one or more of N, O, and S), such as a monocyclic heterocyclyl.

[0342] In this application, the term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 14 or C6~C 10 ) is a cyclic, unsaturated, monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). In the case of polycyclic rings, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl and naphthyl.

[0343] In general, the term "substituted with" indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Furthermore, when a group is substituted with one or more of the specified substituents, the substituents are independent of each other, i.e., the one or more substituents may be different or the same. Unless otherwise expressly indicated, a substituent group may be substituted at every substitutable position of the substituted group. When more than one position in a given structure is substitutable with one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0344] Additionally, it should be noted that, unless explicitly stated otherwise, the terms "...are each independently" and "...are independently" used in this application should be broadly interpreted to mean that the described entities are independent of each other and may independently represent the same or different specific groups. More specifically, the term "...are independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0345] As used herein, the term "treat" refers to therapeutic treatment. With respect to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0346] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0347] The reagents and raw materials used in the present invention are commercially available.

[0348] The positive progress of the present invention is that the compounds of the present application have one or more of the following advantages:

[0349] (1) Novel structure.

[0350] (2) It has excellent biological activity. On the one hand, it can scavenge free radicals and thus reduce the activation of tyrosinase; on the other hand, it can inhibit the activity of activated tyrosinase and reduce the production of melanin in many ways.

[0351] (3) It can reduce the production of skin pigments induced by ultraviolet rays (UVB).

[0352] (4) No obvious irritation or inflammatory cell infiltration was observed during administration, and the drug was safe and well tolerated.

[0353] (5) It has good solubility and preparation properties, good skin feel, and has good application prospects. It is expected to be widely used in the pharmaceutical, cosmetic, and beauty industries. BRIEF DESCRIPTION OF THE DRAWINGS

[0354] Figure 1 The compound has an inhibitory effect on ultraviolet-induced pigment production. DETAILED DESCRIPTION

[0355] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0356] Example 1: Synthesis of Compound TH-001

[0357]

[0358] Step 1: Synthesis of Intermediate 1-2

[0359] Compound 1-1 (2 g, 13.15 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, and triethylamine (3.99 g, 39.44 mmol, 3 eq) and isopropyl chloroformate (3.54 g, 28.92 mmol, 2.2 eq) were added. The reaction system was stirred at 20 ° C for 2 hours. TLC (petroleum ether: ethyl acetate = 4:1) monitored the complete consumption of the starting material and the formation of the main product. The reaction system was diluted with 20 mL of water, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 2). After the organic phases were combined, they were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-2 as a colorless oil (3.2 g, yield: 75.06%). LCMS (ESI): m / z C 16 H 21 O7 + .[M+H] + Calculated value = 325.13. Measured value = 325.1. 1 HNMR(400MHz,DMSO-d6)δppm7.87(d,J=8.6Hz,1H),7.21(dd,J=2.3,8.6Hz,1H ), 7.16 (d, J = 2.4Hz, 1H), 5.09-4.92 (m, 2H), 2.57 (s, 3H), 1.41-1.38 (m, 12H).

[0360] Step 2: Synthesis of Intermediate 1-3

[0361] Intermediate 1-2 (2 g, 6.17 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and compound 1-2a (phenyltrimethylammonium tribromide) (3.48 g, 9.25 mmol, 1.5 eq) was added. The reaction system was stirred at 20°C for 1 hour. TLC (petroleum ether:ethyl acetate = 10:1) monitored the complete consumption of the starting material. The reaction system was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 20g Silica Flash Column; mobile phase gradient: 0-14% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 1-3 as a white solid (2.1 g, yield: 84.46%). LCMS (ESI): m / z C 16 H 20 BrO7 + .[M+H]+ Calculated value = 403.04.405.04 Measured value = 403.0.405.0. 1 H NMR (400MHz, CDCl3) δppm 7.93(d,J=8.8Hz,1H),7.29(d,J=2.3Hz,1H),7.25(dd,J=2.3,8.8Hz,1H),5.03(dd,J=6.1,11.2Hz,2H),4.45(s,2H),1.43-1.40(m,12H).

[0362] Step 3: Synthesis of Intermediate 1-4

[0363] Intermediate 1-3 (1.3 g, 3.22 mmol, 1 eq) was dissolved in 10 mL of acetonitrile, and selenourea (515.59 mg, 4.19 mmol, 1.3 eq) was added. The reaction system was stirred at 50°C for 20 hours. TLC (petroleum ether:ethyl acetate = 4:1) confirmed complete consumption of the starting material and the formation of product spots. The reaction solution was concentrated under reduced pressure to a residue and recrystallized from 10 mL of ethyl acetate to obtain Intermediate 1-4 as a white solid (1.2 g, yield: 87.10%). LCMS (ESI): m / z C 17 H 21 N2O6Se + .[M+H] + Calculated value = 429.06. Measured value = 429.1. 1 H NMR(400MHz,DMSO-d6)δppm 7.73(br d,J=8.6Hz,1H),7.50-7.38(m,1H),7.35-7.29(m,1H),7.23(s,1H),4.93-4 .86(m,1H),4.83-4.78(m,1H),1.33(d,J=6.2Hz,6H),1.26(d,J=6.2Hz,6H).

