Biphenyl compound, preparation method therefor, and intermediate, pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are a biphenyl compound, a preparation method therefor, and an intermediate, a pharmaceutical composition and the use thereof. Specifically provided is a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound has good activity and selectivity on a retinoic acid receptor γ agonist, almost has no agonistic activity on retinoic acid receptors α and / or β, and is thus beneficial to reducing systemic side effects. Preferably, the compound has moderately partial agonistic activity, has low skin irritation and few adverse reactions while maintaining its efficacy, and thus has good safety and compliance, such that the problems generally present in existing RAR compounds are effectively solved, and the compound can be used for treating and preventing diseases related to retinoic acid receptor γ.

Description

Biphenyl compounds, preparation methods, intermediates, pharmaceutical compositions and applications thereof

[0001] This application claims priority to Chinese Patent Application No. 2024100337288 filed on January 9, 2024, and Chinese Patent Application No. 2024119438632 filed on December 26, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to a biphenyl compound, a preparation method, an intermediate, a pharmaceutical composition and application thereof. Background Art

[0003] The retinoic acid receptor (RAR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Its primary ligand is retinoic acid. Upon binding to its ligand, retinoic acid, RAR forms a heterodimer with RXR (Retinoid X receptor) and binds to specific genes, thereby controlling their expression. RARs play a crucial role in processes such as cell growth, differentiation, and apoptosis, and participate in physiological and pathological processes such as embryonic development, tissue differentiation, and tumorigenesis. RARs include three subtypes: RARα, RARβ, and RARγ. RARα is widely distributed in most tissues, including the lung, spleen, and gallbladder. RARβ is primarily expressed in the placenta, kidney, heart, and nervous system. RARγ is primarily expressed in the skin, epithelium, and cartilage.

[0004] Synthetic or endogenous retinoic acid (vitamin A) substances can indirectly regulate keratin formation by binding to and activating RARγ in skin tissue to regulate gene transcription and expression in the suprabasal cells, promoting normal keratinization of the epidermis and inhibiting excessive keratin proliferation. Clinically, existing retinoic acid substances such as tretinoin, isotretinoin, acitretin, acitretin ester, aromatic retinoids, aromatic retinoid ethyl esters, adapalene, and tazarotene are used to treat psoriasis, skin keratinization diseases, eczema, acne, etc. However, because these retinoic acid drugs are RAR non-selective drugs and can bind to receptors such as RARα, RARβ, RARγ, and RXR, while promoting cell growth and metabolism to exert therapeutic effects, they also cause various systemic side effects.

[0005] Since RARγ is mainly expressed in the skin, highly selective RARγ agonists have become a research hotspot in recent years. Thoreau et al. reported RARγ selective agonists such as compound 10Y having the following structure in patent US8362082B2.

[0006] Although these compounds can modestly improve selectivity relative to RARα and RARβ, according to literature reports and research, they have some agonistic activity against RARα and / or RARβ, and pose the risk of systemic or other tissue side effects. Furthermore, existing RARγ selective agonist compounds exhibit a full agonist effect on RARγ similar to retinoic acid, but carry the risk of adverse reactions caused by full activation. These compounds are highly irritating to the skin, with adverse reactions such as severe erythema, scaling, and stinging upon topical application. Therefore, there is a need to develop novel RARγ selective agonists with greater selectivity and / or reduced risk of overactivation and / or low irritation. Summary of the Invention

[0007] The present invention provides a biphenyl compound, preparation method, intermediate, pharmaceutical composition, and application thereof. These compounds exhibit good retinoic acid receptor γ agonist activity and retinoic acid receptor γ selectivity, with little agonist activity toward retinoic acid receptor α and / or retinoic acid receptor β, thus reducing systemic side effects. Furthermore, they exhibit moderate partial agonist activity, maintain efficacy, exhibit minimal skin irritation, exhibit few adverse reactions, and exhibit excellent safety and compliance.

[0008] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0009] A is a 6-10 membered arylene group or a 5-6 membered heteroarylene group; the 5-6 membered heteroarylene group has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0010] Y is -NR 1 -or-CR 1 R'-;

[0011] R 1 H or C 1-6 alkyl;

[0012] R' is H or C 1-6 Alkyl;

[0013] R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring or C 3-8 Carbocyclic ring; the 3-8 membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O and S; the 3-8 membered heterocyclic ring and C 3-8 The carbocyclic ring is optionally substituted with one or more R 2-1 Replacement; R 2-1 C 1-6 Alkyl, C 1-6 Alkoxy and halogen;

[0014] X is -NR 3 -or-CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0015] R 5 H or C 1-6 Alkyl, one or more R 5a Substituted C 1-6 Alkyl, C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0016] R 5a are independently halogen or hydroxy;

[0017] m is 0, 1, 2, or 3;

[0018] R 6 H or C 1-6 alkyl;

[0019] When Y is -CR 1 When R'- 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring or C 3-8 The 3- to 8-membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O and S.

[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 unmentioned groups are as described in any embodiment of the present invention (hereinafter referred to as "in some embodiments").

[0021] In some embodiments, in A, the 6-10 membered arylene group is a phenylene group or a naphthylene group, for example, a phenylene group.

[0022] In some embodiments, in A, the number of heteroatoms of the 5-6 membered heteroarylene group may be 1, and the heteroatom is preferably N, such as pyridylene, and for example ( The a-end is connected to the phenylene group, and the b-end is connected to the carbonyl group).

[0023] In some embodiments, R 1 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0024] In some embodiments, in R', the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0025] In some embodiments, R 2 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0026] In some embodiments, R 1 and R 2 and the atoms between them together form C 3-8 In the carbon ring, the C 3-8 The carbocyclic ring may be a monocyclic ring, for example, C 4-6 Carbocyclic monocyclic ring, for example cyclopentanecarbocycle (5-membered carbocycle).

[0027] In some embodiments, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocyclic ring, wherein the number of heteroatoms in the 3-8 membered heterocyclic ring may be 1, and the heteroatom is preferably N; and / or the ring may be a monocyclic ring; the 3-8 membered heterocyclic ring is preferably a 4-6 membered heterocyclic ring, and more preferably a 4-6 membered heterocyclic monocyclic ring; for example

[0028] In some embodiments, R 3 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0029] In some embodiments, R 4 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0030] In some embodiments, R 5 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0031] In some embodiments, R 5 In the C 1-6 Alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example ethoxy, n-propoxy or n-butoxy.

[0032] In some embodiments, R5a In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0033] In some embodiments, R 5 In the above, one or more R 5a Substituted C 1-6 Alkyl is an R 5a Substituted C 1-6 Alkyl, such as C substituted with a hydroxyl group 1-6 alkyl.

[0034] In some embodiments, R 5 In the above, one or more R 5a Substituted C 1-6 The alkoxy group may be 5a Substituted C 1-6 Alkoxy, such as C substituted with a hydroxyl group 1-6 Alkoxy, for example

[0035] In some embodiments, R 6 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0036] In some embodiments, R 2-1 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0037] In some embodiments, R 2-1 In the C 1-6 The alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0038] In some embodiments, R 2-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0039] In some embodiments, the plurality is 2 or 3.

[0040] In some embodiments, m is 0, 1 or 2. Preferably, m is 1.

[0041] In some embodiments, A is a 6-10 membered arylene group or a 5-6 membered heteroarylene group; the 5-6 membered heteroarylene group has 1 heteroatom, and the heteroatom is N; preferably, A is a 6-10 membered arylene group; more preferably, A is a phenylene group.

[0042] In some embodiments, Y is -NR 1 -or-CHR1 -; preferably, Y is -NR 1 -.

[0043] In some embodiments, R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring or C 3-8 Carbocyclic ring; the 3-8 membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) or C 3-8 Carbocyclic rings (e.g. C 4-6 carbon ring); the 3-8 membered heterocyclic ring is a monocyclic ring having 1 heteroatom, wherein the heteroatom is N; the C 3-8 The carbocyclic ring is a monocyclic ring; more preferably, R 1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) or C 3-8 Carbocyclic rings (e.g. C 4-6 carbon ring); the 3-8 membered heterocyclic ring is a monocyclic ring having 1 heteroatom, wherein the heteroatom is N; the C 3-8 A carbocycle is a monocyclic ring.

[0044] In some embodiments, X is -CR 3 R 4 -.

[0045] In some embodiments, R 3 C 1-6 alkyl.

[0046] In some embodiments, R 4 C 1-6 alkyl.

[0047] In some embodiments, R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 Alkoxy, preferably, R5 To be an R 5a Substituted C 1-6 Alkoxy.

[0048] In some embodiments, R 5a is fluorine, chlorine, bromine or hydroxyl, preferably, R 5a It is a hydroxyl group.

[0049] In some embodiments, R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably, R 6 For H.

[0050] In some embodiments, when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring or C 3-8 Carbocyclic ring; the 3-8 membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring or C 3-8 Carbocycle; the 3-8 membered heterocycle is a monocyclic ring having 1 heteroatom, wherein the heteroatom is N; the C 3-8 A carbocyclic ring is a single ring (e.g., C 4-6 More preferably, when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form C 3-8 carbon ring; the C 3-8 A carbocycle is a monocyclic ring.

[0051] In some embodiments, when Y is -NR 1 -, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring; the 3-8 membered heterocyclic ring is optionally substituted by one or more R 2-1 Replacement; R 2-1 C 1-6 Alkyl, C 1-6 Alkoxy and halogen; the 3-8 membered heterocyclic ring has 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein at least one of the heteroatoms is N; preferably, when Y is -NR 1 -, R 1 and R 2 and the atoms between them together form a 3-8 membered heterocyclic ring; the 3-8 membered heterocyclic ring is optionally substituted by one or more R2-1 Replacement; R 2-1 C 1-6 Alkyl, C 1-6 Alkoxy and halogen; the 3-8 membered heterocyclic ring is a monocyclic ring with 1 heteroatom, and the heteroatom is N.

[0052] In some embodiments,

[0053] m is 0, 1, or 2;

[0054] A is a 6-10 membered arylene group or a 5-6 membered heteroarylene group; the 5-6 membered heteroarylene group has one heteroatom, and the heteroatom is N;

[0055] Y is -NR 1 -or-CHR 1 -;

[0056] R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) or C 3-8 Carbocyclic rings (e.g. C 4-6 carbon ring); the 3-8 membered heterocycle (e.g., 4-6 membered heterocycle) is a monocyclic ring having 1 heteroatom, wherein the heteroatom is N; the C 3-8 Carbocyclic rings (e.g. C 4-6 Carbocycle) is a monocyclic ring;

[0057] X is -NR 3 -or-CR 3 R 4 -;

[0058] R 3 H or C 1-6 alkyl;

[0059] R 4 H or C 1-6 alkyl;

[0060] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0061] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0062] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0063] When Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form C 3-8 carbon ring; the C 3-8 A carbocyclic ring is a single ring (e.g., C 4-6 carbocyclic monocyclic ring).

