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

Abstract

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

Description

BIPHENYL COMPOUND, PREPARATION METHOD THEREFOR, AND INTERMEDIATE, PHARMACEUTICAL COMPOSITION AND USE THEREOF SPECIFICATION

[0001] The present application claims priority to Chinese Patent Application 2024100337288 filed on January 09, 2024 and Chinese Patent Application 2024119438632 filed on December 26, 2024. The contents of the above Chinese patent applications are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to a biphenyl compound, a preparation method therefor, an intermediate thereof, a pharmaceutical composition thereof, and a use thereof. BACKGROUND

[0003] Retinoic acid receptor (RAR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, and its main ligands are retinoids. After binding to its ligand retinoic acid, RAR 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: RAR<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, RAR<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, and RAR<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>, wherein RAR<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> is widely distributed in most tissues such as lung, spleen, and gallbladder, RARB is mainly expressed in placenta, kidney, heart, nervous system, etc., and RARγ is mainly expressed in skin, epithelium, and cartilage tissues.

[0004] Synthetic or endogenous retinoic acid (vitamin A acid) substances can regulate gene transcription and expression in suprabasal cells by binding to and activating RARy in the skin tissue, thereby indirectly regulating keratinization, promoting normal keratinization of the epidermis, and inhibiting excessive proliferation of keratinocytes. Clinically available retinoids such as tretinoin, isotretinoin, acitretin, etretinate, aromatic retinoic acid, ethyl ester of aromatic retinoic acid, adapalene, and tazarotene are used in the treatment of psoriasis, skin keratinization diseases, eczema, acne, etc. However, since these retinoid drugs are non- selective RAR 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] Since RARy is mainly expressed in the skin, highly selective RARy agonists have become a research hotspot in recent years. Thoreau et al. reported in patent US8362082B2 RARy selective agonists such as compound 10Y having the following structure. [Image disponible dans le document PDF, Image available in the PDF document] 10Y

[0006] Although these compounds can appropriately improve selectivity relative to RARa and RARβ, according to literature reports and studies, they have certain agonist activity against RARα and / or RARβ, leading to systemic or other tissue side effects. In addition, existing RARy selective agonist compounds of this type have a full agonist effect on RARy similar to retinoic acid, posing a risk of adverse reactions caused by full activation, causing significant skin irritation, and topical application results in severe adverse reactions such as erythema, desquamation, and stinging. Therefore, there is still a need to develop novel RARy selective agonists with better selectivity and / or reduced risk of overactivation and / or low irritation. SUMMARY

[0007] The present disclosure provides a biphenyl compound, a preparation method therefor, an intermediate thereof, a pharmaceutical composition thereof, and a use thereof. Such compounds have good retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> agonist activity and retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> selectivity, with little to no agonist activity against retinoic acid receptor α and / or retinoic acid receptor β, which is beneficial for reducing systemic side effects; more preferably, they have moderate partial agonist activity, resulting in low skin irritation, few adverse reactions, and excellent safety and compliance while maintaining efficacy.

[0008] In one aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] I

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

[0010] Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR1R′<annotation encoding="application / x-tex">-CR^1R'< / annotation>< / semantics>< / com:Math>-;

[0011] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0012] R' is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0013] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8- membered heterocycle or a C<com:Sub>3-8< / com:Sub> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; the 3- to 8- membered heterocycle and <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle are optionally substituted with one or more <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen;

[0014] X is -NR<com:Sup>3< / com:Sup>- or -CR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>-; R<com:Sup>3< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; R<com:Sup>4< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0015] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more R<com:Sup>5a< / com:Sup>;

[0016] each R<com:Sup>5a< / com:Sup> is independently halogen or hydroxyl;

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

[0018] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0019] when Y is -CR<com:Sup>1< / com:Sup>R'-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8- membered heterocycle or a C<com:Sub>3-8< / com:Sub> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0020] In some embodiments, in the compound of formula I or the pharmaceutically acceptable salt thereof, certain groups have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present disclosure (hereinafter referred to as "in some embodiments").

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

[0022] In some embodiments, in A, the 5- to 6-membered heteroarylene may have 1 heteroatom, and the heteroatom is preferably N, for example, pyridylene, and for another [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] example, or , wherein the a end is connected to phenylene, and the b end is connected to carbonyl).

[0023] In some embodiments, in <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0024] In some embodiments, in R', the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0025] In some embodiments, in <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0026] In some embodiments, in the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle formed by <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> together with the intervening atom, the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle may be monocyclic, such as <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> monocyclic carbocycle, for example, cyclopentane (5-membered carbocycle).

[0027] In some embodiments, in the 3- to 8-membered heterocycle formed by R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup> together with the intervening atom, the 3- to 8-membered heterocycle may have 1 heteroatom, and the heteroatom is preferably N; and / or may be monocyclic; the 3- to 8-membered heterocycle is preferably a 4- to 6-membered heterocycle, more preferably a 4- to 6-membered [Image disponible dans le document PDF, Image available in the PDF document] monocyclic heterocycle; for example, .

[0028] In some embodiments, in <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0029] In some embodiments, in <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0030] In some embodiments, in <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0031] In some embodiments, in <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, ethoxy, n-propoxy, or n-butoxy.

[0032] In some embodiments, in R<com:Sup>5a< / com:Sup>, the halogen may be fluorine, chlorine, bromine, or iodine.

[0033] In some embodiments, in <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, for example, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one hydroxyl.

[0034] In some embodiments, in <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> may be <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, for example, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one hydroxyl, [Image disponible dans le document PDF, Image available in the PDF document] and for another example,

[0035] In some embodiments, in <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0036] In some embodiments, in <com:Math><semantics>ℝ2−1<annotation encoding="application / x-tex">\mathbb{R}^{2-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0037] In some embodiments, in <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0038] In some embodiments, in <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>, the halogen may be fluorine, chlorine, bromine, or iodine.

[0039] In some embodiments, the more than one refers to 2 or 3.

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

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

[0042] In some embodiments, Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-; preferably, Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-.

[0043] In some embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle or a C<com:Sub>3-8< / com:Sub> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic; more preferably, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a C<com:Sub>3-8< / com:Sub> carbocycle (for example, a C<com:Sub>4-6< / com:Sub> carbocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the C<com:Sub>3-8< / com:Sub> carbocycle is monocyclic.

[0044] In some embodiments, X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-.

[0045] In some embodiments, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0046] In some embodiments, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0047] In some embodiments, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, preferably, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^{5}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>.

[0048] In some embodiments, R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl, preferably, R<com:Sup>5a< / com:Sup> is hydroxyl.

[0049] In some embodiments, <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably, R<com:Sup>6< / com:Sup> is H.

[0050] In some embodiments, when Y is <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably, when Y is <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic (for example, the <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> monocyclic carbocycle); more preferably, when Y is -CHR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic.

[0051] In some embodiments, when Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is optionally substituted with one or more <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, wherein at least one of the heteroatoms is N; preferably, when Y is -NR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is optionally substituted with one or more R<com:Sup>2-1< / com:Sup>; each R<com:Sup>2-1< / com:Sup> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen; the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N.

[0052] In some embodiments,

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

[0054] A is 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6- membered heteroarylene has 1 heteroatom, and the heteroatom is N;

[0055] Y is -NR<com:Sup>1< / com:Sup>- or -CHR<com:Sup>1< / com:Sup>-;

[0056] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a C<com:Sub>3-8< / com:Sub> carbocycle (for example, a C<com:Sub>4-6< / com:Sub> carbocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, the <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle) is monocyclic;

[0057] X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-;

[0058] <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0059] <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0060] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0061] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0062] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0063] when Y is -CHR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the C<com:Sub>3-8< / com:Sub> carbocycle is monocyclic (for example, C<com:Sub>4-6< / com:Sub> monocyclic carbocycle).

[0064] In some embodiments,

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

[0066] A is 6- to 10-membered arylene;

[0067] Y is -NR<com:Sup>1< / com:Sup>-;

[0068] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0069] <com:Math><semantics>X is −CR3R4<annotation encoding="application / x-tex">X \text{ is } -CR^3R^4< / annotation>< / semantics>< / com:Math>-;

[0070] <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0071] <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0072] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0073] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0074] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0075] In some embodiments,

[0076] m is 1;

[0077] A is 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6- membered heteroarylene has 1 heteroatom, and the heteroatom is N;

[0078] Y is -NR<com:Sup>1< / com:Sup>- or -CHR<com:Sup>1< / com:Sup>-;

[0079] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, the <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle) is monocyclic;

[0080] X is -NR<com:Sup>3< / com:Sup>- or -CR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>-; R<com:Sup>3< / com:Sup> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; R<com:Sup>4< / com:Sup> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0081] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0082] R<com:Sup>5a< / com:Sup> is hydroxyl;

[0083] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H;

[0084] when Y is -CHR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a C<com:Sub>4-6< / com:Sub> carbocycle), and the C<com:Sub>3-8< / com:Sub> carbocycle (for example, the C<com:Sub>4-6< / com:Sub> carbocycle) is monocyclic.

[0085] In some embodiments,

[0086] m is 1;

[0087] A is 6- to 10-membered arylene;

[0088] Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-;

[0089] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0090] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0091] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0092] R<com:Sup>5a< / com:Sup> is hydroxyl;

[0093] R<com:Sup>6< / com:Sup> is H.

[0094] In some embodiments, the compound of formula I may be a compound of formula I- 1 or a compound of formula I-2: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1 I-2 (for example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-2-a or I-2-b );

[0095] n is 0, 1, 2, or 3; m, A, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, X, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> are as defined above.