[0364] Step 4: Synthesis of Intermediate 1-5

[0365] Intermediate 1-4 (400 mg, 936.09 μmol, 1.0 eq.) was dissolved in 10 mL of dichloromethane, and triethylamine (94.72 mg, 936.09 μmol, 1 eq.) was added. Under stirring at 10 ° C, isobutyryl chloride (199.48 mg, 1.87 mmol, 2 eq.) was slowly added dropwise to the above reaction system. After the addition was completed, the reaction system was stirred at 10 ° C for 10 minutes. LCMS monitoring showed that the raw material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-5 as a colorless oil (360 mg, yield: 77.32%). LCMS (ESI): m / z C 21 H 27 N2O7Se + .[M+H] + Calculated value = 499.10. Measured value = 499.1.

[0366] Step 5: Synthesis of compound TH-001

[0367] Intermediate 1-5 (360 mg, 723.76 μmol, 1 eq) was dissolved in 5 mL of ethanol and 1 M aqueous sodium hydroxide solution (3 mL) was added. The reaction system was stirred at 25°C for 0.5 h. LCMS analysis confirmed complete consumption of the starting material and the formation of product. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue. The residue was purified by reverse-phase column chromatography (column specifications: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [Phase A: water (0.025% formic acid) - Phase B: acetonitrile]; gradient: 45% to 75% B over 7 minutes) to obtain compound TH-001 as a white solid (180 mg, yield: 76.47%). LCMS (ESI): m / z C 13 H 15 N2O3Se + .[M+H] + Calculated value = 327.02. Measured value = 327.0. 1 H NMR(400MHz,DMSO-d6)δppm 12.42(s,1H),11.17(s,1H),9.45(s,1H),7.88(s,1H),7.62(d,J=9.3Hz,1 H), 6.34-6.24 (m, 2H), 2.77 (td, J = 6.8, 13.7Hz, 1H), 1.15 (d, J = 7.0Hz, 6H).

[0368] Example 2: Synthesis of Compound TH-002

[0369]

[0370] Referring to the synthesis method of steps 4 and 5 in Example 1, the corresponding raw materials were substituted and t-valeryl chloride was used as the raw material to prepare compound TH-002 as a white solid. LCMS (ESI): m / z C14 H 17 N2O3Se + .[M+H] + Calculated value = 341.04. Measured value = 341.0. 1 H NMR (400MHz, DMSO-d6) δppm 12.06(s,1H),11.26(s,1H),9.42(s,1H),7.89(s,1H),7.71-7.50(m,1H),6.42-6.18(m,2H),1.34(s,9H).

[0371] Example 3: Synthesis of Compound TH-003

[0372]

[0373] Referring to the synthesis method of Step 4 and Step 5 in Example 1, the corresponding raw materials were substituted and cyclohexanecarbonyl chloride was used as the raw material to prepare compound TH-003 as a white solid. LCMS (ESI): m / z C 16 H 19 N2O3Se + .[M+H] + Calculated value = 367.06. Measured value = 367.0. 1 H NMR(400MHz,DMSO-d6)δppm 12.41(s,1H),11.23(s,1H),9.46(s,1H),7.87(s,1H),7.70-7.54(m,1H),6.43-6.17(m,2H),1.87(br d,J=12.5Hz,2H),1.76(br dd,J=2.9,9.4Hz,2H),1.66(br d,J=10.6Hz,1H),1.52-1.36(m,2H),1.35-1.15(m,4H).

[0374] Example 4: Synthesis of Compound TH-004

[0375]

[0376] Referring to the synthesis method of steps 4 and 5 in Example 1, the corresponding raw materials were substituted and 4-hydropyran-4-carbonyl chloride was used as the raw material to prepare compound TH-004 as a white solid. LCMS (ESI): m / z C 15 H 17 N2O4Se + .[M+H] + Calculated value = 369.03. Measured value = 369.0. 1H NMR(400MHz,DMSO-d6)δppm 12.48(s,1H),11.19(s,1H),9.50(s,1H),7.92(s,1H),7.72-7.49(m,1H),6.42-6.15(m,2H),3.99-3.85(m,2H),3.34(br s,1H),2.86-2.72(m,1H),2.13-2.04(m,1H),1.82-1.64(m,4H).

[0377] Example 5: Synthesis of Compound TH-005

[0378]

[0379] Referring to the synthesis method of steps 4 and 5 in Example 1, the corresponding raw materials were substituted and 4-(chlorocarbonyl)benzyl acetate was used as the raw material to prepare compound TH-005 as a white solid. LCMS (ESI): m / zC 17 H 15 N2O4Se + .[M+H] + Calculated value = 391.02. Measured value = 391.0. 1 H NMR(400MHz, DMSO-d6)δppm 9.47(s,1H),8.11(d,J=8.2Hz,2H),7.90(s,1H),7.69-7.60(m,1H),7.51(d,J=8.2Hz,2H),6.38-6.24(m,2H),5.40(br t,J=4.8Hz,1H),4.61(br d,J=4.5Hz,2H).

[0380] Example 6: Synthesis of Compound TH-006

[0381]

[0382] Referring to the synthesis method in Example 1, the corresponding raw materials were replaced with compound 1-(4-hydroxyphenyl)ethanone as the raw material to prepare compound TH-006 as a white solid. LCMS (ESI): m / z C 13 H 15 N2O2Se + .[M+H] + Calculated value = 311.03. Measured value = 311.0. 1H NMR(400MHz,DMSO-d6)δppm 12.33(s,1H),9.54(s,1H),7.79(s,1H),7.70(d,J=8.6Hz,2H),6.79(d,J=8.5Hz,2H),2.83-2.73(m,1H),1.18-1.10(m,6H).