[0064] In some embodiments,

[0065] m is 0, 1, or 2;

[0066] A is a 6-10 membered arylene group;

[0067] Y is -NR 1 -;

[0068] R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle); the 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) is a monocyclic ring having one heteroatom, which is N;

[0069] X is -CR 3 R 4 -;

[0070] R 3 H or C 1-6 alkyl;

[0071] R 4 H or C 1-6 alkyl;

[0072] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0073] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0074] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0075] In some embodiments,

[0076] m is 1;

[0077] A is a 6-10 membered arylene group or a 5-6 membered heteroarylene group; the 5-6 membered heteroarylene group has one heteroatom, and the heteroatom is N;

[0078] Y is -NR 1 -or-CHR 1 -;

[0079] R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) or C 3-8 Carbocyclic rings (e.g. C 4-6 carbon ring); the 3-8 membered heterocycle (e.g., 4-6 membered heterocycle) is a monocyclic ring having 1 heteroatom, wherein the heteroatom is N; the C 3-8 Carbocyclic rings (e.g. C 4-6 Carbocycle) is a monocyclic ring;

[0080] X is -NR 3 -or-CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0081] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0082] R 5a is hydroxyl group;

[0083] R 6 is H;

[0084] When Y is -CHR 1- When R 1 and R 2 and the atoms between them together form C 3-8 Carbocyclic rings (e.g. C 4-6 carbon ring), the C 3-8 Carbocyclic rings (e.g. C 4-6 carbocycle) is a monocyclic ring.

[0085] In some embodiments,

[0086] m is 1;

[0087] A is a 6-10 membered arylene group;

[0088] Y is -NR 1-;

[0089] R 1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle); the 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) is a monocyclic ring having one heteroatom, which is N;

[0090] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0091] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0092] R 5a is hydroxyl group;

[0093] R 6 For H.

[0094] In some embodiments, the compound represented by Formula I may be a compound of Formula I-1 or a compound of Formula I-2:

[0095] (For example );

[0096] n is 0, 1, 2 or 3; m, A, R 1 、R 2 , X, R 5 and R 6 The definition of is as mentioned above.

[0097] In some embodiments, in the compound of formula I-1,

[0098] m is 0, 1, or 2;

[0099] A is a 6-10 membered arylene group;

[0100] R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle); the 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) is a monocyclic ring having one heteroatom, which is N;

[0101] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0102] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0103] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0104] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0105] In some embodiments, in the compound of formula I-1,

[0106] m is 1; A is a phenylene group;

[0107] R 1 C 1-6 Alkyl; R 2 C 1-6 Alkyl or H; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle); the 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) is a monocyclic ring having one heteroatom, which is N;

[0108] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0109] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0110] R 5a is hydroxyl group;

[0111] R 6 For H.

[0112] In some embodiments, in the compound of formula I-2 (eg, compounds I-2-a, I-2-b),

[0113] n is 0, 1, or 2;

[0114] m is 0, 1, or 2;

[0115] A is a 6-10 membered arylene group or a 5-6 membered heteroarylene group; the 5-6 membered heteroarylene group has one heteroatom, and the heteroatom is N;

[0116] X is -NR 3 -or-CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0117] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0118] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0119] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0120] In some embodiments, in the compound of formula I-2 (eg, compounds I-2-a, I-2-b),

[0121] n is 1; m is 1; A is phenylene;

[0122] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0123] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0124] R 5a is hydroxyl group;

[0125] R 6 For H.

[0126] In some embodiments, the compound represented by Formula I may be a compound of Formula I-1-a, a compound of Formula I-1-b, or a compound of Formula I-1-c: (For example );

[0127] t is 0, 1, 2, or 3; R 1-1 C 1-6 Alkyl; m, A, R 2 , X, R 5 and R 6 The definition of R is as mentioned above. 1-1 In the C 1- 6-Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0128] In some embodiments, in the compound of formula I-1-a,

[0129] m is 0, 1, or 2;

[0130] A is a 6-10 membered arylene group;

[0131] R 2 H or C 1-6 alkyl;

[0132] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0133] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0134] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0135] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0136] In some embodiments, in the compound of formula I-1-a,

[0137] m is 1; A is a phenylene group;

[0138] R 2 H or C 1-6 Alkyl; X is -CR3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0139] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0140] R 5a is hydroxyl group;

[0141] R 6 For H.

[0142] In some embodiments, in the compound of formula I-1-b,

[0143] m is 0, 1, or 2;

[0144] A is a 6-10 membered arylene group;

[0145] R 1-1 C 1-6 alkyl;

[0146] R 2 H or C 1-6 alkyl

[0147] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0148] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0149] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0150] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0151] In some embodiments, in the compound of formula I-1-b,

[0152] m is 1; A is a phenylene group;

[0153] R 1-1 C 1-6 alkyl;

[0154] R 2 H or C 1-6 alkyl;

[0155] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0156] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0157] R 5a is hydroxyl group;

[0158] R 6 For H.

[0159] In some embodiments, in the compound of formula I-1-c (eg, compounds I-1-c-1, I-1-c-2),

[0160] t is 0, 1, or 2;

[0161] m is 0, 1, or 2;

[0162] A is a 6-10 membered arylene group;

[0163] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0164] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 alkoxy;

[0165] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0166] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0167] In some embodiments, in the compound of formula I-1-c (eg, compounds I-1-c-1, I-1-c-2),

[0168] t is 1 or 2; m is 0 or 1; A is phenylene;

[0169] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0170] R 5 For one or more R 5a Substituted C 1-6 alkoxy;

[0171] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0172] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0173] In some embodiments, in the compound of formula I-1-c (eg, compounds I-1-c-1, I-1-c-2),

[0174] t is 1; m is 1; A is phenylene;

[0175] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0176] R 5 To be an R 5a Substituted C 1-6 alkoxy;

[0177] R 5a is hydroxyl group;

[0178] R 6 For H.

[0179] In some embodiments, the compound represented by Formula I may be a compound of Formula I-1-1 or a compound of Formula I-2-1:

[0180] (For example )

[0181] n is 0, 1, 2 or 3; A, R 1 、R 2 and X are defined as above.

[0182] In some embodiments, in the compound of formula I-1-1,

[0183] A is a 6-10 membered arylene group;

[0184] R 1 H or C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle); the 3-8 membered heterocycle (e.g., a 4-6 membered heterocycle) is a monocyclic ring having one heteroatom, which is N;

[0185] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl.

[0186] In some embodiments, in the compound of formula I-1-1,

[0187] A is phenylene;

[0188] R 1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3-8 membered heterocyclic ring; the 3-8 membered heterocyclic ring (e.g., a 4-6 membered heterocyclic ring) is a monocyclic ring having one heteroatom, which is N;

[0189] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl.

[0190] In some embodiments, in the compound of formula I-2-1 (eg, I-2-1-a, I-2-1-b),

[0191] n is 0, 1 or 2; A is a 6-10 membered arylene group;

[0192] X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl.

[0193] In some embodiments, in the compound of formula I-2-1 (eg, I-2-1-a, I-2-1-b),

[0194] n is 1; A is phenylene;

[0195] X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl.

[0196] In some embodiments, the compound represented by Formula I may be a compound of Formula I-1-1-1, a compound of Formula I-1-1-2, or a compound of Formula I-1-1-3: (For example );

[0197] t is 0, 1, 2, or 3; R 1-1 C 1-6 Alkyl; A, R 2 and X are defined as above. 1-1 In the C 1-6 Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0198] In some embodiments, in the compound of formula I-1-1-1,

[0199] A is a 6-10 membered arylene group; R 2 H or C 1-6 Alkyl; X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl.

[0200] In some embodiments, in the compound of formula I-1-1-1,

[0201] A is phenylene; R 2 H or C 1-6 Alkyl; X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl.

[0202] In some embodiments, in the compound of formula I-1-1-2,

[0203] A is a 6-10 membered arylene group; R1-1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl.

[0204] In some embodiments, in the compound of formula I-1-1-2,

[0205] A is phenylene; R 1-1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl.

[0206] In some embodiments, in the compound of formula I-1-1-3 (eg, I-1-1-3-a, I-1-1-3-b),

[0207] t is 0, 1 or 2; A is a 6-10 membered arylene group; X is -CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl.

[0208] In some embodiments, in the compound of formula I-1-1-3 (eg, I-1-1-3-a, I-1-1-3-b),

[0209] t is 1 or 2; A is phenylene; X is -CR 3 R 4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl.

[0210] In some embodiments, in the compound of formula I-1-1-3 (eg, I-1-1-3-a, I-1-1-3-b),

[0211] t is 1; A is phenylene; X is -CR 3 R 4 -;R 3 C1-6 Alkyl; R 4 C 1-6 alkyl.

[0212] In some embodiments, the compound represented by Formula I can be a compound of Formula IA, a compound of Formula IB, a compound of Formula IC, or a compound of Formula ID

[0213] (For example ) (For example (correspond )or );

[0214] R 1-1 C 1-6 Alkyl; X, R 2 、R 3 、R 4 、R 5 and R 6 The definition of R is as mentioned above. 1-1 In the C 1-6 Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl.

[0215] In some embodiments, in the IA compound,

[0216] R 2 H or C 1-6 Alkyl; R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0217] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 Alkoxy; R 5a is fluorine, chlorine, bromine or hydroxyl;

[0218] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0219] In some embodiments, in the IA compound,

[0220] R 2 H or C 1-6 Alkyl; R 3 C 1-6 Alkyl; R 4 C 1-6alkyl;

[0221] R 5 To be an R 5a Substituted C 1-6 Alkoxy; R 5a is hydroxyl; R 6 For H.

[0222] In some embodiments, in the compound of formula IB (eg, IB-1, IB-2),

[0223] R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0224] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 Alkoxy; R 5a is fluorine, chlorine, bromine or hydroxyl;

[0225] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0226] In some embodiments, in the compound of formula IB (eg, IB-1, IB-2),

[0227] R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0228] R 5 To be an R 5a Substituted C 1-6 Alkoxy; R 5a is hydroxyl; R 6 For H.

[0229] In some embodiments, in the compound of formula IC,

[0230] R 1-1 C 1-6 alkyl;

[0231] R 2 H or C 1-6 Alkyl; R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0232] R5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 Alkoxy; R 5a is fluorine, chlorine, bromine or hydroxyl;

[0233] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0234] In some embodiments, in the compound of formula IC,

[0235] R 1-1 C 1-6 Alkyl; R 2 H or C 1-6 Alkyl; R 3 C 1-6 Alkyl; R 4 C 1-6 alkyl;

[0236] R 5 To be an R 5a Substituted C 1-6 Alkoxy; R 5a is hydroxyl; R 6 For H.

[0237] In some embodiments, in the compound of formula ID (eg, ID-1, ID-2),

[0238] X is -NR 3 -or-CR 3 R 4 -;R 3 H or C 1-6 Alkyl; R 4 H or C 1-6 alkyl;

[0239] R 5 C 1-6 Alkoxy or one or more R 5a Substituted C 1-6 Alkoxy; R 5a is fluorine, chlorine, bromine or hydroxyl;

[0240] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0241] In some embodiments, in the compound of formula ID (eg, ID-1, ID-2),

[0242] X is -CR 3 R4 -;R 3 C 1-6 Alkyl; R 4 C 1-6 Alkyl; R 5 To be an R 5a Substituted C 1-6 Alkoxy; R 5a is hydroxyl group;

[0243] R 6 For H.

[0244] In some embodiments, for

[0245] In some embodiments, R 6 For hydrogen.

[0246] In some embodiments, R 5 for

[0247] In some embodiments, for ( The a-end is connected to the phenylene group, and the b-end is connected to the carbonyl group).

[0248] In some embodiments, the compound represented by Formula I is any of the following compounds:

[0249] On the other hand, the present invention also provides a pharmaceutical composition comprising (i) the compound represented by the above formula I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0250] 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 pharmaceutical composition as a medicine.

[0251] 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 pharmaceutical composition for use as a medicine.

[0252] 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 pharmaceutical composition in the preparation of a drug.