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

[0097] m is 0, 1, or 2;

[0098] A is 6- to 10-membered arylene;

[0099] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0100] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0101] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0102] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0103] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0104] In some embodiments, in the compound of formula I-1,

[0105] m is 1; A is phenylene;

[0106] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl or H; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0107] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0108] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0109] R<com:Sup>5a< / com:Sup> is hydroxyl;

[0110] R<com:Sup>6< / com:Sup> is H.

[0111] In some embodiments, in the compound of formula I-2 (for example, compound of I- 2-a or I-2-b),

[0112] n is 0, 1, or 2;

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

[0114] A is 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6- membered heteroarylene has 1 heteroatom, and the heteroatom is N;

[0115] X is -NR<com:Sup>3< / com:Sup>- or -CR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>-; R<com:Sup>3< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; R<com:Sup>4< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0116] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0117] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0118] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0119] In some embodiments, in the compound of formula I-2 (for example, compound of I- 2-a or I-2-b),

[0120] n is 1; m is 1; A is phenylene;

[0121] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0122] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0123] <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl;

[0124] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

[0125] 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: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-a I-1-b [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-c (for example, I-1-c-1 [Image disponible dans le document PDF, Image available in the PDF document] or I-1-c-2 );

[0126] t is 0, 1, 2, or 3; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; m, A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, X, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> are as defined above. In <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0127] In some embodiments, in the compound of formula I-1-a,

[0128] m is 0, 1, or 2;

[0129] A is 6- to 10-membered arylene;

[0130] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0131] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0132] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0133] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0134] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0135] In some embodiments, in the compound of formula I-1-a,

[0136] m is 1; A is phenylene;

[0137] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0138] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0139] <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl;

[0140] R<com:Sup>6< / com:Sup> is H.

[0141] In some embodiments, in the compound of formula I-1-b,

[0142] m is 0, 1, or 2;

[0143] A is 6- to 10-membered arylene;

[0144] <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0145] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0146] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0147] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0148] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0149] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0150] In some embodiments, in the compound of formula I-1-b,

[0151] m is 1; A is phenylene;

[0152] <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0153] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0154] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0155] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0156] <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl;

[0157] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

[0158] In some embodiments, in the compound of formula I-1-c (for example, compound of I-1-c-1 or I-1-c-2),

[0159] t is 0, 1, or 2;

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

[0161] A is 6- to 10-membered arylene;

[0162] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0163] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0164] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0165] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0166] In some embodiments, in the compound of formula I-1-c (for example, compound of I-1-c-1 or I-1-c-2),

[0167] t is 1 or 2; m is 0 or 1; A is phenylene;

[0168] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0169] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0170] R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl;

[0171] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0172] In some embodiments, in the compound of formula I-1-c (for example, compound of I-1-c-1 or I-1-c-2),

[0173] t is 1; m is 1; A is phenylene;

[0174] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0175] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>;

[0176] <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl;

[0177] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> 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: [Image disponible dans le document PDF, Image available in the PDF document] example,

[0179] n is 0, 1, 2, or 3; A, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, and X are as defined above.

[0180] In some embodiments, in the compound of formula I-1-1,

[0181] A is 6- to 10-membered arylene;

[0182] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0183] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0184] In some embodiments, in the compound of formula I-1-1,

[0185] A is phenylene;

[0186] <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle (for example, the 4- to 6-membered heterocycle) is monocyclic and has 1 heteroatom, and the heteroatom is N;

[0187] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0188] In some embodiments, in the compound of formula I-2-1 (for example, I-2-1-a, I-2-1- b),

[0189] n is 0, 1, or 2; A is 6- to 10-membered arylene;

[0190] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0191] In some embodiments, in the compound of formula I-2-1 (for example, I-2-1-a, I-2-1- b),

[0192] n is 1; A is phenylene;

[0193] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0194] 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: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-1 I-1-1-2 or , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-3 (for example, I-1-1-3-a or [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-3-b );

[0195] t is 0, 1, 2, or 3; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, and X are as defined above. In <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−1<annotation encoding="application / x-tex">C_{1-1}< / annotation>< / semantics>< / com:Math> 6 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0196] In some embodiments, in the compound of formula I-1-1-1,

[0197] A is 6- to 10-membered arylene; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

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

[0199] A is phenylene; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0200] In some embodiments, in the compound of formula I-1-1-2,

[0201] A is 6- to 10-membered arylene; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

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

[0203] A is phenylene; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0204] In some embodiments, in the compound of formula I-1-1-3 (for example, I-1-1-3-a, I- <com:Math><semantics>1−1−3−b),<annotation encoding="application / x-tex">1-1-3-b),< / annotation>< / semantics>< / com:Math>

[0205] t is 0, 1, or 2; A is 6- to 10-membered arylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

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

[0207] t is 1 or 2; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

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

[0209] t is 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

[0210] 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 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-D-1 ) or I-D-2 );

[0211] <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>X<annotation encoding="application / x-tex">X< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> are as defined above. In <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0212] In some embodiments, in the compound of formula I-A,

[0213] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0214] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl;

[0215] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

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

[0217] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0218] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

[0219] In some embodiments, in the compound of formula I-B (for example, I-B-1, I-B-2),

[0220] <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0221] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl;

[0222] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0223] In some embodiments, in the compound of formula I-B (for example, I-B-1, I-B-2),

[0224] <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0225] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

[0226] In some embodiments, in the compound of formula I-C,

[0227] <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0228] <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0229] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl;

[0230] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0231] In some embodiments, in the compound of formula I-C,

[0232] <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0233] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

[0234] In some embodiments, in the compound of formula I-D (for example, I-D-1, I-D-2),

[0235] X is -NR<com:Sup>3< / com:Sup>- or -CR<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup>-; R<com:Sup>3< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; R<com:Sup>4< / com:Sup> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl;

[0236] <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl;

[0237] R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0238] In some embodiments, in the compound of formula I-D (for example, I-D-1, I-D-2),

[0239] X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl;

[0240] R<com:Sup>6< / com:Sup> is H. [Image disponible dans le document PDF, Image available in the PDF document]

[0242] In some embodiments, R<com:Sup>6< / com:Sup> is hydrogen. [Image disponible dans le document PDF, Image available in the PDF document]

[0243] In some embodiments, R<com:Sup>5< / com:Sup> is [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0244] In some embodiments, is or [Image disponible dans le document PDF, Image available in the PDF document] , wherein the a end is connected to phenylene, and the b end is connected to carbonyl).

[0245] In some embodiments, the compound of formula I is any one of the following compounds: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] •

[0246] In another aspect, the present disclosure also provides a pharmaceutical composition comprising (i) the above compound of formula I or the pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

[0247] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as a medicament.

[0248] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use as a medicament.

[0249] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the manufacture of a medicament.

[0250] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>) agonist.

[0251] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as a retinoic acid receptor (for example, retinoic acid receptor γ) partial agonist.

[0252] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use as a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>) agonist.

[0253] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use as a retinoic acid receptor (for example, retinoic acid receptor γ) partial agonist.

[0254] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the manufacture of a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>) agonist.

[0255] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the manufacture of a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>) partial agonist.

[0256] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use in treating and / or preventing a disease.

[0257] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0258] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use in treating and / or preventing a disease.

[0259] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0260] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing a disease.

[0261] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0262] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, as a medicament for treating and / or preventing a disease associated with a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>).

[0263] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0264] In another aspect, the present disclosure also provides the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, for use in treating and / or preventing a disease associated with a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>).

[0265] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0266] In another aspect, the present disclosure also provides a use of the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing a disease associated with a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>).

[0267] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0268] In another aspect, the present disclosure also provides a method of treating and / or preventing a disease associated with a retinoic acid receptor (for example, retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>), comprising administering to a subject in need thereof the above compound of formula I or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0269] In some embodiments, the disease is acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

[0270] In another aspect, the present disclosure also provides a compound of formula II or a salt thereof [Image disponible dans le document PDF, Image available in the PDF document] II

[0271] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^{6}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>A<annotation encoding="application / x-tex">A< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X<annotation encoding="application / x-tex">X< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>Y<annotation encoding="application / x-tex">Y< / annotation>< / semantics>< / com:Math> are as defined above.

[0272] In some embodiments, in <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0273] In some embodiments, in <com:Math><semantics>R6<annotation encoding="application / x-tex">R^{6}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, ethyl.

[0274] In some embodiments, the compound of formula II is any one of the following compounds: [Image disponible dans le document PDF, Image available in the PDF document]

[0275] In another aspect, the present disclosure also provides a method for preparing a compound of formula I, comprising the following steps:

[0276] subjecting a compound of formula II to a hydrolysis reaction as shown below (for example, at 50-70°C, further for example, at 60°C) in an organic solvent (for example, an alcohol solvent, further for example, methanol) in the presence of a base (for example, an alkali metal hydroxide, further for example, sodium hydroxide, still further for example, 1 mol / L aqueous sodium hydroxide solution) to obtain the compound of formula I; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0277] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is is attached at the para position of A; m is 1; A, X, Y, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6′<annotation encoding="application / x-tex">R^{6'}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined above.

[0278] In some embodiments, the method for preparing the compound of formula I further comprises the following step: subjecting a compound of formula III and a compound of formula IV to a coupling reaction as shown in the following scheme (for example, at 100-120°C, further for example, at 110°C) in a solvent (for example, a mixed solvent of water and a cyclic ether solvent, further for example, a mixed solvent of water and dioxane, still further for example, dioxane and water in a volume ratio of 20:3 or 4:1) in the presence of a catalyst (for example, a palladium catalyst, further for example, Pd(dppf)Cl<com:Sub>2< / com:Sub>) and an alkali metal halide salt (for example, an alkali metal fluoride salt, further for example, KF) to obtain the compound of formula II; [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document]

[0279] R<com:Sup>8< / com:Sup> is a boronate ester group is halogen (for example, bromine); A, <com:Math><semantics>X,Y,R2,R6′<annotation encoding="application / x-tex">X, Y, R^2, R^{6'}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined above.