[0383] Example 7: Synthesis of Compound TH-007

[0384]

[0385] Step 1: Synthesis of Intermediate 7-2

[0386] Intermediate 1-3 (1.5 g, 3.72 mmol, 1 eq) was dissolved in 10 mL of acetonitrile and compound 7-1a thiourea (368.12 mg, 4.84 mmol, 1.3 eq) was added. The reaction system was stirred at 50°C for 30 hours. TLC (petroleum ether:ethyl acetate = 4:1) confirmed complete consumption of the starting material and the formation of the product. The reaction solution was concentrated to a residue and recrystallized from 15 mL of ethyl acetate to obtain Intermediate 7-2 as a white solid (1.35 g, yield: 95.40%). LCMS (ESI): m / zC 17 H 21 N2O6S + .[M+H] + Calculated value = 381.11. Measured value = 381.1. 1 H NMR(400MHz,DMSO-d6)δppm 8.94-7.92(br,s,2H),7.78(dd,J=2.5,8.6Hz,1H),7.41(s,1H)7.35-7.32(m,1H),6. 92(d,J=3.5Hz,1H),4.97-4.76(m,2H),1.33(d,J=6.3Hz,6H),1.27(d,J=6.2Hz,6H).

[0387] Step 2: Synthesis of Intermediate 7-3

[0388] Intermediate 7-2 (150 mg, 394.31 μmol, 1 eq) was dissolved in 5 mL of dichloromethane, and 4-dimethylaminopyridine (DMAP) (4.81 mg, 39.43 μmol, 0.1 eq), N,N'-dicyclohexylcarbodiimide (DCC) (162.71 mg, 788.61 μmol, 2.0 eq) and compound 7-2a (48.26 mg, 512.60 μmol, 1.3 eq) were added in sequence. The reaction system was stirred at 20 ° C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 4 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 7-3 as a colorless oil (118 mg, yield: 65.55%). LCMS (ESI): m / z C 21 H 21 D6N2O7S + .[M+H] + Calculated value = 457.19. Measured value = 457.2.

[0389] Step 3: Synthesis of compound TH-007

[0390] Intermediate 7-3 (330.43 mg, 723.76 μmol, 1 eq) was dissolved in 5 mL of ethanol and 1 mL of water, and 2.2 mL of 20% aqueous sodium hydroxide solution was added. The reaction system was stirred at 25°C for 30 minutes. Complete consumption of the starting material was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction solution was adjusted to pH 7 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (3 mL x 2). The organic phases were combined, washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue. The residue was purified by reverse-phase column chromatography (column dimensions: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [phase A: water (0.225% formic acid) - phase B: acetonitrile]; gradient: 40% to 70% B over 6 minutes) to obtain compound TH-007 as a white solid (154 mg, yield: 75.2%). LCMS(ESI):m / z C 13 H9D6N2O3S + .[M+H] + Calculated value = 285.12. Measured value = 285.1. 1HNMR (400MHz, DMSO-d6) δppm 12.17 (br s, 1H), 10.90 (br s, 1H), 9.51 (br s, 1H), 7.66 (d, J = 8.2Hz, 1H), 7.40 (s, 1H), 6.39-6.22 (m, 2H), 2.71 (s, 1H).

[0391] Example 8: Synthesis of Compound TH-008

[0392]

[0393] Step 1: Synthesis of Intermediate 8-2

[0394] Compound 8-1 benzyl bromide (4.50 g, 26.29 mmol, 2 eq) was dissolved in 60 mL of acetonitrile, and potassium carbonate (3.63 g, 26.29 mmol, 2 eq) and compound 1-1 (2 g, 13.15 mmol, 1 eq) were added in sequence. The reaction system was stirred at 60°C for 1 hour. TLC (petroleum ether: ethyl acetate = 5:1) monitored the complete consumption of the starting material. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-35% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 8-2 as a white waxy solid (3.63 g, yield: 83.25%). LCMS (ESI): m / z C 22 H 21 O3 + .[M+H] + Calculated value = 333.15. Measured value = 333.1. 1 H NMR (400MHz, CD3Cl) δppm 7.88 (d, J = 9.5Hz, 1H), 7.56-7.33 (m, 10H), 6.71-6.56 (m, 2H), 5.13 (d, J = 10.3Hz, 4H), 2.59 (s, 3H).

[0395] Step 2: Synthesis of Intermediate 8-3

[0396] Intermediate 8-2 (3.32 g, 10 mmol, 1 eq) was dissolved in 15 mL of deuterated water and 15 mL of dioxane, and tetrahydropyrrole (71.12 mg, 1.00 mmol, 0.1 eq) was added. The reaction system was stirred at 50 ° C for 6 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue. It was redissolved in 15 mL of deuterated water and 15 mL of dioxane, and tetrahydropyrrole (71.12 mg, 1.00 mmol, 0.1 eq) was added. The reaction system was stirred at 50 ° C for 6 hours. HNMR monitoring showed that the reaction raw materials were completely consumed. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue, and was chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 12 g SilicaFlash Column; mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 25 mL / min) to prepare intermediate 8-3 as a white waxy solid (2.95 g, yield: 87.95%). LCMS (ESI): m / zC 22 H 18 D3O3 + .[M+H] + Calculated value = 336.17. Measured value = 336.2. 1 H NMR (400MHz, CD3Cl) δppm7.94-7.79(m,1H),7.51-7.33(m,10H),6.71-6.54(m,2H),5.14(s,2H),5.11(s,2H).

