Biphenyl compound, and preparation method, intermediate, pharmaceutical composition and application thereof

Abstract

The invention discloses a biphenyl compound as well as a preparation method, an intermediate, a pharmaceutical composition and application thereof. Specifically provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound has good retinoic acid receptor gamma agonist activity and selectivity, almost has no agonist activity on retinoic acid receptors alpha and / or beta, and is beneficial to reduction of systemic side effects; more preferably, the compound has moderate partial agonistic activity, is small in skin irritation, less in adverse reaction and excellent in safety and compliance under the condition of maintaining the drug effect, effectively solves the ubiquitous problems of the existing RAR compounds, and can be used for treating and preventing diseases related to the retinoic acid receptor gamma. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024100337288 with a filing date of January 9, 2024, and Chinese Patent Application No. 2024119438632 with a filing date of December 26, 2024. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

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

[0003] The retinoic acid receptor (RAR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, and its main ligand is retinoic acid. After RAR binds to its ligand retinoic acid, etc., it can form a heterodimer with RXR (Retinoid X receptor) and bind to specific genes, thereby controlling the expression of specific genes, playing an important role in processes such as cell growth, differentiation, and apoptosis, and participating in physiological and pathological processes such as embryonic development, tissue differentiation, and tumors. RAR includes three subtypes: RARα, RARβ, and RARγ. Among them, RARα is widely distributed in most tissues such as the lung, spleen, and gallbladder, RARβ is mainly expressed in the placenta, kidney, heart, nervous system, etc., and RARγ is mainly expressed in the skin, epithelium, and cartilage tissues.

[0004] Synthetic or endogenous retinoic acid (tretinoin) substances can indirectly regulate keratinization by binding to and activating RARγ in skin tissues to regulate basal upper cell gene transcription and expression, promote normal epidermal keratinization, and inhibit excessive keratin proliferation. Clinically, existing retinoic acid substances such as tretinoin, isotretinoin, acitretin, etretinate, aromatic retinoid, ethyl aromatic retinoid, as well as adapalene and tazarotene, etc. are applied to the treatment of psoriasis, skin keratosis diseases, eczema, acne, etc. However, since these retinoic acid drugs are RAR non-selective drugs, they can bind to receptors such as RARα, RARβ, RARγ, and RXR, and while exerting therapeutic effects in promoting cell growth and metabolism, they also cause various systemic side effects.

[0005] Due to the fact that 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 with the following structure in Patent US8362082B2.

[0006]

[0007] Although these compounds can appropriately improve the selectivity for RARα and RARβ, according to literature reports and research, they have certain agonist activities against RARα and / or RARβ, and there are problems of systemic or other tissue side effects. In addition, existing RARγ selective agonist compounds of this type have a full agonist effect similar to retinoic acid on RARγ, there is a risk of adverse reactions caused by full activation, they have strong skin irritation, and adverse reactions such as severe erythema, desquamation, and stinging occur when used topically. Therefore, there is still a need to develop novel RARγ selective agonists with better selectivity and / or reduced risk of overactivation and / or low irritation. Summary of the Invention

[0008] The present invention provides a biphenyl compound, its preparation method, intermediate, pharmaceutical composition and application. This type of compound has good retinoic acid receptor γ agonist activity and retinoic acid receptor γ selectivity, and has almost no agonist activity against retinoic acid receptor α and / or retinoic acid receptor β, which is beneficial to reducing systemic side effects; more preferably, it has moderate partial agonist activity, has low skin irritation and few adverse reactions while maintaining the drug effect, and has excellent safety and compliance.

[0009] On the one hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0010]

[0011] A is a 6-10 membered arylene or a 5-6 membered heteroarylene; the 5-6 membered heteroarylene has 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0012] Y is -NR 1 - or -CR 1 R'-;

[0013] R 1 is H or C 1-6 alkyl;

[0014] R' is H or C 1-6 alkyl;

[0015] R 2 is H or C 1-6 alkyl; or, 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; the 3-8 membered heterocycle and C 3-8 carbocycle are optionally substituted by one or more R 2-1 ; R 2-1 are each independently C 1-6 alkyl, C1-6 Alkoxy and halogen;

[0016] 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;

[0017] R 5 is H or C 1-6 alkyl, C 5a alkyl substituted by one or more R 1-6 alkyl, C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ;

[0018] R 5a are each independently halogen or hydroxy;

[0019] m is 0, 1, 2 or 3;

[0020] R 6 is H or C 1-6 alkyl;

[0021] When Y is -CR 1 R'- , R 1 and R 2 together with the atoms between them 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.

[0022] In some embodiments, in the compound of formula I or its pharmaceutically acceptable salt, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any aspect of the present invention (hereinafter simply referred to as "in some embodiments").

[0023] In some embodiments, in A, the 6- to 10-membered arylene is phenylene or naphthylene, such as phenylene.

[0024] In some embodiments, in A, the number of heteroatoms of the 5- to 6-membered heteroarylene can be 1, and the heteroatom is preferably N, such as pyridinyl, and also such as ( where the a end is connected to the phenylene and the b end is connected to the carbonyl).

[0025] In some embodiments, in R 1 the C 1-6The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

[0026] In some embodiments, in R', the C 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

[0027] In some embodiments, R 2 In the 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

[0028] In some embodiments, R 1 and R 2 and the atoms between them together form a C 3-8 In the carbocyclic ring, the C 3-8 The carbocyclic ring can be a monocyclic ring, such as C 4-6 A carbocyclic monocyclic ring, such as a cyclopentane carbocyclic ring (a 5-membered carbocyclic ring).

[0029] In some embodiments, R 1 and R 2 and the atoms between them together form a 3- to 8-membered heterocyclic ring. The number of heteroatoms in the 3- to 8-membered heterocyclic ring can be 1, and the heteroatom is preferably N; and / or it can be a monocyclic ring; the 3- to 8-membered heterocyclic ring is preferably a 4- to 6-membered heterocyclic ring, more preferably a 4- to 6-membered heterocyclic monocyclic ring; for example

[0030] In some embodiments, R 3 In the 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0031] In some embodiments, R 4 In the 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0032] In some embodiments, R 5 In the 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0033] In some embodiments, R 5 In the 1-6The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as ethoxy, n-propoxy or n-butoxy.

[0034] In some embodiments, R 5a In, the halogen can be fluorine, chlorine, bromine or iodine.

[0035] In some embodiments, R 5 In, the C 5a alkyl group substituted by one or more R 1-6 is a C 5a alkyl group substituted by one R 1-6 such as a C 1-6 alkyl group substituted by one hydroxyl group.

[0036] In some embodiments, R 5 In, the C 5a alkoxy group substituted by one or more R 1-6 can be 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 again for example

[0037] In some embodiments, R 6 In, the C 1-6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0038] In some embodiments, R 2-1 In, the C 1-6 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0039] In some embodiments, R 2-1 In, the C 1-6 alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0040] In some embodiments, R 2-1 In, the halogen can be fluorine, chlorine, bromine or iodine.

[0041] In some embodiments, the plurality is 2 or 3.

[0042] In some embodiments, m is 0, 1 or 2, preferably, m is 1.

[0043] In some embodiments, 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.

[0044] In some embodiments, Y is -NR 1 - or -CHR 1 -; preferably, Y is -NR 1 -.

[0045] In some embodiments, 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 between them together 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 and the atoms between them 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 with 1 heteroatom, and the heteroatom 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 and the atoms between them 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 with 1 heteroatom, and the heteroatom is N; the C 3-8 carbocycle is a monocyclic ring.

[0046] In some embodiments, X is -CR 3 R 4 -.

[0047] In some embodiments, R 3 is C 1-6 alkyl.

[0048] In some embodiments, R 4is C 1-6 alkyl group.

[0049] In some embodiments, R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ; preferably, R 5 is C 5a alkoxy substituted by one R 1-6 .

[0050] In some embodiments, R 5a is fluorine, chlorine, bromine or hydroxyl; preferably, R 5a is hydroxyl.

[0051] In some embodiments, R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably, R 6 is H.

[0052] In some embodiments, when Y is -CHR 1 -, R 1 and R 2 together with the atoms between them 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, when Y is -CHR 1 -, R 1 and R 2 together with the atoms between them form a 3- to 8-membered heterocycle or a C 3-8 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 (such as a C 4-6 carbocyclic monocyclic ring); more preferably, when Y is -CHR 1 -, R 1 and R 2 together with the atoms between them form a C 3-8 carbocycle; the C 3-8 carbocycle is a monocyclic ring.

[0053] In some embodiments, 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 optionally substituted by one or more R 2-1 ; R 2-1 are each independently C 1-6 alkyl, C 1-6Alkoxy and halogen; the 3- to 8-membered heterocycle has 1, 2 or 3 heteroatoms independently selected from N, O and S, where at least one of the heteroatoms is N; 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 optionally substituted by one or more R 2-1 ; R 2-1 are each independently C 1-6 alkyl, C 1-6 alkoxy and halogen; the 3- to 8-membered heterocycle is a monocyclic ring having 1 heteroatom, and the heteroatom is N.