[0253] 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 pharmaceutical composition as a retinoic acid receptor (eg, retinoic acid receptor γ) agonist.

[0254] 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 pharmaceutical composition as a partial agonist of a retinoic acid receptor (eg, retinoic acid receptor γ).

[0255] 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 pharmaceutical composition, which is a retinoic acid receptor (eg, retinoic acid receptor γ) agonist.

[0256] 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 pharmaceutical composition, which is a partial agonist of a retinoic acid receptor (eg, retinoic acid receptor γ).

[0257] 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 pharmaceutical composition in the preparation of a retinoic acid receptor (eg, retinoic acid receptor γ) agonist.

[0258] 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 pharmaceutical composition described above, in the preparation of a retinoic acid receptor (eg, retinoic acid receptor γ) partial agonist.

[0259] 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 pharmaceutical composition for treating and / or preventing a disease.

[0260] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0261] 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 pharmaceutical composition for treating and / or preventing a disease.

[0262] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0263] 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 pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease.

[0264] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0265] On the other hand, the present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use as a drug for treating and / or preventing diseases related to retinoic acid receptors (such as retinoic acid receptor γ).

[0266] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0267] 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 pharmaceutical composition for treating and / or preventing diseases associated with retinoic acid receptors (eg, retinoic acid receptor γ).

[0268] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0269] 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 pharmaceutical composition described above in the preparation of a drug for treating and / or preventing diseases associated with retinoic acid receptors (eg, retinoic acid receptor γ).

[0270] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0271] On the other hand, the present invention also provides a method for treating and / or preventing diseases related to retinoic acid receptors (e.g., retinoic acid receptor γ), which comprises administering the compound of formula I or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a subject in need of such treatment.

[0272] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, keratinization disorders, pigmentation, or dry eyes.

[0273] On the other hand, the present invention also provides a compound represented by formula II or a salt thereof

[0274] R 6’ C 1-6 Alkyl; R 7 C 1-6 Alkyl; A, R 2 , X and Y are defined as above.

[0275] In some embodiments, R 7 In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0276] In some embodiments, R 6’ In the C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example ethyl.

[0277] In some embodiments, the compound represented by Formula II is any of the following compounds:

[0278] On the other hand, the present invention also provides a method for preparing the compound shown in Formula I, comprising the following steps:

[0279] In an organic solvent (e.g., an alcohol solvent, also such as methanol), in the presence of a base (e.g., an alkali metal hydroxide, also such as sodium hydroxide, also such as a 1 mol / L sodium hydroxide aqueous solution), the compound represented by Formula II undergoes a hydrolysis reaction as shown below (e.g., 50-70° C., also such as 60° C.) to obtain a compound represented by Formula I;

[0280] R 6 H; R 5 for R 5 Connected to the opposite position of A; m is 1; A, X, Y, R 2 、R 6’ and R 7 The definition of is as mentioned above.

[0281] In some embodiments, the method for preparing the compound of formula I further comprises the following steps: in the presence of a catalyst (e.g., a palladium catalyst, also such as Pd(dppf)Cl2) and an alkali metal halide (e.g., an alkali metal fluoride, also such as KF), in a solvent (e.g., a mixed solvent of water and a cyclic ether solvent, also such as a mixed solvent of water and dioxane, and also such as a volume ratio of dioxane to water of 20:3 or 4:1), the compound represented by formula III and the compound represented by formula IV undergo a coupling reaction as shown in the following formula (e.g., 100-120° C., also such as 110° C.) to obtain a compound represented by formula II;

[0282] R 8 Boron ester group R 9 is halogen (e.g., bromine); A, X, Y, R 2 、R 6’ and R 7 The definition of is as mentioned above.

[0283] On the other hand, the present invention also provides a method for preparing a compound as shown in Formula II, comprising the following steps: in the presence of a catalyst (e.g., a palladium catalyst, also such as Pd(dppf)Cl2) and an alkali metal halide (e.g., an alkali metal fluoride, also such as KF), in a solvent (e.g., a mixed solvent of water and a cyclic ether solvent, also such as a mixed solvent of water and dioxane, and also such as a volume ratio of dioxane to water of 20:3 or 4:1), the compound shown in Formula III and the compound shown in Formula IV undergo a coupling reaction as shown in the following formula (e.g., 100-120°C, also such as 110°C) to obtain a compound shown in Formula II;

[0284] R 8 Boron ester group R 9 is halogen (e.g., bromine); A, X, Y, R 2 、R 6’ and R 7 The definition of is as mentioned above.

[0285] The positive progress of the present invention is that the biphenyl compound of the present invention (specifically the compound represented by Formula I or a pharmaceutically acceptable salt thereof) has good retinoic acid receptor γ agonist activity and high retinoic acid receptor γ selectivity, and has almost no agonist activity on retinoic acid receptors α and / or β, which is beneficial for reducing systemic side effects; more preferably, it has moderate partial agonist activity, while maintaining efficacy, with low skin irritation and few adverse reactions, excellent safety and compliance, and can be used to treat and prevent diseases related to retinoic acid receptor γ.

[0286] Definition of terms

[0287] Unless otherwise specified, the terms used in the present invention 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.

[0288] 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.

[0289] In the present invention, the term "plurality" refers to a natural number greater than 2, such as 2, 3, 4 or 5.

[0290] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0291] In the present invention, the term "hydroxyl group" means -OH.

[0292] 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.

[0293] In the present invention, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above.

[0294] In the present invention, the term "carbocycle" refers to a saturated monocyclic or polycyclic ring having a specified number of carbon atoms. 3-8 "Carbocycle" refers to a saturated monocyclic or polycyclic ring having 3 to 8 (e.g., 3, 4, 5, 6, 7 or 8) ring carbon atoms; preferably, C 3-8A carbocycle is a saturated monocyclic ring having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring carbon atoms, such as a C3, C4, C5, or C6 saturated monocyclic ring, specific examples of which include, but are not limited to, cyclopropylcarbocycle (three-membered carbocycle), cyclobutylcarbocycle (four-membered carbocycle), cyclopentylcarbocycle (five-membered carbocycle), cyclohexylcarbocycle (six-membered carbocycle), etc. Polycyclic rings may be spirocyclic, fused, or bridged.

[0295] In the present invention, the term "heterocycle" refers to a saturated ring 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), including monocyclic or polycyclic rings. Polycyclic rings may be spirocyclic, fused, or bridged.

[0296] In the present invention, the term "arylene" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) is a cyclic, unsaturated, divalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., two or three); when polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. Arylene rings include, but are not limited to, phenylene and naphthylene.

[0297] In the present invention, the term "heteroarylene" refers to a cyclic, unsaturated divalent group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic; when it is monocyclic, it may be a pyridylene group, for example In the case of polycyclic rings, two atoms and one bond are shared between the single rings, and each ring is aromatic; polycyclic rings refer to a heteroaromatic ring and one or more aromatic rings or heteroaromatic rings forming a fused ring.

[0298] As used herein, the term "substituted by" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Furthermore, when a group is substituted by one or more of the 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 substitute at every substitutable position of the substituted group. When more than one position in a given structure is substitutable by one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0299] When a group is listed without specifying that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-6 When there is no limitation of "unsubstituted or substituted" before "alkyl", it only refers to "C 1-6 Alkyl" itself or "unsubstituted C 1-6 alkyl".

[0300] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "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.

[0301] In the present invention, the term "optionally substituted by..." means both "substituted by..." and "unsubstituted."

[0302] Combinations of substituents and / or variations thereof are permissible within the present invention only if such combinations result in reasonable compounds.

[0303] 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.

[0304] As used herein, the term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat or prevent the diseases or conditions described herein. The amount of a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient being treated, but can be adjusted as needed by those skilled in the art. Doses outside this range may also be used depending on the dosage form and the severity of the disease.

[0305] 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.

[0306] The reagents and raw materials used in the present invention are commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0307] Figure 1 shows the animal visual observation scores during the efficacy test in the New Zealand rabbit ear acne model. DETAILED DESCRIPTION

[0308] 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.

[0309] General preparation method:

[0310] (1) In the presence of a catalyst (e.g., a palladium catalyst, also such as Pd(dppf)Cl2) and an alkali metal halide (e.g., an alkali metal fluoride, also such as KF), in a solvent (e.g., a mixed solvent of water and a cyclic ether solvent, also such as a mixed solvent of water and dioxane, and also such as a dioxane to water volume ratio of 20:3 or 4:1), the compound represented by Formula III and the compound represented by Formula IV or Formula IV' undergo a coupling reaction as shown below (e.g., 100-120°C, also such as 110°C) to obtain a compound represented by Formula II or Formula II';

[0311] R 8 Boron ester group R 9 is halogen (e.g., bromine); A, X, Y, R 2 、R 6’ and R 7 The definition of is as mentioned above;

[0312] (2) In an organic solvent (e.g., an alcohol solvent, also e.g., methanol), in the presence of a base (e.g., an alkali metal hydroxide, also e.g., sodium hydroxide, also e.g., a 1 mol / L sodium hydroxide aqueous solution), the compound represented by Formula II or the compound represented by Formula II′ undergoes a hydrolysis reaction as shown below (e.g., at 50-70° C., also e.g., at 60° C.) to obtain the compound represented by Formula I;

[0313] R 6 is H; when the reactant is II, R 5 for When m is 1, and the reactant is II', R 5 for m is 1; R 5 Connected to the position opposite to A; A, X, Y, R 2 、R 6 ' and R 7 The definition of is as mentioned above.

[0314] Example 1 Synthesis of Compound Y-001:

[0315] Step 1: Synthesis of intermediate 1-2

[0316] Compound 1-1 (22 g, 127.89 mmol, 1 eq) was dissolved in 300 mL of dichloromethane, and triethylamine (31.99 g, 316.12 mmol, 2.47 eq) and 1-1a (21.23 g, 179.05 mmol, 1.4 eq) were added sequentially. The reaction system was stirred at 25°C for 12 hours. LCMS monitoring showed that the starting material was completely consumed and the main product was generated. TLC (petroleum ether / ethyl acetate = 10:1) monitored that the starting material was completely consumed and a new product spot was generated. 500 mL of water was added to the reaction solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (250 mL*2). After the organic phases were combined, they were washed with saturated brine (100 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: 120 g Silica Flash Column; mobile phase gradient: 0-10% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 1-2 (24 g, yield: 73.85%). LCMS (ESI): m / z calculated value C 11 H 13 BrNO + .[M+H] + =254.02,256.02, measured value [M+H] + =253.9,255.9. 1 H NMR (400MHz, CDCl3) δppm 7.38-7.47(m,4H),7.20(br s,1H),5.70(s,1H),2.22(s,3H),1.90(s,3H).

[0317] Step 2: Synthesis of Intermediates 1-3

[0318] Intermediate 1-2 (23 g, 90.51 mmol, 1 eq) was dissolved in 500 mL of dichloromethane, and aluminum chloride (72.41 g, 543.04 mmol, 6 eq) was added. After the reaction system was stirred at 0 ° C for 1 hour, the temperature was slowly raised to 25 ° C and stirring was continued for 1 hour. LCMS monitored that the raw material was completely consumed and the main product was generated. 1 L of water was added to the reaction solution to quench. The organic phase was separated and the aqueous phase was extracted with dichloromethane (500 mL * 2). After the organic phases were combined, they were washed with saturated sodium bicarbonate solution (300 mL * 2), washed with saturated brine (300 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 rapid liquid preparative chromatograph; column model: 120 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-3 as a white solid (21 g, yield: 91.30%). LCMS (ESI): m / z calculated value C 11 H 13 BrNO + .[M+H] + =254.02,256.02, measured value [M+H] + =253.9,255.9. 1 H NMR (400MHz, CDCl3) δppm 9.34 (br s, 1H), 7.40 (d, J = 1.98Hz, 1H), 7.29 (dd, J = 8.36, 2.20Hz, 1H), 6.75 (d, J = 8.36Hz, 1H), 2.48 (s, 2H), 1.33 (s, 6H).