[0280] In another aspect, the present disclosure also provides a method for preparing a compound of formula II, comprising the following step: subjecting a compound of formula III and a compound of formula IV to a coupling reaction as shown in the following scheme (for example, at 100-120°C, further for example, at 110°C) in a solvent (for example, a mixed solvent of water and a cyclic ether solvent, further for example, a mixed solvent of water and dioxane, still further for example, dioxane and water in a volume ratio of 20:3 or 4:1) in the presence of a catalyst (for example, a palladium catalyst, further for example, Pd(dppf)Cl<com:Sub>2< / com:Sub>) and an alkali metal halide salt (for example, an alkali metal fluoride salt, further for example, KF) to obtain the compound of formula II; [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document]

[0281] R<com:Sup>8< / com:Sup> is a boronate ester group R<com:Sup>9< / com:Sup> is halogen (for example, bromine); A, <com:Math><semantics>X,Y,R2,R6<annotation encoding="application / x-tex">X, Y, R^2, R^6< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined above.

[0282] The positive and progressive effects of the present disclosure lie in that the biphenyl compound of the present disclosure (specifically, the compound of formula I or the pharmaceutically acceptable salt thereof) has good retinoic acid receptor y agonist activity and high retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> selectivity, exhibits almost no agonist activity on retinoic acid receptor <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, which is beneficial for reducing systemic side effects; more preferably, the biphenyl compound has moderate partial agonist activity. While maintaining efficacy, it exhibits low skin irritation, few adverse reactions, and excellent safety and compliance, and can be used for treating and preventing diseases associated with retinoic acid receptor <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>.

[0283] Definition of terms

[0284] Unless otherwise specified, the terms used in the present disclosure have the following definitions, and the definitions of terms not mentioned below are as commonly understood by those skilled in the art to which the present disclosure pertains.

[0285] In the present disclosure, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When the compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0286] In the present disclosure, the term "more than one" refers to a natural number greater than 2, for example, 2, 3, 4, or 5.

[0287] In the present disclosure, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0288] In the present disclosure, the term "hydroxyl" refers to -OH.

[0289] In the present disclosure, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group having a certain number of carbon atoms. <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl refers to an alkyl group having 1 to 6 (for example, 1, 2, 3, 4, 5, 6) carbon atoms, including C<com:Sub>1< / com:Sub> alkyl, C<com:Sub>2< / com:Sub> alkyl, C<com:Sub>3< / com:Sub> alkyl, C<com:Sub>4< / com:Sub> alkyl, C<com:Sub>5< / com:Sub> alkyl, and C<com:Sub>6< / com:Sub> alkyl, for example, 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, <com:Math><semantics>2,3−<annotation encoding="application / x-tex">2,3-< / annotation>< / semantics>< / com:Math> dimethylbutyl, and the like.

[0290] In the present disclosure, the term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined above.

[0291] In the present disclosure, the term "carbocycle" refers to a saturated monocyclic or polycyclic ring having a specified number of carbon atoms. The term "C<com:Sub>3-8< / com:Sub> carbocycle" refers to a saturated monocyclic or polycyclic ring having 3 to 8 (for example, 3, 4, 5, 6, 7, or 8) ring carbon atoms; preferably, C<com:Sub>3-8< / com:Sub> carbocycle is a saturated monocyclic ring having 3 to 8 (for example, 3, 4, 5, 6, 7, or 8) ring carbon atoms, for example, C<com:Sub>3< / com:Sub>, C<com:Sub>4< / com:Sub>, C<com:Sub>5< / com:Sub>, or C<com:Sub>6< / com:Sub> saturated monocyclic ring, specific examples include, but are not limited to, cyclopropane carbocycle (three-membered carbocycle), cyclobutane carbocycle (four-membered carbocycle), cyclopentane (five-membered carbocycle), cyclohexane carbocycle (six-membered carbocycle), and the like. Polycyclic rings may be spiro rings, fused rings, and bridged rings.

[0292] In the present disclosure, the term "heterocycle" refers to a saturated ring having a specified number of ring atoms (for example, 3- to 12-membered), a specified number of heteroatoms (for example, 1, 2, 3, or 4), and a specified type of heteroatoms (one or more of N, O, and S), including monocyclic or polycyclic rings. Polycyclic rings may be spiro rings, fused rings, and bridged rings.

[0293] In the present disclosure, the term "arylene" refers to a cyclic, unsaturated divalent hydrocarbon group having a specified number of carbon atoms (for example, <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math>), which is monocyclic or polycyclic (for example, 2 or 3 rings); when polycyclic, the individual rings share two atoms and one bond, and each ring is aromatic. Arylene rings include, but are not limited to, phenylene, naphthylene.

[0294] In the present disclosure, the term "heteroarylene" refers to a cyclic, unsaturated divalent group having a specified number of ring atoms (for example, 5- to 10-membered), a specified number of heteroatoms (for example, 1, 2, 3, or 4), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic; when monocyclic, [Image disponible dans le document PDF, Image available in the PDF document] it may be pyridylene, further for example, ; when polycyclic, the individual rings share two atoms and one bond, and each ring is aromatic; polycyclic refers to a fused ring formed by one heteroaromatic ring and one or more aromatic rings or heteroaromatic rings.

[0295] In the present disclosure, the term "substituted with..." means that one or more hydrogen atoms in a given structure are substituted with specific substituent(s). Further, when the group is substituted with more than one of the substituents, the substituents are independent of each other, i.e., the more than one substituent may be different from each other or may be the same. Unless otherwise explicitly indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given structural formula can be substituted with one or more substituents selected from the group consisting of specific groups, the substituents may be substituted at each position identically or differently.

[0296] When a listed group does not explicitly indicate that it has a substituent, such group only mean unsubstituted. For example, when "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" is not preceded by the limitation "unsubstituted or substituted", it refers only to "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" itself or "unsubstituted <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl".

[0297] In addition, it should be noted that, unless otherwise explicitly indicated, the descriptive manner "... be independently" used in the present disclosure should be understood in a broad sense, meaning that the described individuals are independent of each other and may independently be the same or different specific groups. More specifically, the descriptive manner "... be independently" may refer to that, in different groups, the specific options expressed by the same symbol do not affect each other; it may also mean that, in the same group, the specific options expressed by the same symbol do not affect each other.

[0298] In the present disclosure, the term "optionally substituted with ..." means either "substituted with ..." or "unsubstituted".

[0299] In the present disclosure, combinations of substituents and / or variants thereof are permissible only if such combinations result in reasonable compounds.

[0300] In the present disclosure, the term "treating" refers to therapeutic therapy. When referring to a specific condition, treating refers to: (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade that causes or leads to the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0301] In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat or prevent the disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed. Dosages exceeding this range may also be used depending on the different dosage forms and the severity of the disease.

[0302] The above preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present disclosure without violating common knowledge in the art.

[0303] The reagents and starting materials used in the present disclosure are all commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0304] FIG. 1 shows the animal visual observation scores during the pharmacodynamic test of New Zealand rabbit ear acne model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0305] The present disclosure will be described in detail below by way of examples, but the scope of the present disclosure is not limited thereto. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.

[0306] General preparation method:

[0307] (1) subjecting a compound of formula III and a compound of formula IV or formula IV' to a coupling reaction as shown in the following scheme (for example, at 100-120°C, further for example, at 110°C) to obtain a compound of formula II or formula II' in a solvent (for example, a mixed solvent of water and a cyclic ether solvent, further for example, a mixed solvent of water and dioxane, still further for example, dioxane and water in a volume ratio of 20:3 or 4:1) in the presence of a catalyst (for example, a palladium catalyst, further for example, Pd(dppf)Cl<com:Sub>2< / com:Sub>) and an alkali metal halide salt (for example, an alkali metal fluoride salt, further for example, KF); [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document]

[0308] R<com:Sup>8< / com:Sup> is a boronate ester group is halogen (for example, bromine); A, <com:Math><semantics>X,Y,R2,R6<annotation encoding="application / x-tex">X, Y, R^2, R^6< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined above;

[0309] (2) subjecting a compound of formula II or a compound of formula II' to a hydrolysis reaction as shown below (for example, at 50-70°C, further for example, at 60°C) in an organic solvent (for example, an alcohol solvent, further for example, methanol) in the presence of a base (for example, an alkali metal hydroxide, further for example, sodium hydroxide, still further for example, 1 mol / L aqueous sodium hydroxide solution) to obtain the compound of formula I; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or [Image disponible dans le document PDF, Image available in the PDF document] I

[0310] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; when the reactant is II, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>HOO<annotation encoding="application / x-tex">HO_{O}< / annotation>< / semantics>< / com:Math>, m is 1; when the reactant is II', <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>HO→O32<annotation encoding="application / x-tex">HO \longrightarrow O^{\frac{3}{2}}< / annotation>< / semantics>< / com:Math>, m is 1; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is attached at the para position of A; A, X, Y, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined above.