[0054] In some embodiments,

[0055] m is 0, 1 or 2;

[0056] 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;

[0057] Y is -NR 1 - or -CHR 1 -;

[0058] 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 between them form a 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) or a C 3-8 carbocyclic ring (such as a C 4-6 carbocyclic ring); the 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the C 3-8 carbocyclic ring (such as a C 4-6 carbocyclic ring) is a monocyclic ring;

[0059] X is -NR 3 - or -CR 3 R 4 -;

[0060] R 3 is H or C 1-6 alkyl;

[0061] R 4 is H or C 1-6 alkyl;

[0062] R 5 is C 1-6 alkoxy or is substituted by one or more R 5aSubstituted C 1-6 alkoxy group;

[0063] R 5a is fluorine, chlorine, bromine or hydroxyl group;

[0064] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0065] 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 (such as a C 4-6 carbocyclic monocyclic ring).

[0066] In some embodiments,

[0067] m is 0, 1 or 2;

[0068] A is a 6-10 membered arylene group;

[0069] Y is -NR 1 -;

[0070] 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 between them form a 3-8 membered heterocyclic ring (such as a 4-6 membered heterocyclic ring); the 3-8 membered heterocyclic ring (such as a 4-6 membered heterocyclic ring) is a monocyclic ring and has 1 heteroatom, and the heteroatom is N;

[0071] X is -CR 3 R 4 -;

[0072] R 3 is H or C 1-6 alkyl;

[0073] R 4 is H or C 1-6 alkyl;

[0074] R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy;

[0075] R 5a is fluorine, chlorine, bromine or hydroxyl group;

[0076] R6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0077] In some embodiments,

[0078] m is 1;

[0079] 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;

[0080] Y is -NR 1 - or -CHR 1 -;

[0081] 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 between them 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 (such as a 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N; the C 3-8 carbocycle (such as a C 4-6 carbocycle) is a monocyclic ring;

[0082] X is -NR 3 - or -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0083] R 5 is a C 5a alkoxy group substituted by one R 1-6 ;

[0084] R 5a is hydroxy;

[0085] R 6 is H;

[0086] When Y is -CHR 1- , R 1 and R 2 and the atoms between them together form a C 3-8 carbocycle (such as a C 4-6 carbocycle), and the C 3-8 carbocycle (such as a C 4-6 carbocycle) is a monocyclic ring.

[0087] In some embodiments,

[0088] m is 1;

[0089] A is a 6- to 10-membered arylene;

[0090] Y is -NR 1 -;

[0091] 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 between them together form a 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (such as a 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N;

[0092] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0093] R 5 is C 5a alkoxy substituted by one R 1-6 ;

[0094] R 5a is hydroxy;

[0095] R 6 is H.

[0096] In some embodiments, the compound represented by Formula I may be a compound of Formula I-1 or a compound of Formula I-2:

[0097] (such as );

[0098] n is 0, 1, 2 or 3; m, A, R 1 、R 2 、X、R 5 and R 6 are as defined above.

[0099] In some embodiments, in the compound of Formula I-1,

[0100] m is 0, 1 or 2;

[0101] A is a 6- to 10-membered arylene;

[0102] R1 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 (e.g., 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N;

[0103] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl;

[0104] R 5 is C 1-6 alkoxy or C alkoxy substituted by one or more R 5a substituted C 1-6 alkoxy;

[0105] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0106] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0107] In some embodiments, in the compound of formula I-1,

[0108] m is 1; A is phenylene;

[0109] R 1 is C 1-6 alkyl; R 2 is C 1-6 alkyl or H; 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 (e.g., 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N;

[0110] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0111] R 5 is C alkoxy substituted by one R 5a substituted C 1-6 alkoxy;

[0112] R 5a is a hydroxyl group;

[0113] R 6 is H.

[0114] In some embodiments, in the compound of formula I-2 (e.g., compounds I-2-a, I-2-b),

[0115] n is 0, 1 or 2;

[0116] m is 0, 1 or 2;

[0117] A is a 6-10 membered arylene or a 5-6 membered heteroarylene; the 5-6 membered heteroarylene has 1 heteroatom, and the heteroatom is N;

[0118] 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;

[0119] R 5 is C 1-6 alkoxy or C 5a substituted by one or more R 1-6 alkoxy;

[0120] R 5a is fluorine, chlorine, bromine or a hydroxyl group;

[0121] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0122] In some embodiments, in the compound of formula I-2 (e.g., compounds I-2-a, I-2-b),

[0123] n is 1; m is 1; A is phenylene;

[0124] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0125] R 5 is C 5a substituted by one R 1-6 alkoxy;

[0126] R 5a is a hydroxyl group;

[0127] R 6 is H.

[0128] In some embodiments, the compound of 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:

[0129]

[0130] (for example );

[0131] 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 as defined above. 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.

[0132] In some embodiments, in the compound of formula I-1-a,

[0133] m is 0, 1, or 2;

[0134] A is a 6- to 10-membered arylene;

[0135] R 2 is H or C 1-6 alkyl;

[0136] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl;

[0137] R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ;

[0138] R 5a is fluorine, chlorine, bromine, or hydroxyl;

[0139] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0140] In some embodiments, in the compound of formula I-1-a,

[0141] m is 1; A is phenylene;

[0142] 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;

[0143] R 5 is C 5a alkoxy substituted by one R 1-6 ;

[0144] R 5a is hydroxy;

[0145] R 6 is H.

[0146] In some embodiments, in the compound of formula I-1-b,

[0147] m is 0, 1 or 2;

[0148] A is a 6- to 10-membered arylene;

[0149] R 1-1 is C 1-6 alkyl;

[0150] R 2 is H or C 1-6 alkyl

[0151] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl;

[0152] R 5 is C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 ;

[0153] R 5a is fluorine, chlorine, bromine or hydroxy;

[0154] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, in the compound of formula I-1-b,

[0155] m is 1; A is a phenylene group;

[0156] R 1-1 is a C 1-6 alkyl group;

[0157] R 2 is H or C 1-6 alkyl group;

[0158] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl group; R 4 is C 1-6 alkyl group;

[0159] R 5 is a C 5a substituted by one R 1-6 alkoxy group;

[0160] R 5a is a hydroxyl group;

[0161] R 6 is H.

[0162] In some embodiments, in the compound of formula I-1-c (such as the compounds I-1-c-1 and I-1-c-2),

[0163] t is 0, 1 or 2;

[0164] m is 0, 1 or 2;

[0165] A is a 6- to 10-membered arylene group;

[0166] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl group; R 4 is H or C 1-6 alkyl group;

[0167] R 5 is C 1-6 alkoxy group or a C 5a substituted by one or more R 1-6 alkoxy group;

[0168] R 5a is fluorine, chlorine, bromine or a hydroxyl group;

[0169] R 6is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, in the compound of formula I-1-c (e.g., compounds I-1-c-1, I-1-c-2), t is 1 or 2; m is 0 or 1; A is phenylene;

[0170] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0171] R 5 is C 5a alkoxy substituted by one or more R 1-6 ;

[0172] R 5a is fluorine, chlorine, bromine or hydroxyl;

[0173] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. In some embodiments, in the compound of formula I-1-c (e.g., compounds I-1-c-1, I-1-c-2), t is 1; m is 1; A is phenylene;

[0174] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0175] R 5 is C 5a alkoxy substituted by one R 1-6 ;

[0176] R 5a is hydroxyl;

[0177] R 6 is H.

[0178] In some embodiments, the compound of formula I may be a compound of formula I-1-1 or a compound of formula I-2-1:

[0179] (e.g., )

[0180] n is 0, 1, 2 or 3; the definitions of A, R 1 , R 2 and X are as described above.

[0181] In some embodiments, in the compound of formula I-1-1,

[0182] A is a 6- to 10-membered arylene group;

[0183] 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 between them form a 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N;

[0184] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl.

[0185] In some embodiments, in the compound of formula I-1-1,

[0186] A is phenylene;

[0187] 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 between them form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle (e.g., 4- to 6-membered heterocycle) is a monocyclic ring having 1 heteroatom, and the heteroatom is N;

[0188] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl.

[0189] In some embodiments, in the compound of formula I-2-1 (e.g., I-2-1-a, I-2-1-b),

[0190] n is 0, 1 or 2; A is a 6- to 10-membered arylene group;

[0191] X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6Alkyl.

[0192] In some embodiments, in the compound of formula I-2-1 (such as I-2-1-a, I-2-1-b),

[0193] n is 1; A is phenylene;

[0194] X is -CR 3 R 4 -; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl.

[0195] In some embodiments, the compound of 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:

[0196]

[0197] (such as );

[0198] t is 0, 1, 2, or 3; R 1-1 is C 1-6 alkyl; A, R 2 and X are as defined above. In R 1-1 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.

[0199] In some embodiments, in the compound of formula I-1-1-1,

[0200] 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.

[0201] In some embodiments, in the compound of formula I-1-1-1,

[0202] 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; R4 is C 1-6 alkyl group.

[0203] In some embodiments, in the compound of formula I-1-1-2,

[0204] A is a 6- to 10-membered arylene group; R 1-1 is C 1-6 alkyl group; R 2 is H or C 1-6 alkyl group; X is -CR 3 R 4 -; R 3 is H or C 1-6 alkyl group; R 4 is H or C 1-6 alkyl group.

[0205] In some embodiments, in the compound of formula I-1-1-2,

[0206] A is phenylene; R 1-1 is 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.

[0207] In some embodiments, in the compound of formula I-1-1-3 (e.g., I-1-1-3-a, I-1-1-3-b),

[0208] 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 group; R 4 is H or C 1-6 alkyl group.

[0209] In some embodiments, in the compound of formula I-1-1-3 (e.g., I-1-1-3-a, I-1-1-3-b),

[0210] t is 1 or 2; A is phenylene; X is -CR 3 R 4 -; R 3 is C 1-6 alkyl group; R 4 is C 1-6 alkyl group.