[0319] Step 3: Synthesis of Intermediates 1-4

[0320] Intermediate 1-3 (6 g, 23.61 mmol, 1 eq) was dissolved in 60 mL of toluene and reacted at 0 ° C. Borane dimethyl sulfide solution (10 M, 3.07 mL, 1.3 eq) was added dropwise. After the addition was complete, the reaction system was slowly warmed to room temperature and further heated to 120 ° C and heated under reflux for 5 hours. TLC (petroleum ether: ethyl acetate = 1:1) monitored the complete consumption of the starting material. LCMS monitored the formation of the main product. The reaction system was quenched with methanol, and saturated sodium bicarbonate solution (200 mL) was added. The mixture was extracted with dichloromethane (500 mL * 2). After the organic phases were combined, they were washed with saturated brine (100 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: 40 g Silica Flash Column; mobile phase gradient: 0-2% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 1-4 as a light yellow oil (5 g, yield: 88.19%). LCMS (ESI): m / z calculated value C 11 H 15 BrN + .[M+H] + =240.04,242.04, measured value [M+H] + =239.9,241.9. 1H NMR (400MHz, CDCl3) δppm 7.25(d,J=2.20Hz,1H),7.02(dd,J=8.58,2.42Hz,1H),6.35(d,J=8.58Hz,1H ), 6.35 (d, J = 8.58Hz, 1H), 3.25-3.35 (m, 2H), 1.66-1.76 (m, 2H), 1.28 (s, 6H).

[0321] Step 4: Synthesis of Intermediates 1-5

[0322] Intermediate 1-4 (4.5 g, 18.74 mmol, 1 eq) and sodium bicarbonate (2.72 g, 32.35 mmol, 1.73 eq) were dissolved in 8 mL of water, and dimethyl sulfate (4.82 g, 38.23 mmol, 2.04 eq) was added. The reaction system was stirred at 10 ° C for 1 hour, then slowly heated to 50 ° C and continued to stir for 1 hour. The reaction solution was diluted with 50 mL of water and extracted with dichloromethane (50 mL * 2). After the organic phases were combined, they were washed with saturated brine (30 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 rapid liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-2% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 1-5 as a light yellow oil (4.2 g, yield: 88.19%). LCMS (ESI): m / z calculated value C 12 H 17 BrN + .[M+H] + =254.05,256.05, measured value [M+H] + =253.9,255.9. 1 H NMR (400MHz, CDCl3) δppm 7.24(d,J=2.38Hz,1H),7.14(dd,J=8.76,2.38Hz,1H),6.44(d,J=8.76Hz,1H),3.19-3.26(m,2H),2.88(s,3H),1.69-1.82(m,2H),1.27(s,6H).

[0323] Step 5: Synthesis of Intermediates 1-6

[0324] Intermediate 1-5 (1 g, 3.93 mmol, 1 eq) and compound 1-5a (1.10 g, 4.33 mmol, 1.1 eq) were dissolved in 10 mL of dioxane, and potassium acetate (772.25 mg, 7.87 mmol, 2 eq) and Pd(dppf)Cl2 (287.89 mg, 393.44 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at 100°C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) confirmed complete consumption of the starting material and the formation of the main product. The reaction solution was diluted with 20 mL of ethyl acetate and 20 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phases 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 purified by silica gel column chromatography (ISCO fast liquid preparative chromatography; column type: 40g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 1-6 as a light yellow oil (927 mg, yield: 78.3%). LCMS (ESI): m / z calculated value C 18 H 29 BNO2 + .[M+H] + =302.23, measured value [M+H] + =302.3.

[0325] Step 6: Synthesis of Intermediates 1-7

[0326] Intermediate I-6a (1.1 g, 2.80 mmol, 1 eq) (preparation method reference patent CN113501758A, 2021) and intermediate I-6 (842.65 mg, 2.80 mmol, 1 eq) were dissolved in 1.5 mL of water and 10 mL of dioxane, and Pd(dppf)Cl2 (102.34 mg, 139.87 μmol, 0.05 eq) and potassium fluoride (487.55 mg, 8.39 mmol, 3 eq) were added. The reaction system was stirred at 110°C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the main product was produced. The reaction solution was diluted with 60 mL of ethyl acetate and 20 mL of water. The organic phase was washed with saturated ammonium chloride solution (20 mL * 2), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (ISCO rapid liquid preparative chromatography; column model: 40 g Silica Flash Column; mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-7 as a light yellow oil (1.1 g, yield: 78.39%). LCMS (ESI): m / z calculated value C 31 H 36 NO5 + .[M+H] + =502.26, measured value [M+H] + =502.2.

[0327] Step 7: Synthesis of Compound Y-001

[0328] Intermediate 1-7 (1.1 g, 2.19 mmol, 1 eq) was dissolved in 50 mL of methanol and an aqueous sodium hydroxide solution (1 M, 8.77 mL, 4 eq) was added. The reaction system was stirred at 60 ° C for 3 hours. LCMS monitored that the raw material was completely consumed and the main product was generated. The reaction system was adjusted to pH 7 with 1 M hydrochloric acid and extracted with ethyl acetate (50 mL * 2). After the organic phases were combined, washed with brine (30 mL), 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 rapid liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare compound Y-001 as a white solid (470 mg, yield: 46.2%, purity: 93%). LCMS (ESI): m / z calculated value C 27 H 30 NO4 + .[M+H] + =432.22, measured value [M+H] + =432.2. 1 H NMR(400MHz,DMSO-d6)δppm 7.98(d,J=8.3Hz,2H),7.79(d,J=8.3Hz,2H),7.60-7.50(m,3H),7.27(dd,J=2.0,8.6Hz,1H),7.16(d,J=8.7Hz,1H),6.60(d,J=8.6Hz, 1H), 4.80 (t, J = 5.1Hz, 1H), 4.14-4.01 (m, 2H), 3.73 (q, J = 5.0Hz, 2H), 3.24-3.19 (m, 2H), 2.88 (s, 3H), 1.81-1.67 (m, 2H), 1.27 (s, 6H).

[0329] Example 2 Synthesis of Compound Y-002

[0330] Step 1 Synthesis of Intermediate 2-2

[0331] Intermediate 2-1 (7 g, 30.96 mmol, 1 eq) and intermediate 2-1a (20.16 g, 154.79 mmol, 5 eq) were dissolved in 150 mL of acetonitrile, and lithium perchlorate (6.45 g, 60.63 mmol, 1.96 eq) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (21.08 g, 92.87 mmol, 3 eq) were added. The reaction system was stirred at -40°C for 1 hour. TLC (petroleum ether / ethyl acetate = 7:1) confirmed complete reaction of the starting materials and the formation of the main product. The reaction solution was quenched with saturated aqueous sodium sulfite (20 mL), and 30 mL of ethyl acetate and 30 mL of water were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (ISCO rapid liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 2-2 as a colorless oil (4.4 g, yield: 50.37%). LCMS (ESI): m / z calculated value C 13 H 17 BrNO + .[M+H] + =282.05, 284.05, measured value [M+H] + =282.0,284.0.

[0332] Step 2 Synthesis of Intermediate 2-3

[0333] Intermediate 2-2 (1.4 g, 4.96 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, and intermediate 2-2a (3.90 g, 10.92 mmol, 2.2 eq) and potassium tert-butoxide (1.11 g, 9.92 mmol, 2 eq) were added. The reaction system was stirred at 70 ° C for 1 hour. TLC (petroleum ether / ethyl acetate = 10:1) monitored the complete reaction of the raw materials. LCMS monitored the formation of products. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO rapid liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 2-3 as a colorless oil (1.1 g, yield: 79.14%). LCMS (ESI): m / z calculated value C 14 H 19 BrN + .[M+H] + =280.07,282.07, measured value [M+H] + =280.1,282.1. 1 H NMR (400MHz, CDCl3) δppm 7.34-7.29(m,2H),6.47(d,J=9.0Hz,2H),4.86(s,1H),4.77(s,1H),3.95-3.77(m,1H),3.43-3.35(m,1H),3.19-3.10(m,1H),2.44(br d,J=14.3Hz,1H),2.13-1.89(m,5H),1.84(s,3H).

[0334] Step 3 Synthesis of Intermediate 2-4

[0335] Intermediate 2-3 (1 g, 3.57 mmol, 1 eq) was dissolved in 10 mL of concentrated sulfuric acid, and the reaction system was stirred at 100 ° C for 4 hours. LCMS monitored the formation of the product. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 ° C. After the addition was complete, the aqueous phase was extracted with ethyl acetate (30 mL * 3). After the organic phases were combined, they were washed with saturated brine (30 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 rapid liquid preparative chromatograph; column model: 20g Silica Flash Column; mobile phase gradient: 0-40% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 2-4 as a white product (870 mg, yield: 87%). LCMS (ESI): m / z calculated value C 14 H 19 BrN + .[M+H] + =280.07,282.07, measured value [M+H] + =280.0,282.0. 1H NMR (400MHz, CDCl3) δppm 7.25(d,J=2.4Hz,1H),7.13(dd,J=2.4,8.7Hz,1H),6.27(d,J=8.6Hz,1H),3.54-3.41(m,1H),3.36-3.27(m,1H),3.25-3.1 5(m,1H),2.18-2.04(m,2H),2.00-1.89(m,1H),1.80(dd,J=3.3,12.7Hz,1H),1.49-1.42(m,1H),1.35(s,4H),1.21(s,3H).

[0336] Step 4 Synthesis of Intermediate 2-5

[0337] Intermediate 2-4 (110 mg, 392.57 μmol, 1 eq) and compound 1-5a (109.66 mg, 431.83 μmol, 1.1 eq) were dissolved in 15 mL of dioxane. Potassium acetate (77.05 mg, 785.15 μmol, 2 eq) and Pd(dppf)Cl2 (28.72 mg, 39.26 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at 100°C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) confirmed complete consumption of the starting material and the formation of the main product. The reaction solution was diluted with 20 mL of ethyl acetate and 20 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (ISCO rapid liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 2-5 as a colorless oil (70 mg, yield: 54.48%). LCMS (ESI): m / z calculated value C 20 H 31 BNO2 + .[M+H] + =328.24, measured value [M+H] + =328.2. 1H NMR (400MHz, CDCl3) δppm 7.64 (s, 1H), 7.55 (d, J = 8.2Hz, 1H), 6.40 (d, J = 8.1Hz, 1H), 3.58-3.49 (m, 1H), 3.43-3.35 (m, 1H), 3.32 -3.24(m,1H),2.17-2.05(m,2H),2.02-1.89(m,1H),1.81(dd,J=3.3,12.6Hz,1H),1.49-1.41(m,4H),1.32(s,13H),1.22(s,3H).