[0397] Step 3: Synthesis of Intermediate 8-4

[0398] Intermediate 8-3 (2 g, 5.96 mmol, 1 eq) was dissolved in 20 mL of tetrahydrofuran, and compound 1-2a (phenyltrimethylammonium tribromide) (2.47 g, 6.56 mmol, 1.1 eq) was added. The reaction system was stirred at 20°C for 1 hour. TLC (petroleum ether:ethyl acetate = 10:1) monitored the complete consumption of the starting material. The reaction system was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 20g Silica Flash Column; mobile phase gradient: 0-25% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 8-4 as a white solid (1.85 g, yield: 75.1%). LCMS (ESI): m / z C 22 H 18 D2BrO3 + .[M+H] + Calculated value = 413.07.415.07 Measured value = 413.0.415.1. 1H NMR (400MHz, CDCl3) δppm 7.94 (d, J = 8.7Hz, 1H), 7.49-7.35 (m, 10H), 6.75-6.53 (m, 2H), 5.14 (d, J = 15.4Hz, 4H).

[0399] Step 4: Synthesis of Intermediate 8-5

[0400] Intermediate 8-4 (1 g, 2.42 mmol, 1 eq) was dissolved in 10 mL of acetonitrile, and deuterated thiourea of ​​compound 8-4a (193.96 mg, 2.42 mmol, 1 eq) was added. The reaction system was stirred at 30 ° C for 5 hours. TLC (petroleum ether: ethyl acetate = 4:1) monitored the complete consumption of the starting material and the formation of the product. The reaction solution was concentrated to a residue, dissolved in 20 mL of dichloromethane, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 12g Silica Flash Column; mobile phase gradient: 0-50% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 8-5 as a white solid (620 mg, yield: 65.77%). LCMS (ESI): m / z C 23 H 20 DN2O2S + .[M+H] + Calculated value = 390.14 Found [M+H] + =390.1. 1 HNMR(400MHz,DMSO-d6)δppm 7.54(d,J=8.6Hz,1H),7.49-7.31(m,10H),6.92(d,J=2.3Hz,1H),6.77(dd,J=2.3,8.6Hz,1H),5.31-5.23(m,2H),5.20-5.13(m,2H).

[0401] Step 5: Synthesis of Intermediate 8-6

[0402] Intermediate 8-5 (300 mg, 770.24 μmol, 1 eq) was dissolved in 4 mL of dichloromethane, and compound 8-5a isobutyric acid (101.79 mg, 1.16 mmol, 1.5 eq), DMAP (9.41 mg, 77.02 μmol, 0.1 eq) and DCC (317.85 mg, 1.54 mmol, 311.62 μL, 2 eq) were added in sequence. The reaction system was stirred at 20 ° C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 8-6 as a colorless oil (305 mg, yield: 86.16%). LCMS (ESI): m / zC 27 H 26 DN2O3S + .[M+H] + Calculated value = 460.18. Measured value = 460.0.

[0403] Step 6: Synthesis of compound TH-008

[0404] Intermediate 8-6 (300 mg, 652.77 μmol, 1 eq) was dissolved in 8 mL of ethanol and palladium hydroxide (91.67 mg, 130.55 μmol, 0.2 eq, 20%) was added under a nitrogen atmosphere. The reaction system was then stirred at 25°C for 12 hours under a hydrogen atmosphere (15 psi). LCMS analysis indicated the presence of residual starting material and the formation of the main product. The reaction system was filtered through celite, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue. The residue was then purified by reverse-phase column chromatography (column dimensions: C18 150 × 40 mm; mobile phase: [Phase A: water (0.225% formic acid) - Phase B: acetonitrile]; gradient: 40% to 70% B over 7 minutes) to obtain compound TH-008 as a white solid (138 mg, yield: 75.68%). LCMS (ESI): m / z C 13 H 14 DN2O3S + .[M+H] + Calculated value = 280.09 Found [M+H] + =279.9. 1H NMR(400MHz,DMSO-d6)δppm 12.17(br s,1H),10.89(s,1H),8.15(s,1H),7.65(d,J=8.3Hz,1H),6.38-6.22(m,2H),2.78-2.71(m,1H),1.13(d,J=6.8Hz,6H).

[0405] Example 9: Synthesis of Compound TH-009

[0406]

[0407] Step 1: Synthesis of Intermediate 9-1

[0408] Intermediate 8-5 (300 mg, 770.24 μmol, 1 eq) was dissolved in 8 mL of DMF, and N-fluorobisbenzenesulfonamide (NFSI) (267.18 mg, 847.27 μmol, 1.1 eq) was added. The reaction system was stirred at 20°C for 11 hours. LCMS monitoring showed that some starting material remained and a main product peak was formed. The reaction solution was diluted with 30 mL of water and 30 mL of ethyl acetate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain Intermediate 9-1 as a light yellow solid (305 mg, crude product). LCMS (ESI): m / zC 23 H 20 FN2O2S + .[M+H] + Calculated value = 407.12 Found [M+H] + =407.0.