[0211] In some embodiments, in the compound of formula I-1-1-3 (e.g., I-1-1-3-a, I-1-1-3-b),

[0212] 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.

[0213] In some embodiments, the compound of 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

[0214] (e.g., ) (e.g., (corresponding to ) or );

[0215] R 1-1 is C 1-6 alkyl; X, R 2 , R 3 , R 4 , R 5 and R 6 are as defined above. In R 1-1 , 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.

[0216] In some embodiments, in the compound of formula I-A,

[0217] 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;

[0218] 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;

[0219] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0220] In some embodiments, in the I-A compound,

[0221] R 2 is H or C 1-6 alkyl; R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0222] R 5 is C 5a alkoxy substituted by one R 1-6 ; R 5a is hydroxy; R 6 is H.

[0223] In some embodiments, in the compound of formula I-B (e.g., I-B-1, I-B-2),

[0224] R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl;

[0225] 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;

[0226] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0227] In some embodiments, in the compound of formula I-B (e.g., I-B-1, I-B-2),

[0228] R 3 is C 1-6 alkyl; R 4 is C 1-6 alkyl;

[0229] R 5 is C 5a alkoxy substituted by one R 1-6 ; R 5a is hydroxy; R 6 is H.

[0230] In some embodiments, in the compound of formula I-C,

[0231] R 1-1 is C 1-6 alkyl;

[0232] 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;

[0233] 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;

[0234] R 6 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0235] In some embodiments, in the compound of formula I-C,

[0236] 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;

[0237] R 5 is C 5a alkoxy substituted by one R 1-6 ; R 5a is hydroxyl; R 6 is H.

[0238] In some embodiments, in the compound of formula I-D (e.g., I-D-1, I-D-2),

[0239] 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;

[0240] 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;

[0241] R 6is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0242] In some embodiments, in the compounds of formula I-D (e.g., I-D-1, I-D-2),

[0243] 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 substituted by one R 1-6 alkoxy; R 5a is hydroxy; R 6 is H.

[0244] In some embodiments, is ( )、 ( )、

[0245]

[0246] In some embodiments, R 6 is hydrogen.

[0247] In some embodiments, R 5 is

[0248] In some embodiments, is ( where the a end is connected to the phenylene group and the b end is connected to the carbonyl group).

[0249] In some embodiments, the compound represented by formula I is any of the following compounds:

[0250]

[0251]

[0252]

[0253] On the other hand, the present invention also provides a pharmaceutical composition comprising (i) a compound represented by formula I above or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0254] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as a drug.

[0255] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use as a drug.

[0256] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug.

[0257] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as an agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0258] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as a partial agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0259] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as an agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0260] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as a partial agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0261] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of an agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0262] On the other hand, the present invention also provides the use of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a partial agonist of a retinoic acid receptor (such as retinoic acid receptor γ).

[0263] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for the treatment and / or prevention of diseases.

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

[0265] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for treating and / or preventing diseases.

[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, skin keratosis disorders, pigmentation, or dry eye.

[0267] On the other hand, the present invention also provides an application of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases.

[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, skin keratosis disorders, pigmentation, or dry eye.

[0269] On the other hand, the present invention also provides an application of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as a drug for treating and / or preventing diseases related to retinoic acid receptors (such as 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, skin keratosis disorders, pigmentation, or dry eye.

[0271] On the other hand, the present invention also provides a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for treating and / or preventing diseases related to retinoic acid receptors (such as retinoic acid receptor γ).

[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, skin keratosis disorders, pigmentation, or dry eye.

[0273] On the other hand, the present invention also provides an application of a compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to retinoic acid receptors (such as retinoic acid receptor γ).

[0274] In some embodiments, the disease is 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 disease.

[0275] On the other hand, the present invention also provides a method for treating and / or preventing a disease associated with a retinoic acid receptor (such as retinoic acid receptor γ), which comprises administering to a subject in need of such treatment the compound of formula I as described above or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0276] In some embodiments, the disease is 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 disease.

[0277] On the other hand, the present invention also provides a compound of formula II or a salt thereof

[0278]

[0279] R 6’ is C 1-6 alkyl; R 7 is C 1-6 alkyl; A, R 2 、X and Y are as defined above.

[0280] In some embodiments, in R 7 ,the C 1-6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0281] In some embodiments, in R 6’ ,the C 1-6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as ethyl.

[0282] In some embodiments, the compound of formula II is any of the following compounds:

[0283]

[0284] On the other hand, the present invention also provides a method for preparing a compound of formula I, which comprises the following steps:

[0285] 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, and for another example, 1 mol / L aqueous sodium hydroxide solution), the compound shown in Formula II undergoes the following hydrolysis reaction (for example, at 50 - 70 °C, for another example, 60 °C) to obtain the compound shown in Formula I;

[0286]

[0287] R 6 is H; R 5 is R 5 connected to the para - position of A; m is 1; the definitions of A, X, Y, R 2 , R 6’ and R 7 are as described above.

[0288] In some embodiments, the method for preparing the compound shown in 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 (such as an alkali metal fluoride, 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, and for another example, the volume ratio of dioxane to water is 20:3 or 4:1), the compound shown in Formula III reacts with the compound shown in Formula IV in the following coupling reaction (for example, at 100 - 120 °C, for another example, 110 °C) to obtain the compound shown in Formula II;

[0289]

[0290] R 8 is a boronic ester group R 9 is a halogen (such as bromine); the definitions of A, X, Y, R 2 , R 6’ and R 7 are as described above.

[0291] On the other hand, the present invention also provides a method for preparing the compound shown in Formula II, which 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 (such as an alkali metal fluoride, 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, and for another example, the volume ratio of dioxane to water is 20:3 or 4:1), the compound shown in Formula III reacts with the compound shown in Formula IV in the following coupling reaction (for example, at 100 - 120 °C, for another example, 110 °C) to obtain the compound shown in Formula II;

[0292]

[0293] R 8 is a borate group R 9 is halogen (such as bromine); A, X, Y, R 2 , R 6’ and R 7 are defined as described above.

[0294] The positive and progressive effects of the present invention are as follows: The biphenyl compounds of the present invention (specifically, the compounds represented by formula I or pharmaceutically acceptable salts thereof) have good retinoic acid receptor γ agonist activity and high retinoic acid receptor γ selectivity, and have almost no agonist activity on retinoic acid receptor α and / or β, which is beneficial to reducing systemic side effects; more preferably, they have moderate partial agonist activity, have low skin irritation and few adverse reactions while maintaining the drug efficacy, have excellent safety and compliance, and can be used for the treatment and prevention of diseases related to retinoic acid receptor γ.

[0295] Term Definition

[0296] Unless otherwise specified, the terms used in the present invention have the following definitions, and the definitions of the terms not involved below are as commonly understood by those skilled in the art to which the present invention pertains.

[0297] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt prepared by a compound and a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, an alkali addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both a relatively acidic and a relatively basic functional group, it can be converted into an alkali addition salt or an acid addition salt.

[0298] In the present invention, the term "plurality" refers to a natural number greater than 2, such as 2, 3, 4, or 5.

[0299] In the present invention, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0300] In the present invention, the term "hydroxyl" means –OH.

[0301] In the present invention, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group having a certain number of carbon atoms. C 1–6Alkyl refers to an alkyl group having 1 to 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, etc.

[0302] In the present invention, the term "alkoxy" refers to -O-alkyl, where the alkyl is the alkyl as defined above.

[0303] In the present invention, the term "carbocyclic ring" refers to a saturated monocyclic or polycyclic ring having a specified number of carbon atoms. The term "C 3-8 carbocyclic ring" 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, the C 3-8 carbocyclic ring is a saturated monocyclic ring having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring carbon atoms, such as C3, C4, C5, or C6 saturated monocyclic rings. Specific examples include, but are not limited to, cyclopropylcarbocyclic ring (ternary carbocyclic ring), cyclobutylcarbocyclic ring (quaternary carbocyclic ring), cyclopentylcarbocyclic ring (quinary carbocyclic ring), cyclohexylcarbocyclic ring (hexagonal carbocyclic ring), etc. The polycyclic ring can be a spiro ring, a fused ring, or a bridged ring.

[0304] In the present invention, the term "heterocyclic ring" 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 heteroatoms (one or more of N, O, and S), including a monocyclic or polycyclic ring. The polycyclic ring can be a spiro ring, a fused ring, or a bridged ring.

[0305] In the present invention, the term "arylene" refers to a cyclic, unsaturated divalent hydrocarbon group having a specified number of carbon atoms (e.g., C6 - C 10 ), which is a monocyclic or polycyclic ring (e.g., 2 or 3); when it is a polycyclic ring, two atoms and one bond are shared between the monocyclic rings, and each ring has aromaticity. Arylene rings include, but are not limited to, phenylene and naphthylene.

[0306] 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), a specified type of heteroatoms (one or more of N, O, and S), which is a monocyclic or polycyclic ring; when it is a monocyclic ring, it can be pyridylene, and for example When it is a polycycle, two atoms and one bond are shared between single rings, and each ring has aromaticity; a polycycle means a heteroaromatic ring forms a fused ring with one or more aromatic rings or heteroaromatic rings.

[0307] In the present invention, the term "substituted by..." means that one or more hydrogen atoms in the given structure are substituted by specific substituents. Further, when the group is substituted by more than one of the above-mentioned substituents, the substituents are independent of each other, that is, the more than one substituents can be different from each other or the same. Unless otherwise clearly indicated, a substituent group can substitute at each substitutable position of the group to be substituted. When there is more than one position in the given structural formula that can be substituted by one or more substituents selected from specific groups, the substituents can substitute at each position either identically or differently.