[0311] Example 1 Synthesis of compound Y-001: [Image disponible dans le document PDF, Image available in the PDF document] 4 4 -

[0312] Step 1: Synthesis of intermediate 1-2

[0313] Compound 1-1 (22 g, 127.89 mmol, 1 eq) was dissolved in 300 mL of dichloromethane, and triethylamine (31.99 g, 316.12 mmol, 2.47 eq) and 1-1a (21.23 g, 179.05 mmol, 1.4 eq) were added sequentially. The reaction system was stirred at 25°C for 12 hours. LCMS monitored the complete consumption of the starting materials and the formation of the main product. TLC (petroleum ether / ethyl acetate = 10:1) monitored the complete consumption of the starting materials and the formation of a new product spot. 500 mL of water was added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (250 mL * 2). The organic phases were combined, then washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 120 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 10% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain intermediate 1-2 (24 g, yield: 73.85%). LCMS (ESI): m / z calculated for <com:Math><semantics>C11H13BrNO+<annotation encoding="application / x-tex">C_{11}H_{13}BrNO^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=254.02,256.02,<annotation encoding="application / x-tex">[M+H]^+=254.02, 256.02,< / annotation>< / semantics>< / com:Math> found <com:Math><semantics>[M+H]+=253.9,255.9<annotation encoding="application / x-tex">[M+H]^+= 253.9, 255.9< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 7.38 - 7.47 (m, 4H), 7.20 (br s, 1 H), 5.70 (s, 1 H), 2.22 (s, 3H), 1.90 (s, 3H).

[0314] Step 2: Synthesis of intermediate 1-3

[0315] Intermediate 1-2 (23 g, 90.51 mmol, 1 eq) was dissolved in 500 mL of dichloromethane, and aluminum trichloride (72.41 g, 543.04 mmol, 6 eq) was added. The reaction system was stirred at 0°C for 1 hour, then slowly warmed to 25°C and stirred for another 1 hour. LCMS monitored the complete consumption of the starting materials and the formation of the main product. The reaction mixture was quenched by adding 1 L of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (500 mL * 2). The organic phases were combined, then washed with saturated sodium bicarbonate solution (300 mL * 2), washed with saturated brine (300 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 120 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 <com:Math><semantics>C11H13BrNO+<annotation encoding="application / x-tex">C_{11}H_{13}BrNO^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=254.02,256.02, found [M+H]+=253.9,255.9.<annotation encoding="application / x-tex">[M+H]^+= 254.02, 256.02, \text{ found } [M+H]^+= 253.9, 255.9.< / annotation>< / semantics>< / com:Math> <com:Sup>1< / com:Sup>H NMR (400) MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 9.34 (br s, 1 H), 7.40 (d, J=1.98 Hz, 1 H), 7.29 (dd, J=8.36, 2.20 Hz, 1 H), 6.75 (d, J=8.36 Hz, 1 H), 2.48 (s, 2 H), 1.33 (s, 6 H).

[0316] Step 3: Synthesis of intermediate 1-4

[0317] Intermediate 1-3 (6 g, 23.61 mmol, 1 eq) was dissolved in 60 mL of toluene, and borane dimethyl sulfide solution (10 M, 3.07 mL, 1.3 eq) was added dropwise to the reaction at 0°C. After the dropwise addition was completed, the reaction system was slowly warmed to room temperature, then further heated to 120°C and refluxed for 5 hours. TLC (petroleum ether:ethyl acetate = 1:1) monitored the complete consumption of the starting materials. LCMS monitored the formation of the main product. The reaction system was quenched with methanol, and saturated sodium bicarbonate solution (200 mL) was added. The mixture was extracted with dichloromethane (500 mL * 2). The organic phases were combined, then washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 2% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 1-4 as a light yellow oil (5 g, yield: 88.19%). LCMS (ESI): m / z calculated for <com:Math><semantics>C11H15BrN+<annotation encoding="application / x-tex">C_{11}H_{15}BrN^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=240.04<annotation encoding="application / x-tex">[M+H]^{+}= 240.04< / annotation>< / semantics>< / com:Math>, 242.04, found <com:Math><semantics>[M+H]+=239.9<annotation encoding="application / x-tex">[M+H]^+= 239.9< / annotation>< / semantics>< / com:Math>, 241.9. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 7.25 (d, J=2.20 Hz, 1 H), 7.02 (dd, J=8.58, 2.42 Hz, 1 H), 6.35 (d, J=8.58 Hz, 1 H), 6.35 (d, J=8.58 Hz, 1 H), 3.25 - 3.35 (m, 2 H), 1.66 - 1.76 (m, 2 H), 1.28 (s, 6 H).

[0318] Step 4: Synthesis of intermediate 1-5

[0319] Intermediate 1-4 (4.5 g, 18.74 mmol, 1 eq) and sodium bicarbonate (2.72 g, 32.35) mmol, 1.73 eq) were dissolved in 8 mL of water, and dimethyl sulfate (4.82 g, 38.23 mmol, 2.04 eq) was added. The reaction system was stirred at 10°C for 1 hour, then slowly warmed to 50°C and stirred for another 1 hour. The reaction mixture was diluted with 50 mL of water and extracted with dichloromethane (50 mL * 2). The organic phases were combined, then washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 2% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain intermediate 1-5 as a light yellow oil (4.2 g, yield: 88.19%). LCMS (ESI): m / z calculated for <com:Math><semantics>C12H17BrN+<annotation encoding="application / x-tex">C_{12}H_{17}BrN^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=254.05<annotation encoding="application / x-tex">[M+H]^+= 254.05< / annotation>< / semantics>< / com:Math>, 256.05, found <com:Math><semantics>[M+H]+=253.9<annotation encoding="application / x-tex">[M+H]^+=253.9< / annotation>< / semantics>< / com:Math>, 255.9. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 7.24 (d, J=2.38) Hz, 1 H), 7.14 (dd, J=8.76, 2.38 Hz, 1 H), 6.44 (d, J=8.76 Hz, 1 H), 3.19 - 3.26 (m, 2 H), 2.88 (s, 3 H), 1.69 - 1.82 (m, 2 H), 1.27 (s, 6 H).

[0320] Step 5: Synthesis of intermediate 1-6

[0321] Intermediate 1-5 (1 g, 3.93 mmol, 1 eq) and compound 1-5a (1.10 g, 4.33 mmol, 1.1 eq) were dissolved in 10 mL of dioxane, and potassium acetate (772.25 mg, 7.87 mmol, 2 eq) and Pd(dppf)Cl<com:Sub>2< / com:Sub> (287.89 mg, 393.44 µmol, 0.1 eq) were added sequentially. The reaction system was stirred at 100°C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) monitored the complete consumption of the starting materials and the formation of the main product. The reaction mixture was diluted with 20 mL of ethyl acetate and 20 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10) mL * 3). The organic phases were combined, then 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain intermediate 1-6 as a light yellow oil (927 mg, yield: 78.3%). LCMS (ESI): m / z calculated for <com:Math><semantics>C18H29BNO2+<annotation encoding="application / x-tex">C_{18}H_{29}BNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=302.23<annotation encoding="application / x-tex">[M+H]^+=302.23< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=302.3<annotation encoding="application / x-tex">[M+H]^+=302.3< / annotation>< / semantics>< / com:Math>.

[0322] Step 6: Synthesis of intermediate 1-7

[0323] Intermediate I-6a (1.1 g, 2.80 mmol, 1 eq) (preparation method referenced in patent CN113501758A, 2021) and intermediate I-6 (842.65 mg, 2.80 mmol, 1 eq) were dissolved in 1.5 mL of water and 10 mL of dioxane, and Pd(dppf)Cl<com:Sub>2< / com:Sub> (102.34 mg, 139.87 μmol, 0.05 eq) and potassium fluoride (487.55 mg, 8.39 mmol, 3 eq) were added. The reaction system was stirred at 110°C for 1 hour. LCMS monitored the complete consumption of the starting materials and the formation of the main product. The reaction mixture was diluted with 60 mL of ethyl acetate and 20 mL of water. The organic phase was washed with saturated ammonium chloride solution (20 mL * 2), washed with and 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 60% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 1-7 as a light yellow oil (1.1 g, yield: 78.39%). LCMS (ESI): m / z calculated for <com:Math><semantics>C31H36NO5+<annotation encoding="application / x-tex">C_{31}H_{36}NO_5^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=502.26<annotation encoding="application / x-tex">[M+H]^+= 502.26< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=502.2<annotation encoding="application / x-tex">[M+H]^+= 502.2< / annotation>< / semantics>< / com:Math>.

[0324] Step 7: Synthesis of compound Y-001

[0325] Intermediate 1-7 (1.1 g, 2.19 mmol, 1 eq) was dissolved in 50 mL of methanol, and aqueous sodium hydroxide solution (1 M, 8.77 mL, 4 eq) was added. The reaction system was stirred at 60°C for 3 hours. LCMS monitored the complete consumption of the starting materials and the formation of the main product. The pH value of the reaction system was adjusted to 7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined, then washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain compound Y-001 as a white solid (470 mg, yield: 46.2%, purity: 93%). LCMS (ESI): m / z calculated for <com:Math><semantics>C27H30NO4+<annotation encoding="application / x-tex">C_{27}H_{30}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=432.22<annotation encoding="application / x-tex">[M+H]^+=432.22< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=432.2<annotation encoding="application / x-tex">[M+H]^+=432.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>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).