[0409] Step 2: Synthesis of Intermediate 9-2

[0410] Intermediate 9-1 (300 mg, 738.06 μmol, 1 eq) was dissolved in 8 mL of dichloromethane, and isobutyric acid (162.57 mg, 1.85 mmol, 2.5 eq), DMAP (9.41 mg, 77.02 μmol, 0.1 eq) and DCC (317.85 mg, 1.54 mmol, 2 eq) were added in sequence. The reaction system was stirred at 20 ° C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-56% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 9-2 as a colorless oil (260 mg, yield: 73.92%). LCMS (ESI): m / zC 27 H 26 FN2O3S + .[M+H] + Calculated value = 477.16. Measured value = 477.1.

[0411] Step 3: Synthesis of compound TH-009

[0412] Intermediate 9-2 (250 mg, 524.59 μmol, 1 eq) was dissolved in 5 mL of dichloromethane, and boron tribromide (2 M, 524.59 μL, 2 eq) was added dropwise to the solution at -78°C. The reaction system was stirred at -78°C for 0.5 h. LCMS monitoring of the original The reaction liquid was quenched with 5 mL of water, the organic phase was separated, and the water The phase was extracted with dichloromethane (3 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue. The residue was then purified by reverse-phase column chromatography (column dimensions: C18 150 × 30 mm × 5 μm; mobile phase: [Phase A: water (0.225% formic acid) -Phase B: acetonitrile]; gradient: 45%-75% B over 7 minutes) to obtain compound TH-009 as a white solid (62 mg, yield: 39.88%). LCMS (ESI): m / z C 13 H 14 FN2O3S + .[M+H] + Calculated value = 297.07 Found [M+H] + =297.0. 1 HNMR(400MHz,DMSO-d6)δppm 12.27(s,1H),10.33(br s,1H),9.61(br s, 1H), 7.32 (d, J = 9.2Hz, 1H), 6.44-6.22 (m, 2H), 2.78-2.60 (m, 1H), 1.13 (d, J = 6.9Hz, 6H).

[0413] Biological Test Example 1 DPPH Free Radical Scavenging Activity

[0414] Test method:

[0415] DPPH is a stable free radical. Its alcohol solution is purple and has a single electron, so it can accept an electron or hydrogen ion. It has a maximum absorption near a wavelength of 517nm. In the presence of a free radical scavenger, the single electron of DPPH is captured, causing its color to become lighter. The absorbance at the wavelength of maximum light absorption decreases, and the degree of decrease is linear. The decrease in absorbance level indicates an increase in antioxidant activity, thereby evaluating the antioxidant capacity of the test sample. Antioxidant capacity can be expressed as an inhibition rate. The greater the inhibition rate, the stronger the antioxidant activity. The experimental steps are as follows:

[0416] 1. Prepare 0.2 mM DPPH solution: Accurately weigh 1.97 mg DPPH and dissolve it in 25 mL of anhydrous ethanol to obtain a 0.2 mM DPPH solution. Store in the dark until ready for use.

[0417] 2. Positive control 1 mg / mL vitamin C solution: Accurately weigh 5 mg and dissolve it in 5 mL of anhydrous ethanol to obtain a 1 mg / mL vitamin C solution. Then, dilute it 2-fold to 9 test concentrations, down to 0.004 mg / mL.

[0418] 3. Solution of the test compound: Prepare test compound sample solutions with different concentration gradients by referring to step 2.

[0419] 4. In a 96-well plate, in the dark, add different concentration gradients of test compound solution or positive control 100 μL and 100 μL DPPH solution to the compound group, with 2 replicates for each concentration; set up a blank group (200 μL of anhydrous ethanol) and a DPPH group (100 μL of DPPH alcohol solution + 100 μL of anhydrous ethanol). Incubate each group at room temperature in the dark for 30 minutes, measure the absorbance at 517 nm (Signal) with a microplate reader, take the average value, and calculate the inhibition rate and IC 50 .

[0420] Inhibition rate and IC 50 The calculation method is as follows:

[0421] % inhibition rate = 1-(Signal 化合物组 -Signal 空白组 ) / (Signal DPPH组 -Signal 空白组 )×100

[0422] The half-maximal inhibitory concentration (IC) was calculated using Excel by logarithmic fitting and regression analysis. 50 .

[0423] The results are as follows :

[0424] Table 1 DPPH free radical scavenging activity of the compounds of the present invention

[0425]

[0426]

[0427] The compounds of the present invention have good DPPH free radical scavenging activity, and the free radical scavenging activity of TH-001 is stronger than that of Thiamidol.

[0428] Biological Test Example 2 Human Tyrosinase Inhibitory Activity

[0429] Test method:

[0430] Quantitatively transfer serially diluted test compounds to the wells of an assay plate, with duplicate wells for each concentration. Add tyrosinase working solution to the assay plate and incubate at room temperature for 30 minutes. Add L-DOPA working solution to the assay plate and incubate at 37°C for 2 hours. Read the absorbance at 475 nm on a plate reader, average the values, and calculate relative inhibition.