[0308] When no substituent is explicitly indicated in the listed groups, such a group only refers to unsubstituted. For example, when there is no limitation of "unsubstituted or substituted" before "C 1-6 alkyl", it only refers to "C 1-6 alkyl" itself or "unsubstituted C 1-6 alkyl".

[0309] In addition, it should be noted that unless otherwise clearly indicated, in the present invention, the description method "... is independently" should be understood in a broad sense, which means that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the description method "... is independently" can either mean that among different groups, the specific options expressed between the same symbols do not affect each other; or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0310] In the present invention, the term "optionally substituted by..." means two situations: "substituted by..." or "unsubstituted".

[0311] In the present invention, a combination of substituents and / or their variants is only allowed if such a combination results in a reasonable compound.

[0312] In the present invention, the term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or leads to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects or side effects related to the disorder, or one or more symptoms, effects or side effects related to the disorder or its treatment, or (4) slowing down the development of the disorder or one or more biological manifestations of the disorder.

[0313] In the present invention, the term "therapeutically effective amount" refers to the amount of a compound that is sufficient to effectively treat or prevent the diseases or disorders described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed. Doses outside this range may also be used depending on the dosage form and the severity of the disease.

[0314] Without departing from the common general knowledge in the art, on the basis of the above preferred conditions, any combination can be made to obtain various preferred examples of the present invention.

[0315] The reagents and raw materials used in the present invention are all commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0316] Figure 1 It is the macroscopic observation score of animals during the efficacy test of the rabbit ear acne model in New Zealand. DETAILED DESCRIPTION OF THE INVENTION

[0317] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or are selected according to the product specifications.

[0318] General preparation method:

[0319] (1) In the presence of a catalyst (such as a palladium catalyst, such as Pd(dppf)Cl2) and an alkali metal halide (such as an alkali metal fluoride, 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 a volume ratio of dioxane to water of 20:3 or 4:1), the compound represented by formula III reacts with the compound represented by formula IV or formula IV' in the following reaction shown by the formula (such as 100 - 120 °C, such as 110 °C) to obtain the compound represented by formula II or formula II';

[0320]

[0321] R 8 is a boronic ester group R 9 is a halogen (such as bromine); A, X, Y, R 2 , R 6’ and R 7 are defined as described above;

[0322] (2) In an organic solvent (such as an alcohol solvent, such as methanol), in the presence of a base (such as an alkali metal hydroxide, such as sodium hydroxide, and for example, a 1 mol / L aqueous sodium hydroxide solution), the compound represented by formula II or the compound represented by formula II’ undergoes the following hydrolysis reaction (such as at 50 - 70 °C, such as 60 °C) to obtain the compound represented by formula I;

[0323]

[0324] R 6 is H; when the reactant is II, R 5 is m is 1, when the reactant is II’, R 5 is m is 1; R 5 is connected to the para-position of A; the definitions of A, X, Y, R 2 , R 6 ’, and R 7 are as described above.

[0325] Synthesis of compound Y - 001 in Example 1:

[0326]

[0327] Step 1: Synthesis of intermediate 1 - 2

[0328] Dissolve compound 1 - 1 (22 g, 127.89 mmol, 1 eq) in 300 mL of dichloromethane, and successively add triethylamine (31.99 g, 316.12 mmol, 2.47 eq) and 1 - 1a (21.23 g, 179.05 mmol, 1.4 eq). Stir the reaction system at 25 °C for 12 hours. Monitor by LCMS until the raw materials are completely consumed and the main product is formed. Monitor by TLC (petroleum ether / ethyl acetate = 10:1) until the raw materials are completely consumed and new product spots are formed. Add 500 mL of water to the reaction solution. Separate the organic phase, and extract the aqueous phase with dichloromethane (250 mL * 2). Combine the organic phases, wash with saturated brine (100 mL * 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which is then prepared by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 120 g Silica Flash Column; mobile phase gradient: 0 - 10% ethyl acetate / petroleum ether; flow rate: 60 mL / minute) to obtain intermediate 1 - 2 (24 g, yield: 73.85%). LCMS (ESI): m / z calculated value for C 11 H 13 BrNO + .[M + H] + = 254.02, 256.02, measured value [M + H]+ = 253.9, 255.9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.38 - 7.47 (m, 4H), 7.20 (br s, 1H), 5.70 (s, 1H), 2.22 (s, 3H), 1.90 (s, 3H).

[0329] Step 2: Synthesis of Intermediate 1-3

[0330] Dissolve Intermediate 1-2 (23 g, 90.51 mmol, 1 eq) in 500 mL of dichloromethane, and add aluminum trichloride (72.41 g, 543.04 mmol, 6 eq). After stirring the reaction system at 0 °C for 1 hour, it was slowly warmed to 25 °C and stirred for another 1 hour. LCMS monitored the complete consumption of the raw materials and the formation of the main product. Add 1 L of water to quench the reaction. Separate the organic phase, and extract the aqueous phase with dichloromethane (500 mL * 2). After combining the organic phases, wash with saturated sodium bicarbonate solution (300 mL * 2), saturated brine (300 mL * 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 120 g Silica Flash Column; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain Intermediate 1-3 as a white solid (21 g, yield: 91.30%). LCMS (ESI): m / z calculated for C 11 H 13 BrNO + .[M + H] + = 254.02, 256.02, found [M + H] + = 253.9, 255.9. 1 H NMR (400 MHz, CDCl3) δ ppm 9.34 (br s, 1H), 7.40 (d, J = 1.98 Hz, 1H), 7.29 (dd, J = 8.36, 2.20 Hz, 1H), 6.75 (d, J = 8.36 Hz, 1H), 2.48 (s, 2H), 1.33 (s, 6H).

[0331] Step 3: Synthesis of Intermediate 1-4

[0332] Dissolve intermediate 1-3 (6 g, 23.61 mmol, 1 eq) in 60 mL of toluene. At 0 °C, add dropwise a solution of borane dimethyl sulfide (10 M, 3.07 mL, 1.3 eq). After the addition, the reaction system is slowly warmed to room temperature and further heated to 120 °C for reflux for 5 hours. Monitor the complete consumption of the starting material by TLC (petroleum ether:ethyl acetate = 1:1). Monitor the formation of the main product by LCMS. Quench the reaction system with methanol and add saturated sodium bicarbonate solution (200 mL). Extract the mixture with dichloromethane (500 mL × 2). Combine the organic phases, wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which is purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 2% ethyl acetate / petroleum ether; flow rate: 40 mL / minute) to obtain intermediate 1-4 as a pale yellow oil (5 g, yield: 88.19%). LCMS (ESI): calculated m / z for C 11 H 15 BrN + .[M + H] + = 240.04, 242.04, found [M + H] + = 239.9, 241.9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.25 (d, J = 2.20 Hz, 1H), 7.02 (dd, J = 8.58, 2.42 Hz, 1H), 6.35 (d, J = 8.58 Hz, 1H), 6.35 (d, J = 8.58 Hz, 1H), 3.25 - 3.35 (m, 2H), 1.66 - 1.76 (m, 2H), 1.28 (s, 6H).

[0333] Step 4: Synthesis of intermediate 1-5

[0334] Dissolve intermediate 1-4 (4.5 g, 18.74 mmol, 1 eq) and sodium bicarbonate (2.72 g, 32.35 mmol, 1.73 eq) in 8 mL of water, and add dimethyl sulfate (4.82 g, 38.23 mmol, 2.04 eq). Stir the reaction system at 10 °C for 1 hour, then slowly warm to 50 °C and continue stirring for 1 hour. Dilute the reaction solution with 50 mL of water and extract with dichloromethane (50 mL × 2). Combine the organic phases, wash with saturated brine (30 mL × 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which is purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g Silica FlashColumn; mobile phase gradient: 0 - 2% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 1-5, which is a light yellow oil (4.2 g, yield: 88.19%). LCMS (ESI): m / z calculated value for C 12 H 17 BrN + .[M+H] + = 254.05, 256.05, measured value [M+H] + = 253.9, 255.9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.24 (d, J = 2.38 Hz, 1H), 7.14 (dd, J = 8.76, 2.38 Hz, 1H), 6.44 (d, J = 8.76 Hz, 1H), 3.19 - 3.26 (m, 2H), 2.88 (s, 3H), 1.69 - 1.82 (m, 2H), 1.27 (s, 6H).

[0335] Step 5: Synthesis of intermediate 1-6

[0336] Dissolve intermediate 1-5 (1 g, 3.93 mmol, 1 eq) and compound 1-5a (1.10 g, 4.33 mmol, 1.1 eq) in 10 mL of dioxane, and successively add potassium acetate (772.25 mg, 7.87 mmol, 2 eq) and Pd(dppf)Cl2 (287.89 mg, 393.44 μmol, 0.1 eq).

[0337] The reaction system was stirred at 100 °C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) monitored the complete consumption of the starting materials 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). After the organic phases were combined, they were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was then subjected to silica column chromatography (ISCO rapid liquid phase 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 1-6, which is a light yellow oil (927 mg, yield: 78.3%). LCMS (ESI): m / z calculated value for C 18 H 29 BNO2 + .[M+H] + = 302.23, measured value [M+H] + = 302.3.