[0326] Example 2 Synthesis of compound Y-002 [Image disponible dans le document PDF, Image available in the PDF document]

[0327] Step 1 Synthesis of intermediate 2-2

[0328] Intermediate 2-1 (7 g, 30.96 mmol, 1 eq) and intermediate 2-1a (20.16 g, 154.79 mmol, 5 eq) were dissolved in 150 mL of acetonitrile, and lithium perchlorate (6.45 g, 60.63 mmol, 1.96 eq) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (21.08 g, 92.87 mmol, 3 eq) were added. The reaction system was stirred at -40°C for 1 hour. TLC (petroleum ether / ethyl acetate = 7:1) monitored the complete reaction of the starting materials and the formation of the main product. The reaction mixture 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). The organic phases were combined, then 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 for <com:Math><semantics>C13H17BrNO+<annotation encoding="application / x-tex">C_{13}H_{17}BrNO^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=282.05,284.05,found<math>[M+H]+=282.0,284.0.<annotation encoding="application / x-tex">[M+H]^+=282.05, 284.05, found [M+H]^+=282.0, 284.0.< / annotation>< / semantics>< / com:Math>

[0329] Step 2 Synthesis of intermediate 2-3

[0330] Intermediate 2-2 (1.4 g, 4.96 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, and intermediate 2-2a (3.90 g, 10.92 mmol, 2.2 eq) and potassium tert-butoxide (1.11 g, 9.92 mmol, 2 eq) were added. The reaction system was stirred at 70°C for 1 hour. TLC (petroleum ether / ethyl acetate <com:Math><semantics>=10:1<annotation encoding="application / x-tex">= 10:1< / annotation>< / semantics>< / com:Math>) monitored the complete reaction of the starting materials. LCMS monitored the formation of the product. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 for <com:Math><semantics>C14H19BrN+<annotation encoding="application / x-tex">C_{14}H_{19}BrN^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=280.07<annotation encoding="application / x-tex">[M+H]^+=280.07< / annotation>< / semantics>< / com:Math>, 282.07, found <com:Math><semantics>[M+H]+=280.1<annotation encoding="application / x-tex">[M+H]^+=280.1< / annotation>< / semantics>< / com:Math>, 282.1. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) 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).

[0331] Step 3 Synthesis of intermediate 2-4

[0332] Intermediate 2-3 (1 g, 3.57 mmol, 1 eq) was dissolved in 10 mL of concentrated sulfuric acid, and the reaction system was stirred at 100°C for 4 hours. LCMS monitored the formation of the product. The reaction mixture was slowly added dropwise to saturated sodium bicarbonate solution at 0°C. After the dropwise addition was completed, the aqueous phase was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, then washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 20 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 40% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain intermediate 2-4 as a white solid (870 mg, yield: 87%). LCMS (ESI): m / z calculated for <com:Math><semantics>C14H19BrN+<annotation encoding="application / x-tex">C_{14}H_{19}BrN^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=280.07,282.07,<annotation encoding="application / x-tex">[M+H]^{+}= 280.07, 282.07,< / annotation>< / semantics>< / com:Math> found <com:Math><semantics>[M+H]+=280.0,282.0.<annotation encoding="application / x-tex">[M+H]^+= 280.0, 282.0.< / annotation>< / semantics>< / com:Math> <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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).

[0333] Step 4 Synthesis of intermediate 2-5

[0334] Intermediate 2-4 (110 mg, 392.57 μmol, 1 eq) and compound 1-5a (109.66 mg, 431.83 μmol, 1.1 eq) were dissolved in 15 mL of dioxane, and potassium acetate (77.05 mg, 785.15 μmol, 2 eq) and Pd(dppf)Cl<com:Sub>2< / com:Sub> (28.72 mg, 39.26 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at <com:Math><semantics>100∘<annotation encoding="application / x-tex">100^{\circ}< / annotation>< / semantics>< / com:Math>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 mixture was diluted with 20 mL of ethyl acetate and 20 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, then 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain intermediate 2-5 as a colorless oil (70 mg, yield: 54.48%). LCMS (ESI): m / z calculated for <com:Math><semantics>C20H31BNO2+<annotation encoding="application / x-tex">C_{20}H_{31}BNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=328.24<annotation encoding="application / x-tex">[M+H]^+=328.24< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=328.2<annotation encoding="application / x-tex">[M+H]^+=328.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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).

[0335] Step 5 Synthesis of intermediate 2-6

[0336] Intermediate 1-6a (79 mg, 200.90 µmol, 1 eq) and intermediate 2-5 (65.75 mg, 200.90 μmol, 1 eq) were dissolved in 1 mL of water and 4 mL of dioxane, and Pd(dppf)Cl<com:Sub>2< / com:Sub> (7.35 mg, 10.05 μmol, 0.05 eq) and potassium fluoride (35.02 mg, 602.70 μmol, 3 eq) were added. The reaction system was stirred at 110°C for 1 hour. LCMS monitored the complete consumption of the starting materials and the formation of the main product. The reaction mixture was diluted with 15 mL of ethyl acetate and 10 mL of water. The organic phase was washed with saturated ammonium chloride solution (10 mL * 2), washed with brine (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 60% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 2-6 as a colorless oil (80 mg, yield: 75.47%). LCMS (ESI): m / z calculated for <com:Math><semantics>C33H38NO5+<annotation encoding="application / x-tex">C_{33}H_{38}NO_5^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=528.27<annotation encoding="application / x-tex">[M+H]^+= 528.27< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=528.2<annotation encoding="application / x-tex">[M+H]^+= 528.2< / annotation>< / semantics>< / com:Math>.

[0337] Step 6 Synthesis of compound Y-002

[0338] 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 the complete consumption of the starting materials and the formation of the main product. The pH value of the reaction system was adjusted to 7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL * 2). The organic phases were combined, then 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 12 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 70% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain compound Y-002 as a white solid (42 mg, yield: 58.16%, purity: 96%). LCMS (ESI): m / z calculated for <com:Math><semantics>C29H32NO4+<annotation encoding="application / x-tex">C_{29}H_{32}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=458.23<annotation encoding="application / x-tex">[M+H]^+=458.23< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=458.2<annotation encoding="application / x-tex">[M+H]^+=458.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>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).

[0339] Example 3 Synthesis of compound Y-003 [Image disponible dans le document PDF, Image available in the PDF document]

[0340] Step 1 Synthesis of intermediate 3-2

[0341] Referring to the synthesis method in Step 4 of Example 1, intermediate 3-2 was prepared as a colorless oil using intermediate 1-4 and diethyl sulfate as starting materials, with the corresponding starting materials being replaced. LCMS (ESI): m / z calculated for <com:Math><semantics>C13H19BrN+<annotation encoding="application / x-tex">C_{13}H_{19}BrN^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=268.07,270.07,found<math>[M+H]+=268.0,270.0.<annotation encoding="application / x-tex">[M+H]^+= 268.07, 270.07, found [M+H]^+= 268.0, 270.0.< / annotation>< / semantics>< / com:Math> <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ ppm 7.25 (d, J=2.42 Hz, 1 H), 7.12 (dd, J=8.80, 2.42 Hz, 1 H), 6.48 (d, J=8.80 Hz, 1 H), 3.35 (q, J=7.12 Hz, 2 H), 3.24 - 3.29 (m, 2 H), 1.69 - 1.78 (m, 2 H), 1.27 (s, 6 H), 1.15 (t, <com:Math><semantics>J=7.04Hz,3H<annotation encoding="application / x-tex">J=7.04 Hz, 3 H< / annotation>< / semantics>< / com:Math>).

[0342] Step 2 Synthesis of intermediate 3-3

[0343] Referring to the synthesis method in Step 5 of Example 1, intermediate 3-3 was prepared as a colorless oil using intermediate 3-2 as a starting material, with the corresponding starting materials being replaced. LCMS (ESI): m / z calculated for C<com:Sub>19< / com:Sub>H<com:Sub>31< / com:Sub>BNO<com:Sub>2< / com:Sub> +. <com:Math><semantics>[M+H]+=316.24<annotation encoding="application / x-tex">[M+H]^+=316.24< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=316.2<annotation encoding="application / x-tex">[M+H]^+=316.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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).

[0344] Step 3 Synthesis of compound Y-003

[0345] Referring to the synthesis methods in Step 6 and Step 7 of Example 1, compound Y- 003 was prepared as a white solid using intermediate 3-3 as a starting material, with the corresponding starting materials being replaced. LCMS (ESI): m / z calculated for C<com:Sub>28< / com:Sub>H<com:Sub>32< / com:Sub>NO<com:Sub>4< / com:Sub> <com:Sup>+< / com:Sup>. <com:Math><semantics>[M+H]+=446.23<annotation encoding="application / x-tex">[M+H]^+= 446.23< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=446.2<annotation encoding="application / x-tex">[M+H]^+= 446.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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).

[0346] Example 4 Chiral separation and preparation of compounds Y-004 and Y-005 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Y-005

[0347] Compound Y-002 (22 mg) prepared in Example 2 was further separated by chiral SFC under chiral preparative conditions: chiral column DAICEL CHIRALPAK AD (specification: 250 mm * 30 mm, particle size: 10 μm), eluent phase: CO<com:Sub>2< / com:Sub> (A): ethanol containing 0.1% aqueous ammonia (B), isocratic gradient (A / B = <com:Math><semantics>60 / 40<annotation encoding="application / x-tex">60 / 40< / annotation>< / semantics>< / com:Math>). Compound Y-004 (earlier-eluting peak) was obtained as a white solid (8.2 mg, yield: 36.52%, ee value: 98%).

[0348] LCMS (ESI): m / z calculated for <com:Math><semantics>C29H32NO4+<annotation encoding="application / x-tex">C_{29}H_{32}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=458.23<annotation encoding="application / x-tex">[M+H]^+=458.23< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=458.23<annotation encoding="application / x-tex">[M+H]^+=458.23< / annotation>< / semantics>< / com:Math> 458.2.

[0349] <com:Sup>1< / com:Sup>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) 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).

[0350] Compound Y-005 (later-eluting peak) was obtained as a white solid (7.9 mg, yield: 35.19%, ee value: 98%).

[0351] LCMS (ESI): m / z calculated for <com:Math><semantics>C29H32NO4+<annotation encoding="application / x-tex">C_{29}H_{32}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=458.23<annotation encoding="application / x-tex">[M+H]^+=458.23< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=458.23<annotation encoding="application / x-tex">[M+H]^+=458.23< / annotation>< / semantics>< / com:Math> 458.2.