[0338] Step 5 Synthesis of Intermediate 2-6

[0339] Intermediate 1-6a (79 mg, 200.90 μmol, 1 eq) and intermediate 2-5 (65.75 mg, 200.90 μmol, 1 eq) were dissolved in 1 mL of water and 4 mL of dioxane, and Pd(dppf)Cl2 (7.35 mg, 10.05 μmol, 0.05 eq) and potassium fluoride (35.02 mg, 602.70 μmol, 3 eq) were added. The reaction system was stirred at 110°C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the main product was generated. The reaction solution was diluted with 15 mL of ethyl acetate and 10 mL of water. The organic phase was washed with saturated ammonium chloride solution (10 mL*2), washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography (ISCO fast liquid preparative chromatography; column model: 40 g Silica Flash Column; mobile phase gradient: 0-60% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 2-6 as a colorless oil (80 mg, yield: 75.47%). LCMS (ESI): m / z calculated value C 33 H 38 NO5 + .[M+H] + =528.27, measured value [M+H] + =528.2.

[0340] Step 6 Synthesis of Compound Y-002

[0341] Intermediate 2-6 (80 mg, 151.62 μmol, 1 eq) was dissolved in 4 mL of methanol and sodium hydroxide solution (1 M, 758.08 μL, 4 eq) was added. The reaction system was stirred at 60 ° C for 1 hour. LCMS monitored that the raw material was completely consumed and the main product was generated. The reaction system was adjusted to pH 7 with 1 M hydrochloric acid and extracted with ethyl acetate (10 mL * 2). After the organic phases were combined, washed with brine (10 mL), 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 rapid liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare compound Y-002 as a white solid (42 mg, yield: 58.16%, purity: 96%). LCMS (ESI): m / z calculated value C 29 H 32 NO4 + .[M+H] + =458.23, measured value [M+H] + =458.2. 1 H NMR(400MHz,DMSO-d6)δppm 7.99(d,J=8.3Hz,2H),7.79(d,J=8.2Hz,2H),7.61-7.49(m,3H),7.27(dd,J=1.9,8.3Hz,1H),7.19-7.11( m,1H),6.41(d,J=8.5Hz,1H),4.79(t,J=5.1Hz,1H),4.07(t,J=5.2Hz,2H),3.73(q,J=5.1Hz,2H),3.46(br d,J=10.7Hz,2H),3.26-3.16(m,1H),2.17-2.00(m,2H),1.97-1.80(m,2H),1.51-1.39(m,1H),1.38-1.29(m,4H),1.21(s,3H).

[0342] Example 3 Synthesis of Compound Y-003

[0343] Step 1 Synthesis of Intermediate 3-2

[0344] Referring to the synthesis method of step 4 of Example 1, the corresponding raw materials were replaced with intermediate 1-4 and diethyl sulfate as raw materials to prepare intermediate 3-2 as a colorless oil. LCMS (ESI): m / z calculated value C 13 H 19 BrN + .[M+H]+ =268.07, 270.07, measured value [M+H] + =268.0,270.0. 1 H NMR (400MHz, CDCl3) δppm 7.25(d,J=2.42Hz,1H),7.12(dd,J=8.80,2.42Hz,1H),6.48(d,J=8.80Hz,1H),3.35(q,J =7.12Hz,2H),3.24-3.29(m,2H),1.69-1.78(m,2H),1.27(s,6H),1.15(t,J=7.04Hz,3H).

[0345] Step 2 Synthesis of Intermediate 3-3

[0346] Referring to the synthetic method of step 5 of Example 1, the corresponding raw materials were substituted and intermediate 3-2 was used as the raw material to prepare intermediate 3-3 as a colorless oil. LCMS (ESI): m / z calculated value C 19 H 31 BNO2 + .[M+H] + =316.24, measured value [M+H] + =316.2. 1 H NMR (400MHz, CDCl3) δppm 7.62(d,J=1.2Hz,1H),7.52(dd,J=1.4,8.2Hz,1H),6.59(d,J=8.2Hz,1H),3.39(q,J=7.0Hz, 2H), 3.34-3.28 (m, 2H), 1.75-1.70 (m, 2H), 1.32 (s, 12H), 1.30 (s, 6H), 1.15 (t, J = 7.0Hz, 3H).

[0347] Step 3 Synthesis of Compound Y-003

[0348] Referring to the synthetic method of step 6 and step 7 of Example 1, the corresponding raw materials were replaced and intermediate 3-3 was used as the raw material to prepare compound Y-003 as a white solid. LCMS (ESI): m / z calculated value C 28 H 32 NO4 + .[M+H] + =446.23, measured value [M+H] + =446.2. 1H NMR(400MHz,DMSO-d6)δppm 7.99(d,J=8.3Hz,2H),7.80(d,J=8.5Hz,2H),7.60-7.52(m,3H),7.26(dd,J=2.1,8.5Hz,1H),7.19-7.11(m,1H),6.63(d,J=8.7Hz,1H),4.82(br s,1H),4.14-4.06(m,2H),3.75(br s,2H),3.41-3.39(m,2H),3.30-3.24(m,2H),1.76-1.66(m,2H),1.26(s,6H),1.09(t,J=7.0Hz,3H).

[0349] Example 4 Chiral Separation and Preparation of Compounds Y-004 and Y-005

[0350] Compound Y-002 (22 mg) prepared in Example 2 was further separated by chiral SFC using the following chiral preparation conditions: a DAICEL CHIRALPAK AD column (size: 250 mm x 30 mm, particle size: 10 μm), with an isocratic eluent consisting of CO (A): ethanol containing 0.1% aqueous ammonia (B) (A / B = 60 / 40). Compound Y-004 was isolated as the leading peak, a white solid (8.2 mg, yield: 36.52%, ee: 98%).

[0351] LCMS (ESI): m / z calculated value C 29 H 32 NO4 + .[M+H] + =458.23, measured value [M+H] + =458.2.

[0352] 1H NMR(400MHz,CD3OD)δppm 7.96(d,J=8.3Hz,2H),7.60(d,J=8.3Hz,2H),7.49-7.38(m,3H),7.16(dd,J=1.9,8.3 Hz,1H),7.03(d,J=8.5Hz,1H),6.38(d,J=8.5Hz,1H),3.99(t,J=4.9Hz,2H),3.76(t,J =4.9Hz,2H),3.49-3.36(m,1H),3.31-3.23(m,2H),2.10-1.98(m,2H),1.95-1.83(m, 1H), 1.77 (dd, J=3.1, 12.6Hz, 1H), 1.41-1.38 (m, 1H), 1.31-1.28 (m, 4H), 1.17 (s, 3H).

[0353] Compound Y-005 was isolated as a white solid (7.9 mg, yield: 35.19%, ee value: 98%).

[0354] LCMS (ESI): m / z calculated value C 29 H 32 NO4 + .[M+H] + =458.23, measured value [M+H] + =458.2.

[0355] 1 H NMR(400MHz,CD3OD)δppm 8.09(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7.60-7.49(m,3H),7.32-7.24(m,1H ),7.15(d,J=8.5Hz,1H),6.50(d,J=8.3Hz,1H),4.11(t,J=4.9Hz,2H),3.94-3.82( m,2H),3.59-3.48(m,1H),3.42-3.35(m,2H),2.21-2.13(m,2H),2.08-1.95(m,1H) ,1.89(dd,J=3.0,12.6Hz,1H),1.56-1.46(m,1H),1.44-1.40(m,4H),1.29(s,3H).

[0356] Chiral analysis conditions: Instrument: Waters UPCC with PDA detector, chiral column: Chiralpak AD-3 (specifications: 150 mm*4.6 mm, particle size: 3 μm), elution phase: CO2 (A): ethanol containing 0.05% ethylenediamine (B), isocratic (A / B = 60 / 40); flow rate: 2.5 mL / min, column temperature: 35°C; compound Y-004, front peak, retention time: approximately 4.53 minutes; compound Y-005, back peak, retention time: approximately 5.45 minutes (the retention time of the isolated compound was compared with that of product Y-005 obtained by the chiral preparation in Example 5 to confirm the absolute chirality of the isolated compound).

[0357] Example 5 Synthesis of Compound Y-005

[0358] Step 1 Synthesis of Intermediate 5-2

[0359] Compound 5-1 (2 g, 7.07 mmol, 1 eq) was dissolved in 3 mL of DMF, and cesium carbonate (5.76 g, 17.67 mmol, 2.5 eq), cuprous iodide (403.92 mg, 2.12 mmol, 0.3 eq) and compound 5-1a (1.19 g, 7.07 mmol, 1 eq) were added in sequence. The reaction solution was stirred at 80 ° C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the main product was generated. After the reaction system was filtered, the filtrate was diluted with 20 mL of ethyl acetate and washed with saturated ammonium chloride solution (10 mL * 2), 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: 40 g Silica Flash Column; mobile phase gradient: 0-70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 5-2 as a colorless oil (1.3 g, yield: 64.71%). LCMS (ESI): m / z calculated value C 12 H 15 BrNO2 + .[M+H] + =284.03,286.03, measured value [M+H] + =284.0,286.0.

[0360] Step 2 Synthesis of Intermediate 5-3

[0361] Compound 5-2 (1.3 g, 4.58 mmol, 1 eq) was dissolved in 40 mL of acetonitrile, and potassium carbonate (1.90 g, 13.73 mmol, 3 eq) and iodomethane (6.49 g, 45.75 mmol, 2.85 mL, 10 eq) were added. The reaction system was stirred at 30 ° C for 2 hours. TLC (petroleum ether: ethyl acetate = 5:1) monitored the complete consumption of the starting material and the formation of the main product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to a residue, and the residue was purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0-12% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 5-3 as a colorless oil (900 mg, yield: 65.97%). LCMS (ESI): m / z calculated value C 13 H 17 BrNO2 + .[M+H] + =298.04,300.04, measured value [M+H] + =298.0,300.0. 1 H NMR(400MHz,CD3OD)δppm 7.35-7.29(m,2H),6.49(d,J=8.9Hz,2H),4.15(dd,J=3.5,6.5Hz,1H),3.73(s,3H),3.41-3.38(m,1H),3. 16(d,J=8.2Hz,1H),2.78-2.73(m,1H),2.27-2.22(m,1H),2.09-2.06(m,3H),1.91(dd,J=2.9,6.7Hz,1H).

[0362] Step 3 Synthesis of intermediate 5-4

[0363] Compound 5-3 (1.30 g, 4.36 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and a tetrahydrofuran solution of methylmagnesium chloride (3 M, 5.81 mL, 4 eq) was slowly added dropwise at 0 ° C. After the addition was complete, the reaction system was stirred at 0 ° C for 5 hours. LCMS monitored that the raw material was completely consumed and the product was generated. The reaction solution was diluted with 20 mL of water and 10 mL of ethyl acetate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL * 2). After the organic phases were combined, they were 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 rapid liquid preparative chromatograph; column model: 12g Silica Flash Column; mobile phase gradient: 0-56% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 5-4 as a colorless oil (550 mg, yield: 42.30%). LCMS (ESI): m / z calculated value C 14 H 21 BrNO + .[M+H] + =298.08,300.08, measured value [M+H] + =298.1,300.1.

[0364] Step 4 Synthesis of Intermediate 5-5

[0365] Compound 5-4 (550 mg, 1.84 mmol, 1 eq) was dissolved in 10 mL of dichloroethane, and aluminum chloride (491.83 mg, 3.69 mmol, 2 eq) was added. The reaction system was stirred at 30 ° C for 4 hours. LCMS monitored that the raw material was completely consumed and the product was generated. The reaction solution was slowly added dropwise to 15 mL of saturated sodium carbonate aqueous solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mL * 2). After the organic phases were combined, they were 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 rapid liquid preparative chromatograph; column model: 4g Silica Flash Column; mobile phase gradient: 0-3% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to prepare intermediate 5-5 as a colorless oil (140 mg, yield: 27.15%). LCMS (ESI): m / z calculated value C 14 H 19 BrN + .[M+H] + =280.07,282.07, measured value [M+H] + =280.0,282.0.