[0338] Step 6: Synthesis of Intermediate 1-7

[0339] Dissolve Intermediate I-6a (1.1 g, 2.80 mmol, 1 eq) (the preparation method refers to Patent CN113501758A, 2021) and Intermediate I-6 (842.65 mg, 2.80 mmol, 1 eq) in 1.5 mL of water and 10 mL of dioxane, and add Pd(dppf)Cl2 (102.34 mg, 139.87 μmol, 0.05 eq) and potassium fluoride (487.55 mg, 8.39 mmol, 3 eq). The reaction system is stirred at 110 °C for 1 hour. LCMS monitors that the raw materials are completely consumed and the main product is formed. The reaction solution is diluted with 60 mL of ethyl acetate and 20 mL of water. The organic phase is washed with saturated ammonium chloride solution (20 mL * 2), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a residue, which is purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 60% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) to obtain Intermediate 1-7 as a light yellow oil (1.1 g, yield: 78.39%). LCMS (ESI): m / z calculated value for C 31 H 36 NO5 + .[M+H] + = 502.26, measured value [M+H] + = 502.2

[0340] Step 7: Synthesis of Compound Y-001

[0341] Dissolve Intermediate 1-7 (1.1 g, 2.19 mmol, 1 eq) in 50 mL of methanol, and add sodium hydroxide aqueous solution (1 M, 8.77 mL, 4 eq). The reaction system is stirred at 60 °C for 3 hours. LCMS monitors that the raw materials are completely consumed and the main product is formed. The pH of the reaction system is adjusted to 7 with 1 M hydrochloric acid, and extracted with ethyl acetate (50 mL * 2). After combining the organic phases, they are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a residue, which is purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 70% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) to obtain Compound Y-001 as a white solid (470 mg, yield: 46.2%, purity: 93%). LCMS (ESI): m / z calculated value for C 27 H 30NO4 + .[M+H] + = 432.22, measured value [M+H] + = 432.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.60 - 7.50 (m, 3H), 7.27 (dd, J = 2.0, 8.6 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 4.80 (t, J = 5.1 Hz, 1H), 4.14 - 4.01 (m, 2H), 3.73 (q, J = 5.0 Hz, 2H), 3.24 - 3.19 (m, 2H), 2.88 (s, 3H), 1.81 - 1.67 (m, 2H), 1.27 (s, 6H).

[0342] Synthesis of Compound Y-002 in Example 2

[0343]

[0344] Step 1 Synthesis of Intermediate 2-2

[0345] Dissolve Intermediate 2-1 (7 g, 30.96 mmol, 1 eq) and Intermediate 2-1a (20.16 g, 154.79 mmol, 5 eq) in 150 mL of acetonitrile, and add lithium perchlorate (6.45 g, 60.63 mmol, 1.96 eq), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (21.08 g, 92.87 mmol, 3 eq). The reaction system was stirred at -40 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 7:1) monitored that the raw materials reacted completely and the main product was formed. The reaction solution was quenched with saturated aqueous sodium sulfite solution (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 * 2). After the organic phases were combined, they were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g Silica FlashColumn; mobile phase gradient: 0 - 20% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain 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.

[0346] Step 2 Synthesis of Intermediate 2-3

[0347] Dissolve Intermediate 2-2 (1.4 g, 4.96 mmol, 1 eq) in 50 mL of tetrahydrofuran, and add Intermediate 2-2a (3.90 g, 10.92 mmol, 2.2 eq) and potassium tert-butoxide (1.11 g, 9.92 mmol, 2 eq). The reaction system was stirred at 70 °C for 1 hour. TLC (petroleum ether / ethyl acetate = 10:1) was used to monitor the complete reaction of the starting materials. LCMS was used to monitor the formation of the product. The reaction solution was concentrated under reduced pressure to a residue, and was purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g SilicaFlash Column; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain 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 (400 MHz, CDCl3) δ ppm 7.34 - 7.29 (m, 2H), 6.47 (d, J = 9.0 Hz, 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 = 14.3 Hz, 1H), 2.13 - 1.89 (m, 5H), 1.84 (s, 3H).

[0348] Step 3 Synthesis of Intermediate 2-4

[0349] Dissolve Intermediate 2-3 (1 g, 3.57 mmol, 1 eq) in 10 mL of concentrated sulfuric acid. The reaction system was stirred at 100 °C for 4 hours. LCMS was used to monitor 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). The combined organic phases 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, and was purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0 - 40% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 2-4, which is a white solid (870 mg, yield: 87%). LCMS (ESI): m / z calculated for C 14 H 19 BrN + .[M + H] + = 280.07, 282.07, found [M + H] + = 280.0, 282.0. 1 H NMR (400 MHz, CDCl3) δ ppm 7.25 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 2.4, 8.7 Hz, 1H), 6.27 (d, J = 8.6 Hz, 1H), 3.54 - 3.41 (m, 1H), 3.36 - 3.27 (m, 1H), 3.25 - 3.15 (m, 1H), 2.18 - 2.04 (m, 2H), 2.00 - 1.89 (m, 1H), 1.80 (dd, J = 3.3, 12.7 Hz, 1H), 1.49 - 1.42 (m, 1H), 1.35 (s, 4H), 1.21 (s, 3H).

[0350] Step 4 Synthesis of intermediate 2-5

[0351] Dissolve intermediate 2-4 (110 mg, 392.57 μmol, 1 eq) and compound 1-5a (109.66 mg, 431.83 μmol, 1.1 eq) in 15 mL of dioxane, and successively add potassium acetate (77.05 mg, 785.15 μmol, 2 eq) and Pd(dppf)Cl2 (28.72 mg, 39.26 μmol, 0.1 eq). Stir the reaction system at 100 °C for 12 hours. Monitor the complete consumption of the starting materials and the formation of the main product by TLC (petroleum ether:ethyl acetate = 4:1). Dilute the reaction solution with 20 mL of ethyl acetate and 20 mL of water. Separate the organic phase, and extract the aqueous phase with ethyl acetate (10 mL * 3). Combine the organic phases, wash with saturated brine (10 mL * 2), dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which is then purified by silica column chromatography (ISCO rapid liquid chromatography preparative instrument; 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, which is a colorless oil (70 mg, yield: 54.48%). LCMS (ESI): m / z calculated for C 20 H 31 BNO2 + .[M + H]+ = 328.24, measured value [M+H] + = 328.2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.64 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 8.1 Hz, 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, 12.6 Hz, 1H), 1.49 - 1.41 (m, 4H), 1.32 (s, 13H), 1.22 (s, 3H).

[0352] Synthesis of Intermediate 2-6 in Step 5

[0353] Dissolve Intermediate 1-6a (79 mg, 200.90 μmol, 1 eq) and Intermediate 2-5 (65.75 mg, 200.90 μmol, 1 eq) in 1 mL of water and 4 mL of dioxane, and add Pd(dppf)Cl2 (7.35 mg, 10.05 μmol, 0.05 eq) and potassium fluoride (35.02 mg, 602.70 μmol, 3 eq). The reaction system is stirred at 110 °C for 1 hour. LCMS monitors the complete consumption of the raw materials and the formation of the main product. The reaction solution is diluted with 15 mL of ethyl acetate and 10 mL of water. The organic phase is washed with saturated ammonium chloride solution (10 mL * 2), brine (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a residue, which is then purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 60% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) to obtain 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.

[0354] Synthesis of Compound Y-002 in Step 6

[0355] 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 formed. The pH of the reaction system was adjusted to 7 with 1 M hydrochloric acid and extracted with ethyl acetate (10 mL * 2). After the organic phases were combined, they were 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 purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0 - 70% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) to obtain Compound Y-002 as a white solid (42 mg, yield: 58.16%, purity: 96%). LCMS (ESI): calculated m / z for C 29 H 32 NO4 + .[M+H] + = 458.23, found [M+H] + = 458.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.61 - 7.49 (m, 3H), 7.27 (dd, J = 1.9, 8.3 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.41 (d, J = 8.5 Hz, 1H), 4.79 (t, J = 5.1 Hz, 1H), 4.07 (t, J = 5.2 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 3.46 (br d, J = 10.7 Hz, 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).

[0356] Example 3 Synthesis of Compound Y-003

[0357]

[0358] Step 1 Synthesis of Intermediate 3-2

[0359] Referring to the synthesis method in Step 4 of Reference Example 1 and replacing the corresponding raw materials, Intermediate 3-2 was prepared using Intermediate 1-4 and diethyl sulfate as raw materials, which was a colorless oil. LCMS (ESI): calculated m / z for C 13 H 19 BrN+ .[M+H] + = 268.07, 270.07, measured value [M+H] + = 268.0, 270.0. 1 H NMR (400 MHz, CDCl3) δ ppm 7.25 (d, J = 2.42 Hz, 1H), 7.12 (dd, J = 8.80, 2.42 Hz, 1H), 6.48 (d, J = 8.80 Hz, 1H), 3.35 (q, J = 7.12 Hz, 2H), 3.24 - 3.29 (m, 2H), 1.69 - 1.78 (m, 2H), 1.27 (s, 6H), 1.15 (t, J = 7.04 Hz, 3H).

[0360] Synthesis of Intermediate 3 - 3 in Step 2

[0361] Referring to the synthesis method in Step 5 of Reference Example 1, replacing the corresponding raw materials, using Intermediate 3 - 2 as the raw material, Intermediate 3 - 3 was prepared, which is 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 (400 MHz, CDCl3) δ ppm 7.62 (d, J = 1.2 Hz, 1H), 7.52 (dd, J = 1.4, 8.2 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 3.39 (q, J = 7.0 Hz, 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 = 7.0 Hz, 3H).