[0431] The inhibition rate calculation formula is as follows:

[0432] % inhibition value = 100-(Signal cmpd -Signal PC ) / (Signal VC -Signal PC )×100

[0433] Signal cmpd : Average value of detection signal of different concentrations of test compounds

[0434] Signal pc : Average value of positive control Thiamidol detection signal

[0435] Signal vc : Average value of DMSO detection signal of solvent control

[0436] % inhibition values ​​and compound concentration logarithms were fitted to nonlinear regression (dose response-variable slope) using Graphpad 8.0 to calculate IC 50 .

[0437] The results are as follows :

[0438] Table 2 Tyrosinase inhibitory activity of the compounds of the present invention

[0439] Compound IC50 (μM) Thiamidol 0.694 TH-001 0.538 TH-002 1.091 TH-003 6.721 TH-004 0.686 TH-005 3.139 TH-006 8.891 TH-007 0.415 TH-008 0.416 TH-009 125.5

[0440] The compounds of the present invention all have an inhibitory effect on human tyrosinase activity, among which TH-001, TH-004, TH-007 and The inhibitory effect of TH-008 is stronger than that of Thiamidol.

[0441] Biological Test Example 3: Inhibition of UV-induced pigmentation, epidermal thickness, and inflammatory cell infiltration Experimental animals and groups :

[0442] Healthy adult brown guinea pigs (half male and half female, weighing 400-500 g) were divided into 5 groups, 8 in each group, as follows:

[0443] 1) Blank control group: no UVB irradiation + matrix cream;

[0444] 2) Model group: UVB irradiation + matrix cream;

[0445] 3) Positive control group (0.5% Thiamidol): UVB irradiation + 0.5% (g / g) Thiamidol cream;

[0446] 4) Low-dose group (0.5% TH-001): UVB irradiation + 0.5% (g / g) TH-001 cream;

[0447] 5) High-dose group (1% TH-001): UVB irradiation + 1.0% (g / g) TH-001 cream.

[0448] The composition of the cream excipients in the positive control group, low-dose group, and high-dose group was the same as the matrix cream in the blank control group and model group except for the active ingredients.

[0449] Test process :

[0450] 1. UV-induced pigmentation model establishment: Guinea pigs were shaved back skin (4 × 4 cm) and irradiated with UVB light (wavelength 280-320 nm) at an initial dose of 50 mJ / cm², three times weekly, with the dose increasing by 10% each time for four weeks. Following irradiation, a photosensitizer (0.1% 8-MOP solution) was applied.

[0451] 2. Dosage regimen: Starting from the 5th week, apply the cream twice a day (8 hours apart) at a dosage of 2 mg / cm2 evenly covering the shaved area for 8 weeks.

[0452] 3. Data collection and testing indicators: After the eighth week of drug administration, skin samples were collected and Fontana-Masson staining was performed to quantify the area ratio of epidermal melanin granules; H&E staining was used to assess epidermal thickness and inflammatory cell infiltration.

[0453] Results and Data Analysis :

[0454] The skin pigmentation inhibition effect was investigated by Fontana-Masson staining. Figure 1As shown in the figure, compared with the model group, the epidermal melanin particles in the drug-treated group were significantly reduced. TH-001 dose-dependently reduced the area of ​​epidermal melanin particles. Compared with the same concentration of Thiamidol, TH-001 had a significant difference ( Figure 1 ), "*" indicates P < 0.05, and "***" indicates P < 0.001. H&E staining showed that no significant increase in epidermal thickness or inflammatory cell infiltration was observed in any group.

[0455] Experimental Conclusion :

[0456] The compounds of the present invention significantly reduced UVB-induced skin pigmentation, with TH-001 showing a significantly better effect than Thiamidol at the same dose. No significant irritation or inflammatory cell infiltration was observed in any of the groups after 8 weeks of administration.