[0366] Step 5 Synthesis of Compound Y-005

[0367] Referring to the synthetic method of steps 4-6 of Example 2, the corresponding raw materials were substituted and intermediate 5-5 was used as the raw material to prepare compound Y-005 as a white solid. LCMS (ESI): m / z calculated value C 29 H 32 NO4 + .[M+H] + =458.23, measured value [M+H] += 458.2. Chiral analysis conditions: Waters UPCC with PDA detector, Chiralpak AD-3 column (size: 150 mm x 4.6 mm, particle size 3 μm), elution phase: CO2 (A): ethanol containing 0.05% ethylenediamine (B), isocratic gradient (A / B = 60 / 40); flow rate 2.5 mL / min, column temperature 35°C; retention time approximately 5.45 minutes.

[0368] Example 6 Synthesis of Compound Y-006

[0369] Step 1 Synthesis of Intermediate 6-2

[0370] Intermediate 5-1 (2.98 g, 10.55 mmol, 2 eq) and compound 6-1a (810 mg, 5.27 mmol, 1 eq) were dissolved in 10 mL of DMSO, and cesium carbonate (4.30 g, 13.18 mmol, 2.5 eq) and cuprous iodide (301.28 mg, 1.58 mmol, 0.3 eq) were added in sequence. The reaction system was stirred at 100 ° C for 10 hours. LCMS monitoring showed that the starting material was completely consumed and the main product was generated. After the reaction system was filtered, the filtrate was diluted with 30 mL of ethyl acetate and washed with saturated ammonium chloride solution (10 mL * 2), 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: 40 g Silica Flash Column; mobile phase gradient: 0-80% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to prepare intermediate 6-2 as a colorless oil (1.15 g, yield: 80.18%). LCMS (ESI): m / z calculated value C 11 H 15 BrNO2 + .[M+H] + =272.03,274.03, measured value [M+H] + =272.0,274.0.

[0371] Step 2 Synthesis of Intermediate 6-3

[0372] Intermediate 6-2 (400 mg, 1.47 mmol, 1 eq) was dissolved in 5 mL of methanol, and 30% aqueous formaldehyde solution (735.56 mg, 7.35 mmol, 674.82 μL, 5 eq) and sodium cyanoborohydride (461.84 mg, 7.35 mmol, 476.12 μL, 5 eq) were added in sequence. The reaction system was stirred at 25 ° C for 5 hours. LCMS monitoring showed that the raw material was completely consumed and the main 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: 0-100% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 6-3 as a colorless oil (385 mg, yield: 91.52%). LCMS (ESI): m / z calculated value C 12 H 17 BrNO2 + .[M+H] + =286.04,288.04, measured value [M+H] + =286.0,288.0.

[0373] Step 3 Synthesis of intermediate 6-4

[0374] Intermediate 6-3 (240 mg, 838.68 μmol, 1 eq) was dissolved in 40 mL of tetrahydrofuran, and a tetrahydrofuran solution of methylmagnesium chloride (3M, 1.12 mL, 4 eq) was added dropwise. After the addition was complete, the reaction system was stirred at 0°C for 1 hour. LCMS monitored the complete consumption of the starting material and the formation of the product. The reaction solution was diluted with 10 mL of water and 10 mL of ethyl acetate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL*2). After the organic phases were combined, they were 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 rapid 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 6-4 as a colorless oil (200 mg, yield: 83.38%). LCMS (ESI): m / z calculated value C 13 H 21 BrNO + .[M+H] + =286.08,288.08, measured value [M+H] + =286.0,288.0.

[0375] Step 4 Synthesis of Intermediate 6-5

[0376] Compound 6-4 (200 mg, 698.79 μmol, 1 eq) was dissolved in 5 mL of dichloroethane, and aluminum chloride (93.18 mg, 698.79 μmol, 1 eq) was added. The reaction system was stirred at 30 ° C for 4 hours. LCMS monitored that the raw material was completely consumed and the product was generated. The reaction solution was slowly added dropwise to 10 mL of saturated sodium carbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL * 2). After the organic phases were combined, they were 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 rapid liquid preparative chromatograph; column model: 4g Silica Flash Column; mobile phase gradient: 0-5% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to prepare intermediate 6-5 as a colorless oil (160 mg, yield: 85.37%). LCMS (ESI): m / z calculated value C 13 H 19 BrN + .[M+H] + =268.07,270.07, measured value [M+H] + =268.0,270.0. 1 H NMR (400MHz, CD3OD) δppm 7.21 (d, J=2.3Hz, 1H), 7.14 (dd, J=2.4, 8.7Hz, 1H), 6.46 (br d,J=8.8Hz,1H),3.40-3.36(m,1H),2.88(s,3H),1.74-1.70(m,1H),1.61-1.58(m,1H),1.32(s,3H),1.24(br d,J=6.0Hz,3H),1.18(s,3H).

[0377] Step 5 Synthesis of Intermediate 6-6

[0378] Referring to the synthetic method of step 5 of Example 5, the corresponding raw materials were substituted and intermediate 6-5 was used as the raw material to prepare intermediate 6-6 as a colorless oil. LCMS (ESI): m / z calculated value C 19 H 31 BNO2 + .[M+H] + =316.24, measured value [M+H] + =316.2. 1H NMR(400MHz,CD3OD)δppm 7.63-7.50(m,2H),6.58(d,J=8.2Hz,1H),3.54-3.33(m,1H),2.94(s,3H),1.77-1.68 (m,1H),1.62(s,1H),1.39(s,3H),1.32(s,12H),1.25(d,J=6.1Hz,3H),1.19(s,3H).

[0379] Step 5 Synthesis of Compound Y-006

[0380] Referring to the synthesis method of Y-005 in Example 5, the corresponding raw materials were replaced and intermediate 6-6 was used as the raw material to prepare compound Y-006 as a white solid. LCMS (ESI): m / z calculated value C 28 H 32 NO4 + .[M+H] + =446.23, measured value [M+H] + =446.2. 1 H NMR(400MHz,CD3OD)δppm 12.90(br s,1H),7.99(d,J=8.3Hz,2H),7.80(d,J=8.5Hz,2H),7.61-7.54(m,2H),7.49(d,J=2.0Hz,1H),7.28(dd,J=2.0, 8.6Hz,1H),7.16(d,J=9.3Hz,1H),6.63(d,J=8.7Hz,1H),4.80(t,J=5.3Hz,1H),4.07(t,J=5.2Hz,2H),3.73(br d,J=5.2Hz,2H),3.39(br s,1H),2.88(s,3H),1.76(dd,J=4.2,13.2Hz,1H),1.55(dd,J=11.0,13.1Hz,1H),1.32(s,3H),1.23(d,J=6.1Hz,3H),1.19(s,3H).

[0381] Biological Test Example 1

[0382] The agonist activity and selectivity of compounds against RARα, RARβ and RARγ were tested using HEK-293 cell lines transfected with RARα, RARβ and RARγ luciferase reporter genes.

[0383] Experimental steps:

[0384] 1. Cell Culture

[0385] HEK293 cells were cultured in DMEM + 10% FBS medium in a humidified CO2 incubator at 37°C with 5% CO2.

[0386] 2. Plasmid Transfection and Cell Seeding

[0387] Trypsinize HEK293 cells and adjust the HEK293 cell suspension to 200,000 cells per mL (96-well plate: 100 μL / well) in culture medium. Prepare the transfection reagent mixture according to the table below, mix thoroughly, and let it stand at room temperature for 20 minutes.

[0388] Experimental transfection materials

[0389] *Select the corresponding plasmid pBIND-RARα, pBIND-RARβ or pBIND-RARγ according to the test receptor

[0390] Add the prepared transfection reagent mixture to 10 mL of the resuspension buffer adjusted for cell density, mix thoroughly by inverting, and seed each well into a 96-well plate at a volume of 100 μL / well. Incubate the 96-well plate in a humidified incubator at 37°C and 5% CO2 for 24 hours.

[0391] 3. Drug treatment

[0392] Serially dilute the positive control retinoic acid and test compound stock solutions at specific ratios to create a series of 21x compound solutions. Add 5 μL of either the retinoic acid dilution or the test compound dilution to each well (presumably containing 100 μL of cell culture medium). Add 5 μL of 10% DMSO culture medium to the negative control wells (Min wells). Add 5 μL of 6.3 μM retinoic acid (dissolved in culture medium, 10% DMSO, to a final concentration of 300 nM for the Max wells) to the positive control wells. Return the assay plate to the incubator and incubate for 24 hours.

[0393] 4. Luciferase Assay

[0394] The side plates were detected using Promega's Dual-Glo Luciferase Assay System kit, and the Firefly luciferase fluorescence signal and the Renilla luciferase fluorescence signal were read using an EnSpire microplate reader.

[0395] 5. Test results

[0396] 5.1EC 50 value

[0397] Import the data into MS Excel for curve fitting and obtain EC 50 The test results are as follows.

[0398] EC of the agonist activity of RAR series compounds on RARγ, RARα, and RARβ 50 Test results

[0399] Note: When the maximum activation rate is less than 50% of the retinoic acid Max well, the result is expressed as EC 50 >Maximum tested concentration.

[0400] The compounds of the present invention have good agonist activity and selectivity for RARγ, almost no agonist activity for RARα and / or RARβ, and few systemic or other tissue side effects. Compared with existing RARγ selective agonists (such as 10Y compounds), the agonist activity for RARα and RARβ is weaker and the selectivity is better.

[0401] 5.2E max value

[0402] The activation rate at each concentration was calculated by formula (1), and the maximum agonist activity E of the compound on RARγ was obtained by curve fitting. max (%).

[0403] Formula (1)

[0404] The compounds Y-004, Y-005 and Y-006 of the present invention exhibited RARγ partial agonist activity (E max The values ​​relative to retinoic acid are all less than 75%). Compared with existing RARγ full agonists (such as retinoic acid, 10Y compounds, etc.), this type of compound is expected to reduce the related adverse reactions caused by complete activation of RARγ.

[0405] Biological Test Example 2

[0406] Study on the skin irritation of topical drug administration to miniature pigs

[0407] Experimental Design:

[0408] The local skin irritation of the test substance was evaluated by the miniature pig self-comparison method. The back skin of three female miniature pigs was divided into two areas, the front and back, and the drug administration area of ​​each area was approximately 300cm 2, 4 groups of test substances were cross-evaluated in 4 cycles, and one test substance was administered to the skin once a day for 3 consecutive days. In order to avoid unexpected interference, a 2-day washout period was set between the administration of groups G2 and G3 and between the administration of groups G3 and G4. The test substances were G1 blank cream group, G2 Y-004 cream 0.05% group (each gram of cream contained 500 μg of the active ingredient compound Y-004 of the present invention, that is, the specification was 500 μg / g), G3 10Y cream 0.05% group (each gram of cream contained 500 μg of the active ingredient compound 10Y, that is, the specification was 500 μg / g), G4 10Y cream 0.025% group (each gram of cream contained 250 μg of the active ingredient compound 10Y, that is, the specification was 250 μg / g). The composition of the creams in groups G2, G3, and G4 was the same as that of the blank cream group except for the active ingredient. The structure of compound 10Y is as follows

[0409] Before the start of the trial, shave the marked dosing area, ensuring thorough and non-invasive removal. The shaved area should extend beyond the marked area. Mark the dosing area with a marker. Before dosing, clean the area with soapy water and purified water, then wipe it clean with dry gauze.