[0362] Synthesis of Compound Y - 003 in Step 3

[0363] Referring to the synthesis methods in Step 6 and Step 7 of Reference Example 1, replacing the corresponding raw materials, using Intermediate 3 - 3 as the raw material, Compound Y - 003 was prepared, which is a white solid. LCMS (ESI): m / z calculated value C 28 H 32 NO4 + .[M+H] + = 446.23, measured value [M+H] + = 446.2. 11H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.60 - 7.52 (m, 3H), 7.26 (dd, J = 2.1, 8.5 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.63 (d, J = 8.7 Hz, 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 = 7.0 Hz, 3H).

[0364] Chiral Separation and Preparation of Compounds Y-004 and Y-005 in Example 4

[0365]

[0366] The compound Y-002 (22 mg) prepared in Example 2 was further separated by chiral SFC. The chiral preparation conditions were as follows: chiral column DAICEL CHIRALPAK AD (specification: 250 mm * 30 mm, particle size 10 μm), the eluent was CO2 (A): ethanol containing 0.1% ammonia water (B), isocratic gradient (A / B = 60 / 40). The compound Y-004, the front peak, was obtained as a white solid (8.2 mg, yield: 36.52%, ee value: 98%).

[0367] LCMS (ESI): m / z calculated value C 29 H 32 NO4 + .[M + H] + = 458.23, measured value [M + H] + = 458.2.

[0368] 11H NMR (400 MHz, CD3OD) δ ppm 7.96 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.49 - 7.38 (m, 3H), 7.16 (dd, J = 1.9, 8.3 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.38 (d, J = 8.5 Hz, 1H), 3.99 (t, J = 4.9 Hz, 2H), 3.76 (t, J = 4.9 Hz, 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, 12.6 Hz, 1H), 1.41 - 1.38 (m, 1H), 1.31 - 1.28 (m, 4H), 1.17 (s, 3H).

[0369] Compound Y - 005 was obtained, the later peak, as a white solid (7.9 mg, yield: 35.19%, ee value: 98%).

[0370] LCMS (ESI): calculated m / z for C 29 H 32 NO4 + .[M + H] + = 458.23, found [M + H] + = 458.2.

[0371] 1 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.60 - 7.49 (m, 3H), 7.32 - 7.24 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 8.3 Hz, 1H), 4.11 (t, J = 4.9 Hz, 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, 12.6 Hz, 1H), 1.56 - 1.46 (m, 1H), 1.44 - 1.40 (m, 4H), 1.29 (s, 3H).

[0372] Chiral analysis conditions: The instrument is Waters UPCC equipped with a PDA detector, and the chiral column is Chiralpak AD-3 (specification: 150 mm * 4.6 mm, particle size 3 μm). The eluent is CO2 (A): ethanol (B) containing 0.05% ethylenediamine, isocratic gradient (A / B = 60 / 40); the flow rate is 2.5 mL per minute, and the column temperature is 35 °C; for compound Y-004, the front peak, retention time: about 4.53 minutes; for compound Y-005, the rear peak, retention time: about 5.45 minutes (compare the retention time of the separated compound with that of the product Y-005 prepared by chiral preparation in Example 5 to confirm the absolute chirality of the separated compound).

[0373] Synthesis of Compound Y-005 in Example 5

[0374]

[0375] Step 1 Synthesis of Intermediate 5-2

[0376] Dissolve compound 5-1 (2 g, 7.07 mmol, 1 eq) in 3 mL of DMF, and successively add cesium carbonate (5.76 g, 17.67 mmol, 2.5 eq), copper(I) iodide (403.92 mg, 2.12 mmol, 0.3 eq) and compound 5-1a (1.19 g, 7.07 mmol, 1 eq). The reaction solution is stirred at 80 °C for 1 hour. LCMS monitors that the raw materials are completely consumed and the main product is formed. After filtering the reaction system, the filtrate is 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 is evaporated to dryness under reduced pressure to obtain a residue, which is then purified by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain 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.

[0377] Step 2 Synthesis of Intermediate 5-3

[0378] Dissolve compound 5-2 (1.3 g, 4.58 mmol, 1 eq) in 40 mL of acetonitrile, and add potassium carbonate (1.90 g, 13.73 mmol, 3 eq) and methyl iodide (6.49 g, 45.75 mmol, 2.85 mL, 10 eq). The reaction system was stirred at 30 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) monitored that the raw materials were completely consumed and the main product spot was formed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to a residue, which was purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 12% ethyl acetate / petroleum ether; flow rate: 60 mL / minute) to obtain intermediate 5-3 as a colorless oil (900 mg, yield: 65.97%). LCMS (ESI): m / z calculated value for C 13 H 17 BrNO2 + .[M + H] + = 298.04, 300.04, found [M + H] + = 298.0, 300.0. 1 H NMR (400 MHz, CD3OD) δ ppm 7.35 - 7.29 (m, 2H), 6.49 (d, J = 8.9 Hz, 2H), 4.15 (dd, J = 3.5, 6.5 Hz, 1H), 3.73 (s, 3H), 3.41 - 3.38 (m, 1H), 3.16 (d, J = 8.2 Hz, 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, 6.7 Hz, 1H).

[0379] Step 3 Synthesis of intermediate 5-4

[0380] Dissolve compound 5-3 (1.30 g, 4.36 mmol, 1 eq) in 10 mL of tetrahydrofuran, and slowly add a tetrahydrofuran solution of methylmagnesium chloride (3 M, 5.81 mL, 4 eq) at 0 °C. After the addition was complete, the reaction system was stirred at 0 °C for 5 hours. LCMS monitored that the raw materials were completely consumed and the product was formed. 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 purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 12 g SilicaFlash Column; Mobile phase gradient: 0 - 56% ethyl acetate / petroleum ether; Flow rate: 30 mL / min) to obtain intermediate 5-4 as a colorless oil (550 mg, yield: 42.30%). LCMS (ESI): m / z calculated for C 14 H 21 BrNO + .[M+H] + = 298.08, 300.08, found [M+H] + = 298.1, 300.1.

[0381] Step 4 Synthesis of intermediate 5-5

[0382] Dissolve compound 5-4 (550 mg, 1.84 mmol, 1 eq) in 10 mL of dichloroethane and add aluminum trichloride (491.83 mg, 3.69 mmol, 2 eq). Stir the reaction system at 30 °C for 4 hours. Monitor the reaction by LCMS until the raw material is completely consumed and the product is formed. Slowly add the reaction solution dropwise to 15 mL of saturated aqueous sodium carbonate solution. Separate the organic phase, and extract the aqueous phase with ethyl acetate (5 mL * 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate the filtrate under reduced pressure to obtain a residue, which is purified by silica column chromatography (ISCO rapid liquid chromatography preparative instrument; column model: 4 g Silica Flash Column; Mobile phase gradient: 0 - 3% ethyl acetate / petroleum ether; Flow rate: 20 mL / min) to obtain intermediate 5-5 as a colorless oil (140 mg, yield: 27.15%). LCMS (ESI): m / z calculated for C 14 H 19 BrN + .[M+H] + = 280.07, 282.07, found [M+H] + = 280.0, 282.0.

[0383] Step 5 Synthesis of compound Y-005

[0384] Refer to the synthesis method in steps 4 - 6 of Example 2, replace the corresponding raw materials, and use intermediate 5-5 as the raw material to obtain compound Y-005 as a white solid. LCMS (ESI): m / z calculated for C 29 H 32 NO4 + .[M+H] + = 458.23, found [M+H] += 458.2. Chiral analysis conditions: Instrument Waters UPCC equipped with a PDA detector, chiral column Chiralpak AD-3 (specification: 150 mm * 4.6 mm, particle size 3 μm), elution phase is CO2 (A): ethanol containing 0.05% ethylenediamine (B), isocratic gradient (A / B = 60 / 40); flow rate 2.5 mL per minute, column temperature 35 °C; retention time is about 5.45 minutes.

[0385] Synthesis of Compound Y-006 in Example 6

[0386]

[0387] Step 1 Synthesis of Intermediate 6-2

[0388] Dissolve Intermediate 5-1 (2.98 g, 10.55 mmol, 2 eq) and Compound 6-1a (810 mg, 5.27 mmol, 1 eq) in 10 mL of DMSO, and successively add cesium carbonate (4.30 g, 13.18 mmol, 2.5 eq) and copper(I) iodide (301.28 mg, 1.58 mmol, 0.3 eq). Stir the reaction system at 100 °C for 10 hours. Monitor the consumption of raw materials by LCMS, and the main product is formed. After filtering the reaction system, dilute the filtrate with 30 mL of ethyl acetate, wash it with saturated ammonium chloride solution (10 mL * 2), saturated brine (10 mL * 2), dry it over anhydrous sodium sulfate, filter, evaporate the filtrate under reduced pressure to obtain a residue, and prepare Intermediate 6-2 by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 40 g Silica Flash Column; mobile phase gradient: 0 - 80% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to obtain 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.

[0389] Step 2 Synthesis of Intermediate 6-3

[0390] The 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 successively. The reaction system was stirred at 25 °C for 5 hours. LCMS monitored that the raw materials were completely consumed and the main product was formed. The reaction solution was concentrated under reduced pressure to a residue, and the intermediate 6-3 was prepared by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0 - 100% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) as a colorless oil (385 mg, yield: 91.52%). LCMS (ESI): calculated m / z for C 12 H 17 BrNO2 + .[M+H] + = 286.04, 288.04, measured value [M+H] + = 286.0, 288.0.