[0457] The compounds of the present invention have free radical scavenging effects on one hand, and can inhibit tyrosinase activity on the other hand. Some compounds have stronger activity than the reference compound Thiamidol, and in cell experiments, they also show stronger activity in inhibiting melanin production. Guinea pig efficacy tests show that they can reduce UVB-induced skin pigmentation, and no obvious irritation or inflammatory cell infiltration is observed during administration. They are expected to be used in the preparation of cosmetics and pharmaceutical compositions, such as skin whitening agents, or for the treatment of related diseases such as chloasma and pigmentation.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof, R 1 C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 are independently D or hydroxyl; R 1-2 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more hydroxyl groups; Y is H, D or halogen; Z is S or Se; K is 1, 2 or 3; R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D or halogen; (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 It is D.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: It meets one or more of the following conditions: (1)R 1 wherein the C1-C6 alkyl group is replaced by one or more R 1-1 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are each independently a linear or branched C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further such as isopropyl or tert-butyl. Preferably, the C1-C6 alkyl groups are each independently a C3-C4 alkyl group, such as n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further such as isopropyl or tert-butyl. Further preferably, the C1-C6 alkyl groups are each independently a C3 alkyl group, such as isopropyl. (2)R 1 wherein the C3-C8 cycloalkyl group is a monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and another example is cyclohexyl; (3)R 1 In the embodiment, the 3-8 membered heterocyclic group is a monocyclic heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; preferably, the 3-8 membered heterocyclic group is a 4-6 membered heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; further preferably, the 3-8 membered heterocyclic group is a 6 membered heterocyclic group, the number of heteroatoms is 1, and the heteroatom is O; for example, the 3-8 membered heterocyclic group is (4)R 1 In the C6-C 14 Aryl and one or more R 1-2 Substituted C6-C 14 C6-C 14 Aryl is each independently phenyl or naphthyl, for example phenyl; (5)R 1 In the above, one or more R 1-1 Substituted C1-C6 alkyl is substituted by 6 R 1-1 Substituted C3-C4 alkyl groups, such as (6)R 1 In the above, one or more R 1-2 Substituted C6-C 14 Aryl is substituted by 1 R 1-2 Substituted C6-C 14 Aryl, preferably substituted with 1 R 1-2 Substituted phenyl groups, such as (7)R 1-2 wherein the C1-C6 alkyl group and the C1-C6 alkyl group substituted by one or more hydroxyl groups are each independently a linear or branched C1-C6 alkyl group, preferably a linear or branched C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and another example is methyl; (8)R 1-2 In the embodiment, the C1-C6 alkyl group substituted by one or more hydroxyl groups is a C1-C6 alkyl group substituted by one hydroxyl group, for example (9) In Y, the halogen is fluorine, chlorine or bromine, for example, fluorine.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: It meets one or more of the following conditions: (1)R 1 Meet any of the following conditions: (a)R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (b)R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (c)R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O; (d)R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C1-C6 alkyl, the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S; (e)R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O; (f)R 1 is a C1-C6 alkyl group, preferably C 3- C4 alkyl, more preferably C3 alkyl, such as isopropyl; (g)R 1 is a 6-membered monocyclic heterocyclic group having 1 heteroatom, wherein the heteroatom is O, for example, R 1 for (h)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D, preferably, R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 For D, for example R 1 for (2)R 1-1 is D; (3)R 1-2 is a C1-C6 alkyl group substituted by one or more hydroxyl groups, preferably, R 1-2 is a C1-C3 alkyl group substituted with one or more hydroxyl groups; (4) The plurality of is 2, 3, 4, 5, 6, 7, 8 or 9, preferably, R 1 In the above, one or more R 1-1 The plurality of substituted C1-C6 alkyl groups is 6; (5) K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for (6) Y is H or D, for example, D; (7) Z is Se.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The compound represented by formula I is a compound represented by formula I-1 or I-2; Among them, R 1 , Y, K and R 2 Each independently as claimed in any one of claims 1 to 3.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein: The compound represented by formula I-1 satisfies one or more of the following conditions: (1)R 1 Meet any of the following conditions: (a)R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (b)R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (c)R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O; (d)R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C1-C6 alkyl, the 3-8 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms independently selected from N, O and S; (e)R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O; (f)R 1 is a C1-C6 alkyl group, preferably a C3-C4 alkyl group, more preferably a C3 alkyl group, such as isopropyl; (g)R 1 is a 6-membered monocyclic heterocyclic group having 1 heteroatom, wherein the heteroatom is O, for example, R 1 for (h)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 D, preferably surrounded by 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 For D, for example R 1 for (2)R 1-1 is D; (3)R 1-2 is a C1-C6 alkyl group substituted by one or more hydroxyl groups, preferably, R 1-2 is a C1-C3 alkyl group substituted with one or more hydroxyl groups; (4) K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for And / or, the compound represented by formula I-2 satisfies one or more of the following conditions: (1)R 1 Meet any of the following conditions: (a)R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (b)R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; (c)R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O; (d)R 1 is C1-C6 alkyl or is replaced by one or more R 1-1 Substituted C1-C6 alkyl; preferably, the C1-C6 alkyl is a C3-C4 alkyl; (e)R 1 is a C3 alkyl group, such as isopropyl; (f)R 1 For the 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 For D, for example R 1 for (2)R 1-1 is D; (3)R 1-2 is a C1-C6 alkyl group substituted by one or more hydroxyl groups, preferably, R 1-2 is a C1-C3 alkyl group substituted with one or more hydroxyl groups; (4) K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for (5) Y is D or halogen, for example, D.