[0410] Adhere a quantitative amount of the test substance (1 ml / kg) to the dosing site. Then, use an applicator (e.g., a triangular glass rod) to evenly apply the preparation to the shaved, marked dosing site on the animal's skin. After the dosing preparation is evenly applied, cover it with elastic, breathable cotton gauze to ensure that the gauze is fixed at the dosing site and the skin surface is breathable. Considering that the animal's tearing, pulling, and other actions may affect the effective coverage of the drug, use a mesh elastic bandage to secure the area to prevent the animal's resistance from affecting the dosing.

[0411] Six hours after test substance application, the skin application site was gently cleansed with soap and water to remove any unabsorbed cream residue. Skin irritation was observed and recorded for three consecutive days of test substance administration within each cycle to compare the short-term irritation of the four groups after three consecutive days of skin administration.

[0412] Clinical observation and skin irritation reaction scoring:

[0413] Observe the patient 6 hours after each administration (before cleaning and removing the drug) and 24 hours before the next administration, focusing on the presence of any skin reactions or symptoms such as erythema, crust formation, edema, and skin thickening at the administration site. On the last day of each cycle (D3, D6, D11, and D16), photograph the administration site to record skin reactions. The specific time for taking photos is 10 minutes to 1 hour after the drug is removed. Skin irritation reaction scores are calculated according to the skin irritation reaction scoring criteria in the "Technical Guidelines for Drug Irritation, Allergy, and Hemolytic Studies."

[0414] Test results:

[0415] Under the conditions of this study, after three consecutive days of administration, the G1 blank cream group and the G2 Y-004 cream 0.05% (500 μg / g) group showed no skin irritation (skin irritation intensity score of 0) in miniature Bama pigs, with no abnormal skin reactions or symptoms observed. However, the G3 10Y cream 0.05% (500 μg / g) group and the G4 10Y cream 0.025% (250 μg / g) group showed skin irritation, primarily manifested by erythema, swelling, and subsequent scabs and desquamation. The severity and duration of symptoms were dose-dependent, with the highest skin irritation intensity scores of 2 and 4 for the 250 μg / g and 500 μg / g groups, respectively, indicating some individual variability. No abnormal changes related to the test substance were observed in clinical signs, body weight, or food intake.

[0416] Biological Test Example 3

[0417] Evaluation of the efficacy of compounds on the New Zealand rabbit ear acne model

[0418] Experimental Design:

[0419] Models were established in quarantined male New Zealand rabbits (Suzhou Xishan Biotechnology Co., Ltd., certificate number 370823241100331316). Each animal's left ear was evenly smeared with 0.4-0.5 mL of oleic acid using a sterile cotton swab soaked in 75% oleic acid. The right ear remained untreated. The smear was applied once daily for 11 consecutive days. On day 7 (MDay7), the dosing area (2 cm × 3 cm) was determined based on the animal's ear acne symptoms and marked using a small animal tattooing machine. On the 11th day of modeling (MDay11), 24 rabbits with moderate or moderate-to-severe ear infections scored by visual observation on the modeling side were randomly divided into: a model control group (Y-004 blank cream, the same as the blank cream group in Biological Test Example 2), a 0.025% tretinoin cream control group (commercially available, specification 250 μg / g, active ingredient tretinoin, each gram of cream contains 250 μg of tretinoin), and a 0.025% Y-004 cream group (specification 250 μg / g, active ingredient Y-004 of the present invention, each gram of cream contains 250 μg of the present compound Y-004 of the present invention, and the excipient composition other than the active ingredient is the same as that of the model control group blank cream). Each group consisted of 8 animals, all male. Approximately 24 hours after the last modeling, administer the corresponding control substance / test substance to the marked area, 0.06 mL / side ear, once a day. Clean the residual drug with a cotton ball soaked in 0.9% sodium chloride injection 6 h ± 0.5 h after each administration. Administer the drug continuously for 7 days, and perform an autopsy 24 h after the last administration.

[0420] During the experiment, the general symptoms of the animals and skin changes at the modeling / dosing sites were observed and recorded daily; the animals were weighed once a week, and the modeling / dosing sites of the animals were visually observed and scored before the first administration and before autopsy.

[0421] Acne grading standards based on visual observation

[0422] Note: #Before dissection, due to the effect of treatment or self-recovery of the model control, the acne during the modeling period has transformed into dilated and bulged hair follicle openings.

[0423] Definition of noun:

[0424] 1. Acne: A tiny white macule or papule with a diameter of 0.5-3mm, mostly less than 1mm.

[0425] 2. Papules: small red, slightly hard protrusions with a diameter of less than 0.5 cm.

[0426] 3. Pustules: A bordered bulge appears on the skin at the top of the papule, containing yellow-white exudate.

[0427] 4. Nodules / cysts: Located under the skin, with no skin damage on the surface, they are mostly hard foreign bodies or cystic cavities formed after the acne has undergone an inflammatory reaction and has not been completely destroyed. The inner wall is repaired and sealed.

[0428] Test results:

[0429] General condition of animals: During the administration period, the animals in each group were in good general condition and no obvious abnormalities were observed.

[0430] Body weight: The body weight of the animals in each group remained stable during the administration period, with no significant abnormalities observed. After 7 consecutive days of administration, the body weights of the animals in each group were basically consistent (P>0.05).

[0431] Macroscopic observation scores of the administration area: Before the first administration (the day of grouping, the 11th day of modeling), the macroscopic observation scores of acne manifestations in the administration area of ​​animals in the model control group (blank cream group), tretinoin cream 0.025% control group and Y-004 cream 0.025% group were basically the same (P>0.05). After 7 consecutive days of administration, the macroscopic observation scores of acne manifestations in the administration area of ​​animals in the tretinoin cream 0.025% control group and Y-004 cream 0.025% group were lower than those in the model control group (blank cream group) during the same period, among which the degree of reduction in the Y-004 cream group was more obvious (P<0.05). The macroscopic observation scores of animals during the experiment (Mean±SD) are shown in Figure 1 (Note: n=8 in each group. *P<0.05 compared with the model control group, P>0.05 compared with the tretinoin cream control group.)

[0432] The 0.025% group of the Y-004 cream of the present invention can significantly reduce the naked eye observation score of acne manifestations in the New Zealand rabbit ear acne model, and has a significant improvement effect.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, A is a 6- to 10-membered arylene or a 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1, 2 or 3 heteroatoms independently selected from N, O and S; Y is -NR 1 - or -CR 1 R’-; R 1 is H or C 1-6 alkyl; R’ is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle or a C 3-8 carbocycle; the 3- to 8-membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S; the 3- to 8-membered heterocycle and the C 3-8 carbocycle are optionally substituted by one or more R 2-1 substituents; R 2-1 are each independently C 1-6 alkyl, C 1-6 alkoxy and halogen; X is -NR 3 - or -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is H, C 1-6 alkyl, C 5a alkyl substituted with one or more R 1-6 alkyl, C 1-6 alkoxy or C 5a alkoxy substituted with one or more R 1- 6 alkoxy; R 5a each independently is halogen or hydroxy; m is 0, 1, 2 or 3; R 6 is H or C 1-6 alkyl; When Y is -CR 1 -R', R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle or a C 3-8 carbocycle; the 3- to 8-membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S.

2. The compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) In A, the 6- to 10-membered arylene is phenylene or naphthylene, such as phenylene; (2)In A, the number of heteroatoms in the 5- or 6-membered heteroaryl group is 1, and the heteroatom is preferably N, such as a pyridinyl group, and for example ( where the a end is connected to the phenylene and the b end is connected to the carbonyl group); (3)R 1 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; (4) In R’, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; (5)R 2 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; (6)R 1 and R 2 and their atoms together form C 3-8 In the carbon ring, the C 3-8 carbon ring is a single ring; for example, C 4-6 a single carbon ring; for example, a cyclopentane ring; (7)R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle, wherein the 3- to 8-membered heterocycle is a monocyclic ring; (8)R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle, wherein the 3- to 8-membered heterocycle is a 4- to 6-membered heterocycle, preferably a 4- to 6-membered heterocyclic monoring, such as (9)R 1 and R 2 Together with the atoms between them, they form a 3- to 8-membered heterocycle in which the number of heteroatoms is 1, and the heteroatom is preferably N; (10)R 3 In which, said C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (11)R 4 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; (12)R 5 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (13)R 5 Among them, the C 1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as ethoxy, n-propoxy or n-butoxy; (14)R 5a wherein the halogen is fluorine, chlorine, bromine or iodine; (15)R 5 wherein the C 5a alkyl substituted by one or more R 1-6 is a C 5a alkyl substituted by one R 1-6 , such as a C 1-6 alkyl substituted by one hydroxyl group; (16)R 5 wherein the C 5a alkoxy group substituted by one or more R 1-6 is a C 5a alkoxy group substituted by one R 1-6 such as a C 1-6 alkoxy group substituted by one hydroxyl group, and for another example (17)R 6 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (18)R 2-1 Among them, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (19)R 2-1 Among them, the C 1-6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (20)R 2-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (21) The plurality is 2 or 3.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) m is 0, 1 or 2, preferably, m is 1; (2) A is a 6- to 10-membered arylene or a 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is N; preferably, A is a 6- to 10-membered arylene; more preferably, A is phenylene; (3) Y is -NR 1 - or -CHR 1 -; when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form a 3 - 8 - membered heterocycle or a C 3-8 carbocycle; the 3 - 8 - membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form a 3 - 8 - membered heterocycle or a C 3-8 carbocycle; the 3 - 8 - membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the C 3-8 carbocycle is a monocyclic ring (such as a C 4-6 carbocyclic monocyclic ring); more preferably, when Y is -CHR 1 -, R 1 and R 2 and the atoms between them together form a C 3-8 carbocycle; the C 3-8 carbocycle is a monocyclic ring; (4) Y is -NR 1 -; (5)R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle or a C 3-8 carbocycle; the 3- to 8-membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) or a C 3-8 carbocycle (such as a C 4-6 carbocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom which is N; the C 3-8 carbocycle is a monocyclic ring; more preferably, R 1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 together with the atoms therebetween form a 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) or a C 3-8 carbocycle (such as a C 4-6 carbocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom which is N; the C 3-8 carbocycle is a monocyclic ring; (6) X is -CR 3 R 4 -; (7)R 3 is C 1-6 alkyl; (8)R 4 is C 1-6 alkyl; (9)R 5 is C 1-6 alkoxy or C 5a alkoxy substituted with one or more R 1-6 , preferably, R 5 is C 5a alkoxy substituted with one R 1-6 ; (10)R 5a is fluorine, chlorine, bromine or a hydroxyl group, preferably, R 5a is a hydroxyl group; (11) R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably, R 6 is H; (12) Y is -NR 1 -, R 1 and R 2 together with the atoms between them form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein at least one of the heteroatoms is N; the 3- to 8-membered heterocycle is optionally substituted by one or more R 2-1 substituents; R 2-1 are each independently C 1-6 alkyl, C 1-6 alkoxy and halogen; preferably, when Y is -NR 1 -, R 1 and R 2 together with the atoms between them form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the 3- to 8-membered heterocycle is optionally substituted by one or more R 2-1 substituents; R 2-1 are each independently C 1-6 alkyl, C 1-6 alkoxy and halogen.

4. The compound represented by Formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies one or more of the following conditions: (1) For (2)R 6 is hydrogen; (3)R 5 For (4) For ( where the a end is connected to the phenylene and the b end is connected to the carbonyl group).