[0391] Step 3 Synthesis of intermediate 6-4

[0392] The intermediate 6-3 (240 mg, 838.68 μmol, 1 eq) was dissolved in 40 mL of tetrahydrofuran, and a tetrahydrofuran solution of methylmagnesium chloride (3 M, 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 that the raw materials were completely consumed and the product was formed. 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, and the intermediate 6-4 was prepared by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 12 g Silica FlashColumn; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) as a colorless oil (200 mg, yield: 83.38%). LCMS (ESI): calculated m / z for C 13 H 21 BrNO + .[M+H] + = 286.08, 288.08, measured value [M+H] + = 286.0, 288.0.

[0393] Step 4 Synthesis of intermediate 6-5

[0394] Compound 6-4 (200 mg, 698.79 μmol, 1 eq) was dissolved in 5 mL of dichloroethane, and aluminum trichloride (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 materials were completely consumed and the product was formed. 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 prepared by silica column chromatography (ISCO rapid liquid phase preparation chromatograph; column model: 4 g Silica Flash Column; mobile phase gradient: 0 - 5% ethyl acetate / petroleum ether; flow rate: 20 mL / minute) to obtain intermediate 6-5 as a colorless oil (160 mg, yield: 85.37%). LCMS (ESI): calculated m / z for C 13 H 19 BrN + .[M + H] + = 268.07, 270.07, measured value [M + H] + = 268.0, 270.0. 1 H NMR (400 MHz, CD3OD) δ ppm 7.21 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 2.4, 8.7 Hz, 1H), 6.46 (br d, J = 8.8 Hz, 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 = 6.0 Hz, 3H), 1.18 (s, 3H).

[0395] Step 5 Synthesis of Intermediate 6-6

[0396] Referring to the synthesis method of Step 5 in Reference Example 5, replacing the corresponding raw materials, using intermediate 6-5 as the raw material, intermediate 6-6 was prepared as a colorless oil. LCMS (ESI): calculated m / z for C 19 H 31 BNO2 + .[M + H] + = 316.24, measured value [M + H] + = 316.2. 11H NMR (400 MHz, CD3OD) δ ppm 7.63 - 7.50 (m, 2H), 6.58 (d, J = 8.2 Hz, 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 = 6.1 Hz, 3H), 1.19 (s, 3H).

[0397] Step 5 Synthesis of Compound Y - 006

[0398] Referring to the synthesis method of Y - 005 in Reference Example 5, replacing the corresponding raw materials, using Intermediate 6 - 6 as the raw material, Compound Y - 006 was prepared as a white solid. LCMS (ESI): m / z calculated for C 28 H 32 NO4 + .[M + H] + = 446.23, found [M + H] + = 446.2. 1 1H NMR (400 MHz, CD3OD) δ ppm 12.90 (br s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.61 - 7.54 (m, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 2.0, 8.6 Hz, 1H), 7.16 (d, J = 9.3 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 4.80 (t, J = 5.3 Hz, 1H), 4.07 (t, J = 5.2 Hz, 2H), 3.73 (br d, J = 5.2 Hz, 2H), 3.39 (br s, 1H), 2.88 (s, 3H), 1.76 (dd, J = 4.2, 13.2 Hz, 1H), 1.55 (dd, J = 11.0, 13.1 Hz, 1H), 1.32 (s, 3H), 1.23 (d, J = 6.1 Hz, 3H), 1.19 (s, 3H).

[0399] Biological Test Example 1

[0400] Using HEK - 293 cell lines transfected with RARα, RARβ and RARγ luciferase reporter genes, the agonist activities and selectivities of the compounds against RARα, RARβ and RARγ were tested

[0401] Experimental procedure:

[0402] 1. Cell culture

[0403] HEK293 cells were cultured in DMEM + 10% FBS medium in a humidified carbon dioxide incubator at 37 °C with 5% carbon dioxide concentration.

[0404] 2. Plasmid transfection and cell plating

[0405] Digest HEK293 cells with trypsin and adjust the HEK293 cell resuspension to 200,000 cells per milliliter with medium (96-well plate: 100 μL / well). Prepare the transfection reagent mixture according to the following table, mix well and let stand at room temperature for 20 minutes.

[0406] Test transfection materials

[0407] Experimental Transfection Materials Volume (μL) pG5 Luc Plasmid (100 ng / uL) 25 <![CDATA[pBIND-RARα / pBIND-RARβ / pBIND-RARγ(100ng / uL) * > 25 Opti-MEM Medium 250.0 P3000 10.00 Opti-MEM Medium 250.0 Lipofectamine 7.5

[0408] * Select the corresponding plasmid pBIND-RARα, pBIND-RARβ or pBIND-RARγ according to the test receptor

[0409] Add the prepared transfection reagent mixture to 10 mL of the resuspended cells with adjusted cell density respectively, mix well by inverting up and down, and seed into 96-well plates at a volume of 100 μL / well. Incubate the 96-well plates in a humidified incubator at 37 °C with 5% carbon dioxide concentration for 24 hours.

[0410] 3. Drug treatment

[0411] Serial dilute the positive control retinoic acid and the stock solution of the test compound into a series of 21× compound solutions according to a certain ratio, and add 5 μL of the retinoic acid dilution or the test compound dilution to each well of cells (already containing 100 μL of cell culture medium). Add 5 μL of 10% DMSO medium to the negative control wells (Min wells), and add 5 μL of 6.3 μM retinoic acid (dissolved in medium, 10% DMSO, final concentration 300 nM for Max wells) to the positive control wells. Place the detection plate back into the incubator and incubate for 24 hours.

[0412] 4. Luciferase assay

[0413] Use the Dual-Glo Luciferase Assay System kit from Promega to detect the test side plate, and use an EnSpire microplate reader to read the Firefly luciferase fluorescence signal and the Renilla Luciferase fluorescence signal respectively.

[0414] 5. Test results

[0415] 5.1 EC 50 Value

[0416] Import the data into MS Excel for curve fitting to obtain the EC 50 value. The test results are as follows.

[0417] The agonist activities of RAR series compounds against RARγ, RARα, and RARβ, EC 50 Test results

[0418]

[0419] Note: When the maximum activation rate is less than 50% of that of retinoic acid in the well x , the result is expressed as EC 50 > the maximum test concentration.

[0420] The compounds of the present invention have good agonist activity and selectivity against RARγ, almost no agonist activity against RARα and / or RARβ, have little systemic or other tissue side effects, and are less potent and more selective in agonist activity against RARα and RARβ compared to existing RARγ selective agonists (such as compound 10Y).

[0421] 5.2 E max value

[0422] The activation rate at each concentration is calculated by formula (1), and the maximum agonist activity E max (%) of the compound against RARγ is obtained through curve fitting.

[0423] Formula (1)

[0424] The compounds Y-004, Y-005, and Y-006 of the present invention exhibit partial agonist activity against RARγ (E max value is less than 75% relative to retinoic acid), and compared to existing RARγ full agonists (such as retinoic acid, compound 10Y, etc.), these compounds are expected to reduce the related adverse reactions caused by the full activation of RARγ.

[0425] Biological Test Example 2

[0426] Study on the skin irritation of local skin administration in minipigs

[0427] Test design:

[0428] The local skin irritation of the test substance was evaluated by the self-contrast method of the same minipig. The back skin of 3 female minipigs was divided into two regions, and the administration area of each region was about 300 cm 2, four groups of test substances were cross-evaluated in 4 cycles. One test substance was topically administered to the skin once a day for 3 consecutive days. To avoid unexpected interference, a 2-day washout period was set between the administrations of G2 and G3 groups and between the administrations of G3 and G4 groups. The test substances were G1 blank cream group, G2 0.05% Y-004 cream group (each gram of cream contains 500 μg of the active ingredient, the compound Y-004 of the present invention, i.e., the specification is 500 μg / g), G3 0.05% 10Y cream group (each gram of cream contains 500 μg of the active ingredient, compound 10Y, i.e., the specification is 500 μg / g), G4 0.025% 10Y cream group (each gram of cream contains 250 μg of the active ingredient, compound 10Y, i.e., the specification is 250 μg / g). The compositions of the creams in G2, G3, and G4 groups were the same as those in the blank cream group except for the active ingredients. The structure of compound 10Y is as follows

[0429]

[0430] Before the start of the experiment, the marked administration area was shaved and prepared for skin application. Pay attention to thorough removal without trauma. The shaved area should exceed the marked area. The administration area was marked with a marker pen. Before administration, it was washed with soapy water and pure water and wiped clean with a dry gauze.

[0431] A quantitative and equal amount of the test substance (1 ml / kg) was adhered to the administration site, and then a spreading device (such as a triangular glass rod) was used to evenly spread the preparation on the shaved and marked skin site of the animal. After the administration preparation was evenly spread, it was covered with an elastic breathable cotton gauze to ensure that the gauze at the administration site was fixed and the skin surface was breathable. Considering the influence of the animal's tearing, rubbing and other actions on the effective coverage of the drug, a net elastic bandage was used for fixation to prevent the administration from being affected by the animal's resistance actions.

[0432] Six hours after the administration of the test substance, the skin administration site was gently washed with soap and pure water to remove the residual unabsorbed cream. The skin irritation was observed and recorded within 3 consecutive days of continuous administration of the corresponding test substance in each cycle to compare the short-term irritation differences of the 4 groups of test substances after 3 consecutive days of skin administration.