[0352] <com:Math><semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>< / com:Math>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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).

[0353] Chiral analysis conditions: Instrument Waters UPCC equipped with PDA detector, chiral column Chiralpak AD-3 (specification: 150 mm * 4.6 mm, particle size: 3 µm), eluent phase: <com:Math><semantics>CO2<annotation encoding="application / x-tex">CO_2< / annotation>< / semantics>< / com:Math> (A): ethanol containing 0.05% ethylenediamine (B), isocratic gradient (A / B = 60 / 40); flow rate: 2.5 mL / min, column temperature: 35°C; compound Y-004, earlier-eluting peak, retention time: about 4.53 min; compound Y-005, later-eluting peak, retention time: about 5.45 min (the absolute chirality of the separated compound was confirmed by comparing the retention time of the separated compound with the retention time of the product Y-005 obtained from chiral preparation in Example 5).

[0354] Example 5 Synthesis of compound Y-005 [Image disponible dans le document PDF, Image available in the PDF document]

[0355] Step 1 Synthesis of intermediate 5-2

[0356] Compound 5-1 (2 g, 7.07 mmol, 1 eq) was dissolved in 3 mL of DMF, and cesium carbonate (5.76 g, 17.67 mmol, 2.5 eq), cuprous iodide (403.92 mg, 2.12 mmol, 0.3 eq), and compound 5-1a (1.19 g, 7.07 mmol, 1 eq) were added sequentially. The reaction mixture was stirred at 80°C for 1 hour. LCMS monitored the complete consumption of the starting materials and the formation of the main product. After filtration of the reaction system, the filtrate was diluted with 20 mL of ethyl acetate, washed with saturated ammonium chloride solution (10 mL * 2), 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 for <com:Math><semantics>C12H15BrNO2+<annotation encoding="application / x-tex">C_{12}H_{15}BrNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=284.03,286.03,found<math>[M+H]+=284.0,286.0.<annotation encoding="application / x-tex">[M+H]^+= 284.03, 286.03, found [M+H]^+= 284.0, 286.0.< / annotation>< / semantics>< / com:Math>

[0357] Step 2 Synthesis of intermediate 5-3

[0358] Compound 5-2 (1.3 g, 4.58 mmol, 1 eq) was dissolved in 40 mL of acetonitrile, and potassium carbonate (1.90 g, 13.73 mmol, 3 eq) and iodomethane (6.49 g, 45.75 mmol, 2.85 mL, 10 eq) were added. The reaction system was stirred at 30°C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) monitored the complete consumption of the starting materials and the formation of the main product spot. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 12% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to obtain intermediate 5-3 as a colorless oil (900 mg, yield: 65.97%). LCMS (ESI): m / z calculated for <com:Math><semantics>C13H17BrNO2+<annotation encoding="application / x-tex">C_{13}H_{17}BrNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=<annotation encoding="application / x-tex">[M+H]^+=< / annotation>< / semantics>< / com:Math> 298.04, 300.04, found <com:Math><semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>< / com:Math> = 298.0, 300.0. <com:Sup>1< / com:Sup>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 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 <com:Math><semantics>(dd,J=2.9,6.7Hz,1H).<annotation encoding="application / x-tex">(dd, J=2.9, 6.7 Hz, 1H).< / annotation>< / semantics>< / com:Math>

[0359] Step 3 Synthesis of intermediate 5-4

[0360] Compound 5-3 (1.30 g, 4.36 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and a solution of methylmagnesium chloride in tetrahydrofuran (3 M, 5.81 mL, 4 eq) was slowly added dropwise at 0°C. After the dropwise addition was completed, the reaction system was stirred at 0°C for 5 hours. LCMS monitored the complete consumption of the starting materials and the formation of the product. The reaction mixture 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). The organic phases were combined, then 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 gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 12 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 <com:Math><semantics>C14H21BrNO+<annotation encoding="application / x-tex">C_{14}H_{21}BrNO^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=298.08,300.08,found<math>[M+H]+=298.1,300.1.<annotation encoding="application / x-tex">[M+H]^{+}= 298.08, 300.08, found [M+H]^{+}= 298.1, 300.1.< / annotation>< / semantics>< / com:Math>

[0361] Step 4 Synthesis of intermediate 5-5

[0362] Compound 5-4 (550 mg, 1.84 mmol, 1 eq) was dissolved in 10 mL of dichloroethane, and aluminum trichloride (491.83 mg, 3.69 mmol, 2 eq) was added. The reaction system was stirred at 30°C for 4 hours. LCMS monitored the complete consumption of the starting materials and the formation of the product. The reaction mixture was slowly added dropwise to 15 mL of saturated aqueous sodium carbonate solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL * 2). The organic phases were combined, then 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 gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 4 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 <com:Math><semantics>C14H19BrN+<annotation encoding="application / x-tex">C_{14}H_{19}BrN^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=280.07,282.07,found<math>[M+H]+=<annotation encoding="application / x-tex">[M+H]^{+}= 280.07, 282.07, found [M+H]^{+}=< / annotation>< / semantics>< / com:Math> 280.0, 282.0.

[0363] Step 5 Synthesis of compound Y-005

[0364] Referring to the synthesis methods in Steps 4-6 of Example 2, compound Y-005 was prepared as a white solid using intermediate 5-5 as a starting material, with the corresponding starting materials being replaced. LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> calculated for <com:Math><semantics>C29H32NO4+<annotation encoding="application / x-tex">C_{29}H_{32}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=<annotation encoding="application / x-tex">[M+H]^+=< / annotation>< / semantics>< / com:Math> 458.23, found [M+H]<com:Sup>+< / com:Sup>= 458.2. Chiral analysis conditions: Instrument Waters UPCC equipped with PDA detector, chiral column Chiralpak AD-3 (specification: 150 mm * 4.6 mm, particle size: 3 µm), eluent phase: CO<com:Sub>2< / com:Sub> (A): ethanol containing 0.05% ethylenediamine (B), isocratic gradient (A / B = <com:Math><semantics>60 / 40<annotation encoding="application / x-tex">60 / 40< / annotation>< / semantics>< / com:Math>); flow rate: 2.5 mL / min, column temperature: 35°C; retention time: about 5.45 minutes.

[0365] Example 6 Synthesis of compound Y-006 [Image disponible dans le document PDF, Image available in the PDF document]

[0366] Step 1 Synthesis of intermediate 6-2

[0367] Intermediate 5-1 (2.98 g, 10.55 mmol, 2 eq) and compound 6-1a (810 mg, 5.27 mmol, 1 eq) were dissolved in 10 mL of DMSO, and cesium carbonate (4.30 g, 13.18 mmol, 2.5 eq) and cuprous iodide (301.28 mg, 1.58 mmol, 0.3 eq) were added sequentially. The reaction system was stirred at 100°C for 10 hours. LCMS monitored the complete consumption of the starting materials and the formation of the main product. After filtration of the reaction system, the filtrate was diluted with 30 mL of ethyl acetate, washed with saturated ammonium chloride solution (10 mL * 2), 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 prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 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 for <com:Math><semantics>C11H15BrNO2+<annotation encoding="application / x-tex">C_{11}H_{15}BrNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=272.03,274.03,found<math>[M+H]+=272.0,274.0.<annotation encoding="application / x-tex">[M+H]^+= 272.03, 274.03, found [M+H]^+= 272.0, 274.0.< / annotation>< / semantics>< / com:Math>

[0368] Step 2 Synthesis of intermediate 6-3

[0369] 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 sequentially. The reaction system was stirred at 25°C for 5 hours. LCMS monitored the complete consumption of the starting materials and the formation of the main product. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was prepared by silica gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 12 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 100% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 6-3 as a colorless oil (385 mg, yield: 91.52%). LCMS (ESI): m / z calculated for <com:Math><semantics>C12H17BrNO2+<annotation encoding="application / x-tex">C_{12}H_{17}BrNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=286.04,288.04,found<annotation encoding="application / x-tex">[M+H]^+= 286.04, 288.04, found< / annotation>< / semantics>< / com:Math> <com:Math><semantics>[M+H]+=286.0,288.0.<annotation encoding="application / x-tex">[M+H]^+=286.0, 288.0.< / annotation>< / semantics>< / com:Math>

[0370] Step 3 Synthesis of intermediate 6-4

[0371] Intermediate 6-3 (240 mg, 838.68 µmol, 1 eq) was dissolved in 40 mL of tetrahydrofuran, and a solution of methylmagnesium chloride in tetrahydrofuran (3 M, 1.12 mL, 4 eq) was added dropwise. After the dropwise addition was completed, the reaction system was stirred at 0°C for 1 hour. LCMS monitored the complete consumption of the starting materials and the formation of the product. The reaction mixture 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). The organic phases were combined, then 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 gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 12 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 30% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to obtain intermediate 6-4 as a colorless oil (200 mg, yield: 83.38%). LCMS (ESI): m / z calculated for <com:Math><semantics>C13H21BrNO+<annotation encoding="application / x-tex">C_{13}H_{21}BrNO^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=286.08,288.08,found<math>[M+H]+=286.0,288.0.<annotation encoding="application / x-tex">[M+H]^+= 286.08, 288.08, found [M+H]^+= 286.0, 288.0.< / annotation>< / semantics>< / com:Math>