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The compound represented by Formula I is Scheme 1, Scheme 2, Scheme 3 or Scheme 4: Scheme 1: m is 0, 1 or 2; A is a 6- to 10-membered arylene or a 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is N; Y is -NR 1 - or -CHR 1 -; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle) or a C 3-8 carbocycle (e.g., a C 4-6 carbocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the C 3-8 carbocycle is a monocyclic ring X is -NR 3 - or -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; When Y is -CHR 1 -, R 1 and R 2 together with the atoms between them form a C 3-8 carbocyclic ring; the C 3-8 carbocyclic ring is a monocyclic ring (e.g., C 4-6 carbocyclic monocyclic ring); Scheme 2: m is 0, 1 or 2; A is a 6- to 10-membered arylene; Y is -NR 1 -; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Scheme 3: m is 1; A is a 6- to 10-membered arylene or a 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is N; Y is -NR 1 - or -CHR 1 -; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) or a C 3-8 carbocycle (such as a C 4-6 carbocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the C 3-8 carbocycle is a monocyclic ring X is -NR 3 - or -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; When Y is -CHR 1 -, R 1 and R 2 together with the atoms therebetween form a C 3-8 carbocyclic ring (e.g., C 4-6 carbocyclic ring), and the C 3-8 carbocyclic ring is a monocyclic ring; Scheme 4: m is 1; A is a 6- to 10-membered arylene; Y is -NR 1 -; R 1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C 5a alkoxy group substituted by an R 1-6 ; R 5a is a hydroxyl group; R 6 is H.

6. The compound of formula I as described in any one of claims 1-4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is a compound of Formula I-1 or a compound of Formula I-2: (for example ); n is 0, 1, 2 or 3; m, A, R 1 , R 2 , X, R 5 and R 6 are defined as described in any one of claims 1 - 4; Preferably, the compound represented by Formula I satisfies one or two of the following conditions: (1) In the compound of Formula I-1, m is 0, 1 or 2; A is a 6- to 10-membered arylene; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of Formula I-1, m is 1; A is phenylene; R 1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; (2) In the compound of Formula I-2 (such as the compounds of I-2-a and I-2-b), n is 0, 1 or 2; m is 0, 1 or 2; A is a 6- to 10-membered arylene; X is -NR 3 - or -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of Formula I-2 (such as the compounds of I-2-a and I-2-b), n is 1; m is 1; A is phenylene; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 be replaced by an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; More preferably, the compound represented by Formula I is a compound of Formula I-1-a, a compound of Formula I-1-b or a compound of Formula I-1-c: (For example )； t is 0, 1, 2 or 3; R 1-1 is C 1-6 alkyl; m, A, R 2 , X, R 5 and R 6 are defined as described in any one of claims 1 - 4; R 1-1 in, the C 1-6 alkyl is preferably methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl or tert - butyl, such as methyl or ethyl; More preferably, the compound represented by Formula I satisfies one or more of the following conditions: (1) In the compound of Formula I-1-a, m is 0, 1 or 2; A is a 6- to 10-membered arylene; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of Formula I-1-a, m is 1; A is phenylene; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is replaced by an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; (2) In the compound of Formula I-1-b, m is 0, 1 or 2; A is a 6- to 10-membered arylene; R 1-1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of Formula I-1-b, m is 1; A is phenylene; R 1-1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; (3) In the compound of Formula I-1-c (such as the compounds of I-1-c-1 and I-1-c-2), t is 0, 1 or 2; m is 0, 1 or 2; A is a 6- to 10-membered arylene; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of Formula I-1-c (such as the compounds of I-1-c-1 and I-1-c-2), t is 1 or 2; m is 0 or 1; A is phenylene; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C alkoxy group substituted by one or more R 5a substituted C 1-6 alkoxy group; R 5a is fluorine, chlorine, bromine or a hydroxyl group; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; More preferably, in the compound of Formula I-1-c (such as the compounds of I-1-c-1 and I-1-c-2), t is 1; m is 1; A is a phenylene group; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C 5a alkoxy group substituted by an R 1-6 ; R 5a is a hydroxyl group; R 6 is H.

7. The compound of formula I as described in any one of claims 1-4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is a compound of Formula I-1-1 or a compound of Formula I-2-1: (for example ) n is 0, 1, 2 or 3; A, R 1 , R 2 and X are defined as described in any one of claims 1 - 4; Preferably, the compound represented by the formula I satisfies one or both of the following conditions: (1) In the compound of formula I-1-1, A is a 6- to 10-membered arylene group; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle (e.g., a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Preferably, in the compound of formula I-1-1, A is a phenylene group; R 1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; or, R 1 and R 2 and the atoms therebetween together form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; (2) In the compound of formula I-2-1 (such as I-2-1-a, I-2-1-b), n is 0, 1 or 2; A is a 6- to 10-membered arylene group; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Preferably, in the compound of formula I-2-1 (such as I-2-1-a, I-2-1-b), n is 1; A is a phenylene group; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; More preferably, the compound represented by Formula I is a compound of Formula I-1-1-1, a compound of Formula I-1-1-2 or a compound of Formula I-1-1-3: (For example )； t is 0, 1, 2 or 3; R 1-1 is C 1-6 alkyl; A, R 2 and X are defined as in any one of claims 1 - 4, R 1-1 in which the C 1- 6 alkyl is preferably methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl or tert - butyl, such as methyl or ethyl; More preferably, the compound represented by the formula I satisfies one or more of the following conditions: (1) In the compound of formula I-1-1-1, A is a 6- to 10-membered arylene group; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Preferably, in the compound of formula I-1-1-1, A is a phenylene group; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; (2) In the compound of formula I-1-1-2, A is a 6- to 10-membered arylene group; R 1-1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Preferably, in the compound of formula I-1-1-2, A is a phenylene group; R 1-1 is a C 1-6 alkyl group; R 2 is H or C 1-6 alkyl group; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl group; R 4 is C 1-6 alkyl group; (3) In the compound of formula I-1-1-3 (such as I-1-1-3-a, I-1-1-3-b), t is 0, 1 or 2; A is a 6- to 10-membered arylene group; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; Preferably, in the compound of formula I-1-1-3 (such as I-1-1-3-a, I-1-1-3-b), t is 1 or 2; A is phenylene; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; More preferably, in the compound of formula I-1-1-3 (such as I-1-1-3-a, I-1-1-3-b), t is 1; A is phenylene; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl.

8. The compound of formula I as described in any one of claims 1-4 or a pharmaceutically acceptable salt thereof, characterized in that The compound represented by Formula I may be a compound of Formula I-A, a compound of Formula I-B, a compound of Formula I-C or a compound of Formula I-D (for example ) (for example ); R 1-1 is C 1-6 alkyl; X, R 2 , R 3 , R 4 , R 5 and R 6 are defined as described in any one of claims 1-4; R 1-1 in, the C 1- 6 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; Preferably, the compound represented by the formula I satisfies one or more of the following conditions: (1) In the compound I-A, R 2 is H or C 1-6 alkyl; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ; R 5a is fluorine, chlorine, bromine or hydroxyl; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound I-A, R 2 is H or C 1-6 alkyl; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is replaced by an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; (2) In the compound of formula I-B (such as I-B-1, I-B-2), R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy; R 5a is fluorine, chlorine, bromine or hydroxyl; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of formula I-B (such as I-B-1, I-B-2), R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C alkoxy group substituted by an R 5a ; R 1-6 is a hydroxyl group; R 5a is H; 6 ​ (3) In the compound of formula I-C, R 1-1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ; R 5a is fluorine, chlorine, bromine or hydroxyl; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of formula I-C, R 1-1 is C 1-6 alkyl; R 2 is H or C 1-6 alkyl; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C alkoxy group substituted by an R 5a ; R 1-6 is a hydroxyl group; R 5a is H; 6 ​ (4) In the compound of formula I-D (such as I-D-1, I-D-2), X is -NR 3 - or -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ; R 5a is fluorine, chlorine, bromine or hydroxy; R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, in the compound of formula I-D (such as I-D-1, I-D-2), X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is C 5a alkoxy substituted by one R 1-6 ; R 5a is hydroxy; R 6 is H.

9. The compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any one of the following compounds:

10. A pharmaceutical composition comprising (i) a compound represented by the formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

11. Use of a compound represented by the formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 10 as a retinoic acid receptor γ agonist.

12. Use of a compound represented by the formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 10 in the preparation of a drug for treating and / or preventing diseases related to retinoic acid receptor γ; Preferably, the diseases related to retinoic acid receptor γ may be acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), acne vulgaris, psoriasis, ichthyosis, skin keratosis, pigmentation or dry eye.

13. Use of a compound of formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 10 in the preparation of a medicament; Preferably, the medicament is used for treating and / or preventing acne (including acne vulgaris, rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), acne vulgaris, psoriasis, ichthyosis, skin keratosis disorders, pigmentation or dry eye.

14. A compound of formula II or a salt thereof R 6’ is C 1-6 alkyl; R 7 is C 1-6 alkyl; A, R 2 、X and Y are defined as described in any one of claims 1-9; R 7 Among them, the C 1-6 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl; R 6’ Among them, the C 1-6 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as ethyl; Preferably, the compound represented by Formula II is any one of the following compounds:

15. A method for preparing a compound represented by Formula I, characterized in that, It includes the following steps: in an organic solvent (such as an alcohol solvent, for example methanol), in the presence of a base (such as an alkali metal hydroxide, for example sodium hydroxide, for example a 1 mol / L aqueous sodium hydroxide solution), the compound shown by formula II undergoes the following hydrolysis reaction (such as 50 - 70 °C, for example 60 °C) to obtain the compound shown by formula I; R 6 is H; R 5 is R 5 is connected to the para-position of A, and m is 1; A, X, Y, and R 2 are defined as described in any one of claims 1-9, and R 6’ and R 7 are defined as described in claim 14; Preferably, the method for preparing the compound represented by Formula I further comprises the following steps: in the presence of a catalyst (such as a palladium catalyst, for example Pd(dppf)Cl2) and an alkali metal halide salt (such as an alkali metal fluoride salt, for example KF), in a solvent (such as a mixed solvent of water and a cyclic ether solvent, for example a mixed solvent of water and dioxane, or for example a mixed solvent of dioxane and water with a volume ratio of 20:3 or 4:1), the compound represented by Formula III and the compound represented by Formula IV undergo the following coupling reaction (such as 100 - 120 °C, for example 110 °C) to obtain the compound represented by Formula II; R 8 is a borate group R 9 is a halogen (for example bromine); A, X, Y and R 2 as described in any one of claims 1 - 9; R 6’ and R 7 are defined as described in claim 14.

16. A method for preparing a compound represented by Formula II, which comprises the following steps: in the presence of a catalyst (such as a palladium catalyst, such as Pd(dppf)Cl2) and an alkali metal halide salt (such as an alkali metal fluoride salt, such as KF), in a solvent (such as a mixed solvent of water and a cyclic ether solvent, such as a mixed solvent of water and dioxane, or for example, the volume ratio of dioxane to water is 20:3 or 4:1), the compound represented by Formula III reacts with the compound represented by Formula IV in the coupling reaction shown by the following formula (such as 100-120 °C, such as 110 °C) to obtain the compound represented by Formula II; R 8 is a borate group R 9 is a halogen (such as bromine); A, X, Y, and R 2 as described in any one of claims 1-9; R 6’ and R 7 are defined as described in claim 14.

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