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein: In the compound represented by formula I-1, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 is D; R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups; K is 1 or 2; R 2 is hydroxyl group; Preferably, in the compound represented by formula I-1, R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group, a 1-1 Substituted C1-C6 alkyl; said 3-8 The membered heterocyclyl group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 is D; K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for R 2 is hydroxyl group; More preferably, in the compound represented by formula I-1, R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O; R 1-1 is D; K is 1 or 2, for example, K is 2; preferably, K is 2, and the two R 2 In meta position, e.g. for R 2 is hydroxyl group; More preferably, in the compound represented by formula I-1, R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl, for example, the C3 alkyl is isopropyl; R 1-1 is D; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; And / or, in the compound represented by formula I-2, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 is D; R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups; Y is H, D or halogen; K is 1 or 2; R 2 is hydroxyl group; At the same time, one or more (for example, one or two) of the following conditions are met: (1) Y is D or halogen, for example, D; (2)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; Preferably, in the compound represented by formula I-2, R 1 is C1-C6 alkyl or is replaced by one or more R 1-1 Substituted C1-C6 alkyl; R 1-1 is D; Y is H, D or halogen; K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for R 2 is hydroxyl group; At the same time, one or more (for example, one or two) of the following conditions are met: (1) Y is D or halogen, for example, D; (2)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; More preferably, in the compound represented by formula I-2, R 1 is C3-C4 alkyl or is replaced by one or more R 1-1 substituted C3-C4 alkyl; R 1-1 is D; Y is H, D or halogen; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; At the same time, one or more (for example, one or two) of the following conditions are met: (1) Y is D or halogen, for example, D; (2)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; More preferably, in the compound represented by formula I-2, R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl; for example, the C3 alkyl is isopropyl; R 1-1 is D; Y is H, D or halogen; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; At the same time, one or more (for example, one or two) of the following conditions are met: (1) Y is D or halogen, for example, D; (2)R 1 For one or more R 1-1 Substituted C3 alkyl, R 1-1 It is D.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein: The compound represented by formula I-1 is the compound represented by formula I-1-1; Among them, R 1 As claimed in any one of claims 1 to 6; Alternatively, the compound represented by formula I-2 is the compound represented by formula I-2-1; Among them, R 1 As claimed in any one of claims 1 to 6; Alternatively, the compound represented by formula I-2 is a compound represented by formula I-2-2; Among them, R 1 As claimed in any one of claims 1 to 6; Preferably, in the compound represented by formula I-2-2, R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; preferably, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; more preferably, R 1 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; for example, R 1 for Alternatively, the compound represented by formula I-2 is a compound represented by formula I-2-3; Among them, R 1 As claimed in any one of claims 1 to 6; Preferably, in the compound represented by formula I-2-3, R 1 is C1-C6 alkyl or is replaced by one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 D(R 1 is C3-C4 alkyl or is replaced by one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D); preferably, R 1 is a C1-C6 alkyl group (R 1 is a C3-C4 alkyl group, preferably a C3 alkyl group); More preferably, in the compound represented by formula I-2-3, R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; preferably, R 1 6 R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; for example, R 1 for 8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound represented by formula I is any of the following schemes: Option 1: In the compound represented by formula I, R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 Each independently is D; R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups; Y is H, D or halogen; Z is S or Se; K is 1 or 2, for example, K is 2; preferably, K is 2, and the two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D or halogen; (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; Option 2: R 1 C1-C6 alkyl, C3-C8 monocyclic cycloalkyl, 3-8 membered monocyclic heterocyclic group, C6-C 14 Aryl, one or more R 1-1 Substituted C1-C6 alkyl or one or more R 1-2 Substituted C6-C 14 Aryl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 Each independently is D; R 1-2 are each independently a C1-C6 alkyl group substituted with one or more hydroxyl groups; Y is H or D; Z is S or Se; K is 1 or 2, for example, K is 2; preferably, K is 2, and two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D; (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; Option 3: R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group, a 1-1 Substituted C3-C4 alkyl or one or more R 1-2 Substituted phenyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, and the heteroatom is O; R 1-1 Each independently is D; R 1-2 are independently a C1-C6 alkyl group substituted by one or more hydroxyl groups, preferably, the C1-C6 alkyl group is a C1-C3 alkyl group; Y is H, D or halogen; Z is S or Se; K is 1 or 2, for example, K is 2; preferably, K is 2, and the two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D or halogen; (3)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; Option 4: R 1 is a C1-C6 alkyl group, a 3-8 membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C1-C6 alkyl; the 3-8 membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms independently selected from N, O and S; R 1-1 is D; Y is H or D; Z is S or Se, for example, Se; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D; (3)R 1 For one or more R 1-1 Substituted C1-C6 alkyl, R 1-1 is D; Option 5: R 1 is a C3-C4 alkyl group, a 6-membered monocyclic heterocyclic group or a group consisting of one or more R 1-1 Substituted C3-C4 alkyl; the 6-membered monocyclic heterocyclic group has 1 heteroatom, which is O; R 1-1 is D; Y is H or D; Z is S or Se, for example, Se; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D; (3)R 1 For one or more R 1-1 Substituted C3-C4 alkyl, R 1-1 is D; Option 6: R 1 is C3 alkyl or is replaced by one or more R 1-1 Substituted C3 alkyl; R 1-1 is D; Y is H or D; Z is S or Se, for example, Se; K is 2, two R 2 In meta position, e.g. for R 2 is hydroxyl group; The compound represented by Formula I satisfies one or more (e.g., 1, 2, or 3) of the following conditions: (1) Z is Se; (2) Y is D; (3)R 1 For one or more R 1-1 Substituted C3 alkyl, R 1-1 It is D.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: It meets one or more of the following conditions: (1)R 1 for (2) for (3) Y is H, D or F; (4) Z is S or Se.

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound represented by formula I is any of the following compounds:

11. A composition comprising (i) a compound of formula I according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and (ii) an excipient, wherein the composition is preferably used as a medicine or a cosmetic.

12. A use of the compound of formula I according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, or the composition according to claim 11, characterized in that: The application is selected from one or more of the following: (i) for the preparation of tyrosinase inhibitors; (ii) for preparing a medicament for treating and / or preventing a disease associated with tyrosinase, preferably, the disease is pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots or dark circles; (iii) for use in the preparation of cosmetics; (iv) for preparing a medicament for treating and / or preventing pigmentation, such as chloasma, freckles, pathological scars, ichthyosis, moles, age spots, pregnancy spots or dark circles.

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