[0372] Step 4 Synthesis of intermediate 6-5

[0373] 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 the complete consumption of the starting materials and the formation of the product. The reaction mixture was slowly added dropwise to 10 mL of saturated aqueous sodium carbonate solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL * 2). The organic phases were combined, then 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 gel column chromatography (ISCO flash liquid preparative chromatograph; column model: 4 g SepaFlash® Silica Flash Column; mobile phase gradient: 0 to 5% ethyl acetate / petroleum ether; flow rate: 20 mL / min) to obtain intermediate 6-5 as a colorless oil (160 mg, yield: 85.37%). LCMS (ESI): m / z calculated for <com:Math><semantics>C13H19BrN+<annotation encoding="application / x-tex">C_{13}H_{19}BrN^{+}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=268.07,270.07,found<math>[M+H]+=268.07<annotation encoding="application / x-tex">[M+H]^{+}= 268.07, 270.07, found [M+H]^{+}= 268.07< / annotation>< / semantics>< / com:Math> 268.0, 270.0. <com:Sup>1< / com:Sup>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 7.21 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 2.4, <com:Math><semantics>8.7 Hz<annotation encoding="application / x-tex">8.7 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>6.46<annotation encoding="application / x-tex">6.46< / annotation>< / semantics>< / com:Math> (br d, <com:Math><semantics>J=8.8 Hz<annotation encoding="application / x-tex">J = 8.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.40−3.36<annotation encoding="application / x-tex">3.40-3.36< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.88<annotation encoding="application / x-tex">2.88< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.74−1.70<annotation encoding="application / x-tex">1.74-1.70< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>1H<annotation encoding="application / x-tex">1\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.61−1.58<annotation encoding="application / x-tex">1.61-1.58< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.32<annotation encoding="application / x-tex">1.32< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.24<annotation encoding="application / x-tex">1.24< / annotation>< / semantics>< / com:Math> (br d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>1.18<annotation encoding="application / x-tex">1.18< / annotation>< / semantics>< / com:Math> (s, 3H).

[0374] Step 5 Synthesis of intermediate 6-6

[0375] Referring to the synthesis method in Step 5 of Example 5, intermediate 6-6 was prepared as a colorless oil using intermediate 6-5 as a starting material, with the corresponding starting materials being replaced. LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> calculated for <com:Math><semantics>C19H31BNO2+<annotation encoding="application / x-tex">C_{19}H_{31}BNO_2^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+=316.24<annotation encoding="application / x-tex">[M+H]^+= 316.24< / annotation>< / semantics>< / com:Math>, found <com:Math><semantics>[M+H]+=316.2<annotation encoding="application / x-tex">[M+H]^+= 316.2< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 7.63 - 7.50 <com:Math><semantics>(m,2H),6.58(d,J=8.2Hz,1H),3.54−3.33(m,1H),2.94(s,3H),1.77−1.68(m,1H),1.62<annotation encoding="application / x-tex">(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< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,1H),1.39(s,3H),1.32(s,12H),1.25(d,J=6.1Hz,3H),1.19(s,3H).<annotation encoding="application / x-tex">(s, 1H), 1.39 (s, 3H), 1.32 (s, 12H), 1.25 (d, J = 6.1 Hz, 3H), 1.19 (s, 3H).< / annotation>< / semantics>< / com:Math>

[0376] Step 5 Synthesis of compound Y-006

[0377] Referring to the synthesis method of Y-005 in Example 5, compound Y-006 was prepared as a white solid using intermediate 6-6 as a starting material, with the corresponding starting materials being replaced. LCMS (ESI): m / z calculated for <com:Math><semantics>C28H32NO4+<annotation encoding="application / x-tex">C_{28}H_{32}NO_4^+< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>< / com:Math> 446.23, found <com:Math><semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics>< / com:Math> = 446.2. <com:Sup>1< / com:Sup>H NMR (400 MHz, CD<com:Sub>3< / com:Sub>OD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 12.90 (br s, 1H), 7.99 <com:Math><semantics>(d,J=8.3Hz,2H),7.80(d,J=8.5Hz,2H),7.61−7.54(m,2H),7.49(d,J=2.0Hz,1H),7.28<annotation encoding="application / x-tex">(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< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(dd,J=2.0,8.6Hz,1H),7.16(d,J=9.3Hz,1H),6.63(d,J=8.7Hz,1H),4.80(t,J=5.3Hz,1H)<annotation encoding="application / x-tex">(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)< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>4.07<annotation encoding="application / x-tex">4.07< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.73<annotation encoding="application / x-tex">3.73< / annotation>< / semantics>< / com:Math> (br d, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.39<annotation encoding="application / x-tex">3.39< / annotation>< / semantics>< / com:Math> (br s, 1H), <com:Math><semantics>2.88<annotation encoding="application / x-tex">2.88< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>1.76<annotation encoding="application / x-tex">1.76< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=4.2,13.2 Hz,1H<annotation encoding="application / x-tex">J = 4.2, 13.2 \text{ Hz}, 1H< / annotation>< / semantics>< / com:Math>), 1.55 (dd, <com:Math><semantics>J=11.0,13.1 Hz,1H<annotation encoding="application / x-tex">J = 11.0, 13.1 \text{ Hz}, 1H< / annotation>< / semantics>< / com:Math>), 1.32 (s, 3H), 1.23 (d, <com:Math><semantics>J=6.1 Hz,3H<annotation encoding="application / x-tex">J = 6.1 \text{ Hz}, 3H< / annotation>< / semantics>< / com:Math>), 1.19 (s, 3H).

[0378] Biological test example 1

[0379] Using HEK-293 cell lines transfected with RARα, RARβ, and RARγ luciferase reporter genes to test the agonistic activity and selectivity of compounds against RARα, RARB and RARY

[0380] Experimental steps:

[0381] 1. Cell culture

[0382] HEK293 cells were cultured in DMEM + 10% FBS medium in a humidified CO<com:Sub>2< / com:Sub> incubator at 37°C with 5% CO<com:Sub>2< / com:Sub>.

[0383] 2. Plasmid transfection and cell seeding

[0384] HEK293 cells were digested with trypsin, and the HEK293 cell resuspension was adjusted to 200,000 cells per mL with culture medium (96-well plate: 100 µL / well). According to the table below, the transfection reagent mixture was prepared, mixed thoroughly, and allowed to stand at room temperature for 20 minutes.

[0385] Test transfection materials [Image disponible dans le document PDF, Image available in the PDF document]

[0386] * The corresponding plasmid (pBIND-RARα, pBIND-RARβ, or pBIND-RARγ) was selected according to the test receptor

[0387] The prepared transfection reagent mixture was added to 10 mL of the resuspension with adjusted cell density, mixed thoroughly by inverting up and down, and seeded into a 96- well plate at a volume of 100 μL / well. The 96-well plate was placed in a humidified incubator at 37°C with 5% CO<com:Sub>2< / com:Sub> and incubated for 24 hours.

[0388] 3. Drug treatment

[0389] The stock solutions of the positive control retinoic acid and the test compounds were serially diluted at a certain ratio to obtain a series of 21× compound solutions. To each well of cells (already containing 100 μL of cell culture medium), 5 μL of the retinoic acid dilution or the test compound dilution was added. 5 µL of 10% DMSO medium was added to the negative control wells (Min wells), and 5 μL of 6.3 μM retinoic acid (dissolved in medium, 10% DMSO, final concentration of 300 nM as Max wells) was added to the positive control wells. The assay plate was returned to the incubator and incubated for 24 hours.

[0390] 4. Luciferase assay

[0391] The assay plate was detected using Promega's Dual-Glo Luciferase Assay System kit, and the Firefly luciferase fluorescence signal and the Renilla luciferase fluorescence signal were read using an EnSpire microplate reader.

[0392] 5. Test results

[0393] 5.1 EC<com:Sub>50< / com:Sub> values

[0394] The data were imported into MS Excel for curve fitting to obtain EC<com:Sub>50< / com:Sub> values. The test results are as follows.

[0395] Agonistic activity EC<com:Sub>50< / com:Sub> test results of RAR series compounds against RAR<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>, RARα, and RARβ [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0396] Note: When the maximum activation rate is less than 50% of the retinoic acid Max well, the result is expressed as <com:Math><semantics>EC50>maximum test concentration<annotation encoding="application / x-tex">EC_{50} > \text{maximum test concentration}< / annotation>< / semantics>< / com:Math>.

[0397] The compounds of the present disclosure have good agonistic activity and selectivity against RAR<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> and almost no agonistic activity against RAR<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and / or RAR<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, with low systemic or other tissue side effects. Compared with existing RARy selective agonists (for example, compound 10Y), the compounds of the present disclosure have weaker agonistic activity against RAR<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and RAR<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and better selectivity.

[0398] <com:Math><semantics>5.2Emax<annotation encoding="application / x-tex">5.2 E_{\text{max}}< / annotation>< / semantics>< / com:Math> values

[0399] The activation rate at each concentration was calculated using Formula (1), and the maximum agonistic activity <com:Math><semantics>Emax<annotation encoding="application / x-tex">E_{max}< / annotation>< / semantics>< / com:Math> (%) of the compound against RAR<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> was obtained by curve fitting. [Image disponible dans le document PDF, Image available in the PDF document]

[0401] The compounds Y-004, Y-005, and Y-006 of the present disclosure exhibit partial agonistic activity against RAR<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> (E<com:Sub>max< / com:Sub> values are all less than 75% relative to retinoic acid). Compared with existing RARy full agonists (for example, retinoic acid, compound 10Y, etc.), these compounds are expected to reduce the adverse reactions associated with full activation of RARγ.