[0433] Clinical observation and skin irritation response scoring:

[0434] Observe once at 6 h (before cleaning and removing the drug) and 24 h (before the next drug administration) after each drug administration. Focus on observing whether there are any skin reactions or symptoms such as erythema, crust formation, edema, skin thickening, etc. at the drug administration site. On the last day of each cycle (D3, D6, D11, D16), take pictures of the drug administration site to record the skin reaction. Try to take pictures of the drug administration site for recording the skin reaction at 10 min - 1 h after removing the drug, and refer to the skin irritation reaction scoring criteria in the "Technical Guidelines for the Study of Drug Irritation, Hypersensitivity and Hemolysis" to conduct the skin irritation reaction scoring.

[0435] Test results:

[0436] Under the conditions of this test, after continuous drug administration for 3 days, the G1 blank cream group and the G2 Y-004 cream 0.05% (500 μg / g) specification group had no irritation to the skin of miniature Bama pigs (the skin irritation intensity score was 0), and no abnormal skin reactions or symptoms were found; while the G3 10Y cream 0.05% (500 μg / g) specification group and the G4 10Y cream 0.025% (250 μg / g) specification group had irritation to the skin of miniature Bama pigs, mainly manifested as erythema, redness and swelling, and secondary crusting and desquamation symptoms. Moreover, the degree and duration of the symptoms showed a certain dose-dependence. The highest scores of skin irritation intensity for the 250 μg / g and 500 μg / g specifications were 2 points and 4 points respectively, with certain individual differences. No abnormal changes related to the test substance were found in clinical signs, body weight, and food intake.

[0437] Biological Test Example 3

[0438] Evaluate the pharmacodynamic effect of the compound on the New Zealand rabbit ear acne model

[0439] Test design:

[0440] Male New Zealand rabbits that passed quarantine (Suzhou Xishan Biotechnology Co., Ltd., quarantine certificate number 370823241100331316) were selected for model establishment. For each animal, the left ear was evenly smeared with 0.4 - 0.5 mL / ear of a disinfected cotton swab soaked with 75% oleic acid, and the right ear of the animal was not treated. It was smeared once a day for 11 consecutive days of model establishment. On the 7th day of model establishment (MDay7), the drug administration area (2 cm × 3 cm) was determined according to the acne symptoms on the animal's ear, and a special tattoo machine for small animals was used to mark the drug administration area. On the 11th day of model establishment (MDay11), 24 animals with moderate or moderately severe macroscopic observation scores on the modeled rabbit ears were selected and randomly and evenly 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, the active ingredient is tretinoin, and each g of cream contains 250 μg of tretinoin), and a 0.025% Y - 004 cream group (specification 250 μg / g, the active ingredient is the compound Y - 004 of the present invention, and each g of cream contains 250 μg of the compound Y - 004 of the present invention. The excipients except the active ingredient are the same as those of the blank cream in the model control group). Each group had 8 animals, all of which were male. Approximately 24 hours after the last model establishment, the corresponding control product / test article was administered within the marked area, 0.06 mL / ear, once a day. After each administration, the residual drug was cleaned with a cotton ball soaked with 0.9% sodium chloride injection 6 h ± 0.5 h later. The administration was continued for 7 days, and the animals were dissected 24 h after the last administration.

[0441] During the experiment, the general symptoms of the animals and the skin changes at the model establishment / drug administration site were observed and recorded daily; the animal body weight was measured once a week, and macroscopic observation scores were made on the model establishment / drug administration area of the animals before the first administration and before dissection.

[0442] Macroscopic observation grading criteria for acne manifestations

[0443]

[0444] Note: #Before dissection, due to the therapeutic effect or self - recovery of the model control, the comedones during model establishment had turned into dilated and elevated hair follicle orifices. Nomenclature definitions:

[0445] 1. Comedo: A tiny white macule or papule, 0.5 - 3 mm in diameter, mostly less than 1 mm.

[0446] 2. Papule: A small, slightly hard, red protrusion less than 0.5 cm in diameter.

[0447] 3. Pustule: A circumscribed elevation appears on the skin at the top of the papule, containing yellow - white exudate.

[0448] 4. Nodules / cysts: Located under the skin, with no skin damage on the surface, most of them are 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.

[0449] Test results:

[0450] General condition of animals: During the administration period, the animals in each group were in good general condition and no obvious abnormalities were observed.

[0451] Body weight: The body weight of animals in each group was relatively stable during the administration period, and no obvious abnormality was observed. After 7 consecutive days of administration, the body weight of animals in each group was basically consistent (P>0.05).

[0452] 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), retinoic acid 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 retinoic acid 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, and 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 in each group compared with the model control group, P>0.05 in the Y-004 cream group compared with the retinoic acid cream control group.)

[0453] The Y-004 cream 0.025% group of the present invention can significantly reduce the acne manifestation naked eye observation score of 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 by one or more R 1-6 alkyl, C 1-6 alkoxy or C 5a alkoxy substituted by one or more R 1-6 alkoxy; R 5a are each independently a halogen or a hydroxyl group; m is 0, 1, 2 or 3; R 6 is H or C 1-6 alkyl; When Y is -CR 1 R'- then 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 of formula I satisfies one or more of the following conditions: (1) In A, the 6- to 10-membered arylene is phenylene or naphthylene, for example, 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 phenyl group 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 and the atoms therebetween together form a 3- to 8-membered heterocyclic ring, and the 3- to 8-membered heterocyclic ring 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 and the atoms between them together form a 3- to 8-membered heterocycle, with the number of heteroatoms being 1, and the heteroatom is preferably N; (10)R 3 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; (11)R 4 wherein said 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 Among them, the C 5a alkoxy group substituted by one or more Rs 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 also such as (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 In which, said 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 as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of 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 and the atoms therebetween together 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 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 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 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 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 by one or more R 1-6 Preferably, R 5 is C 5a alkoxy substituted by 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 and the atoms therebetween together 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 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; 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 of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The compound of 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 a phenylene group and the b-end is connected to a 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 of 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 therebetween form a C 3-8 carbocyclic ring; the C 3-8 carbocyclic ring is a monocyclic ring (e.g., a 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 heterocyclic ring (e.g., 4- to 6-membered heterocyclic ring); the 3- to 8-membered heterocyclic ring 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 alkoxy substituted by one or more R 1-6 ; 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 (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 C 1-6 alkyl; R 4 is C 1-6 alkyl; R 5 is a C alkoxy group substituted by an R 5a substituted by an R 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 between them form a C 3-8 carbocyclic ring (e.g., a 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., 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 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 or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that The compound of 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 of 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., 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; 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 together with the atoms therebetween 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 compounds 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 compounds 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 is an R 5a substituted C 1-6 alkoxy group; R 5a is a hydroxyl group; R 6 is H; More preferably, the compound of 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; Also preferably, the compound of 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 a C alkoxy group substituted by an R 5a substituted by an R 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 compounds 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 I-1-c-1 and I-1-c-2), t is 1 or 2; m is 0 or 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 one or more R 1-6 groups; 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 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 an R 5a substituted C 1-6 alkoxy group; 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 of 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 as defined in any one of claims 1-4; Preferably, the compound of 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., 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 and 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 and 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 of 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; Even more preferably, the compound of 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 and 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 and 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 and 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 of 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; in R 1-1 , 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 of 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 hydroxy; 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 a C 5a alkoxy group substituted by an R 1-6 ; R 5a is a hydroxyl group; R 6 is H; (2) In the compound of formula I-B (such as I-B-1 and 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 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-B (such as I-B-1 and I-B-2), 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; (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 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-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 and 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 and 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 claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I is any of the following compounds:

10. A pharmaceutical composition comprising (i) a compound of 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 of 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 of 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, acne rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, psoriasis, ichthyosis, skin keratosis disorders, 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 the pharmaceutical composition as described in claim 10 in the preparation of a drug; Preferably, the drug is used for treating and / or preventing acne (including acne vulgaris, acne rosacea, nodulocystic acne, conglobate acne, and secondary acne caused by sunlight or drug treatment), comedones, 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 In which, said C 1-6 The 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 of 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, such as methanol), in the presence of a base (such as an alkali metal hydroxide, such as sodium hydroxide, such as 1 mol / L aqueous sodium hydroxide solution), the compound of formula II undergoes the following hydrolysis reaction (such as 50-70 °C, such as 60 °C) to obtain the compound of formula I; R 6 is H; R 5 is R 5 is connected to the para-position of A, m is 1; A, X, Y and R 2 are defined as described in any one of claims 1-9, R 6’ and R 7 are defined as described in claim 14; Preferably, the preparation method of the compound of formula I further includes 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, such as the volume ratio of dioxane to water is 20:3 or 4:1), the compound of formula III reacts with the compound of formula IV in the following coupling reaction (such as 100-120 °C, such as 110 °C) to obtain the compound of formula II; R 8 is a borate group R 9 is a halogen (such as bromine); A, X, Y, and R 2 are as described in any one of claims 1 - 9; R 6’ and R 7 are defined as described in claim 14 16. A preparation method of a compound of formula II, which includes 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, such as the volume ratio of dioxane to water is 20:3 or 4:1), the compound of formula III reacts with the compound of formula IV in the following coupling reaction (such as 100-120 °C, such as 110 °C) to obtain the compound of formula II; R 8 is a borate group R 9 is a halogen (e.g., bromine); A, X, Y, and R 2 are 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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