[0402] Biological test example 2

[0403] Study on skin irritation of topical skin administration in miniature pigs

[0404] Experimental design:

[0405] The local skin irritation of the test articles was evaluated using the intra-animal self- comparison method in miniature pigs. The dorsal skin of three female miniature pigs was divided into two regions, anterior and posterior, with an administration area of approximately 300 cm<com:Sup>2< / com:Sup> for each region. Four groups of test articles were evaluated crosswise over 4 cycles, with one test article administered to the skin once daily for 3 consecutive days. To avoid unexpected interference, a 2-day washout period was set between the administrations of groups G2 and G3 and between the administrations of groups G3 and G4. The test articles were: G1 blank cream group, G2 Y-004 cream 0.05% group (containing 500 µg of the active ingredient compound Y-004 of the present disclosure per gram of cream, i.e., specification 500 µg / g), G3 10Y cream 0.05% group (containing 500 μg of the active ingredient compound 10Y per gram of cream, i.e., specification 500 μg / g), and G4 10Y cream 0.025% group (containing 250 μg of the active ingredient compound 10Y per gram of cream, i.e., specification 250 µg / g). The cream compositions of the groups G2, G3, and G4 were the same as the blank cream group except for the active ingredient. The structure of compound 10Y is as follows [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document]

[0406] Before the start of the experiment, the marked administration region was shaved for hair removal and skin preparation, ensuring thorough removal without trauma. The shaved area should exceed the marked region. The administration region was marked using a marker pen, cleaned with soapy water and purified water before administration, and wiped dry with a dry gauze.

[0407] A quantitative and equal amount of the test article (1 mL / kg) was adhered to the administration site, and then the formulation was evenly spread onto the shaved and marked skin site of the animal using an application tool (for example, a triangular glass rod). After the administration formulation was evenly applied, the site was covered with elastic breathable cotton gauze to ensure that the gauze was fixed at the administration site and the skin surface was breathable. Considering that the animal's movements such as scratching and rubbing could affect the effective coverage of the drug, a mesh elastic bandage was used for fixation to prevent the administration from being affected by the animal's resistive movements.

[0408] Six hours after application of the test article, the skin at the administration site was gently washed with soap and purified water to remove residual unabsorbed cream. Skin irritation was observed and recorded during three consecutive days of administration of the corresponding test article in each cycle, in order to compare the short-term irritation differences among the four groups of test articles after three consecutive days of skin administration.

[0409] Clinical observation and skin irritation reaction scoring:

[0410] After each administration, observations were performed once at 6 hours (before cleaning and removal of the drug) and at 24 hours (before the next administration), with a focus on observing whether any skin reactions or symptoms such as erythema, scab formation, edema, skin thickening, etc. were present at the administration site. On the last day of each cycle (D3, D6, D11, D16), photographs of the administration sites were taken to record skin reactions. Specifically, the photographs were taken as much as possible within 10 min to 1 hour after the removal of the administration to record skin reactions at the administration site, and skin irritation reaction scoring was performed with reference to the skin irritation reaction scoring criteria in the "Technical Guidelines for Studies on Drug Irritation, Sensitization and Hemolysis".

[0411] Test results:

[0412] Under the conditions of this test, after 3 consecutive days of administration, G1 blank cream group and G2 Y-004 cream 0.05% (500 µg / g) specification group showed no skin irritation in miniature Bama pigs (skin irritation intensity score of 0), and no abnormal skin reactions or symptoms were observed. In contrast, G3 10Y cream 0.05% (500 µg / g) specification group and G4 10Y cream 0.025% (250 μg / g) specification group exhibited skin irritation in the miniature Bama pigs, mainly manifested as erythema, redness and swelling, and secondary scab formation and desquamation. The severity and duration of the symptoms were dose-dependent to a certain extent. The highest skin irritation intensity scores for the 250 μg / g and 500 μg / g specifications were 2 and 4, respectively, with certain individual variability. No test article-related abnormal changes were observed in clinical signs, body weight, or food intake.

[0413] Biological test example 3

[0414] Evaluation of the pharmacodynamic effects of compounds on a New Zealand rabbit ear acne model

[0415] Experimental design:

[0416] Male New Zealand rabbits qualified for quarantine inspection (Suzhou Xishan Biotechnology Co., Ltd., certificate No. 370823241100331316) were selected for model establishment. For each animal, the left ear was evenly applied with 0.4-0.5 mL / ear of 75% oleic acid using a disinfected cotton swab fully soaked with the 75% oleic acid, while the right ear was left untreated. The application was performed once daily for 11 consecutive days of modeling. On Day 7 of modeling (MDay7), the administration region (2 cm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3 cm) was determined based on the symptoms of ear acne in the animals, and the administration region was marked using a small animal-specific tattoo machine. On Day 11 of modeling (MDay11), 24 animals with moderate and moderately severe scores from visual observation of the modeled rabbit ears were selected and randomly and evenly divided into: a model control group (Y-004 blank cream, same as the blank cream group in biological test example 2), a tretinoin cream 0.025% control group (commercially available, specification 250 µg / g, active ingredient: tretinoin, containing 250 µg tretinoin per gram of cream), and a Y-004 cream 0.025% group (specification 250 µg / g, active ingredient: the compound Y-004 of the present disclosure, containing 250 µg of the compound Y-004 of the present disclosure per gram of cream, with excipient composition identical to the blank cream of the model control group except for the active ingredient), with 8 animals per group, all male. Approximately 24 hours after the last modeling, the corresponding control / test article was administered within the marked region at <com:Math><semantics>0.06 mL / ear<annotation encoding="application / x-tex">0.06 \text{ mL / ear}< / annotation>< / semantics>< / com:Math>, once daily. At 6 hours <com:Math><semantics>±0.5<annotation encoding="application / x-tex">\pm 0.5< / annotation>< / semantics>< / com:Math> hours after each administration, residual drug was cleaned by washing with a cotton ball soaked in 0.9% sodium chloride injection. Administration was continued for 7 consecutive days, and necropsy was performed 24 hours after the last administration.

[0417] During the test, general symptoms of the animals and skin changes at the modeling / administration site were observed and recorded daily; the body weight of the animals was measured once per week; visual observation scoring of the modeling / administration region was performed before the first administration and before necropsy.

[0418] Visual observation grading criteria for acne manifestations [Image disponible dans le document PDF, Image available in the PDF document]

[0419] Note: # Before necropsy, due to the therapeutic effect or self-recovery of the model control, the comedones during the modeling period have transformed into dilated and elevated follicular orifices.

[0420] Definition of terms:

[0421] 1. Comedo: A tiny white macule or papule, 0.5–3 mm in diameter, mostly less than 1 mm.

[0422] 2. Papule: Small, slightly firm, red protrusion with a diameter of less than 0.5 cm.

[0423] 3. Pustule: A well-defined elevation of the skin appeared at the top of the papule, containing yellowish-white exudate.

[0424] 4. Nodule / Cyst: Located subcutaneously with no surface skin breakage, mostly formed from comedones that have undergone an inflammatory reaction but have not been completely destroyed, with the inner wall repaired and closed to form a firm foreign body or a cystic cavity.

[0425] Test results:

[0426] General condition of animals: During the administration period, the animals in each group were in good general condition, with no obvious abnormalities observed.

[0427] Body weight: During the administration period, the body weights of animals in each group were relatively stable, with no obvious abnormalities observed. After 7 consecutive days of administration, the body weights of the animals among the groups were basically consistent (<com:Math><semantics>P>0.05<annotation encoding="application / x-tex">P > 0.05< / annotation>< / semantics>< / com:Math>).

[0428] Visual observation scores of the administration region: Before the first administration (on the day of grouping, Day 11 of modeling), the visual observation scores of acne manifestations in the administration regions of animals in the model control group (blank cream group), tretinoin cream 0.025% control group, and Y-004 cream 0.025% group were basically consistent (<com:Math><semantics>P>0.05<annotation encoding="application / x-tex">P > 0.05< / annotation>< / semantics>< / com:Math>). After 7 consecutive days of administration, the visual observation scores of acne manifestations in the administration regions of animals in tretinoin cream 0.025% control group and Y-004 cream 0.025% group were both lower than those in the model control group (blank cream group) at the same time point, with a more pronounced reduction in the Y- 004 cream group (<com:Math><semantics>P<0.05<annotation encoding="application / x-tex">P < 0.05< / annotation>< / semantics>< / com:Math>). The visual observation scores of the animals during the test period (Mean <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> SD) are shown in FIG. 1 (Note: n=8 for each group. * <com:Math><semantics>P<0.05<annotation encoding="application / x-tex">P < 0.05< / annotation>< / semantics>< / com:Math> for each group compared with the model control group, <com:Math><semantics>P>0.05<annotation encoding="application / x-tex">P > 0.05< / annotation>< / semantics>< / com:Math> for the Y-004 cream group compared with the tretinoin cream control group.)

[0429] The Y-004 cream 0.025% group of the present disclosure can significantly reduce the visual observation scores of acne manifestations in the New Zealand rabbit ear acne model, demonstrating an obvious improvement effect.

Claims

CLAIMS 1. A compound of formula I or a pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] I A is 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR1R′<annotation encoding="application / x-tex">-CR^1R'< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; R' is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8- membered heterocycle or a C<com:Sub>3-8< / com:Sub> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; the 3- to 8- membered heterocycle and <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle are optionally substituted with one or more <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen; X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more R<com:Sup>5a< / com:Sup>; each R<com:Sup>5a< / com:Sup> is independently halogen or hydroxyl; m is 0, 1, 2, or 3; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; when Y is -CR<com:Sup>1< / com:Sup>R'-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8- membered heterocycle or a C<com:Sub>3-8< / com:Sub> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S.

2. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein 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 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is [Image disponible dans le document PDF, Image available in the PDF document] preferably N, for example, pyridylene, and for another example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or , wherein the a end is connected to phenylene, and the b end is connected to carbonyl); (3) in <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; (4) in R', the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; (5) in <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; (6) in the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle formed by <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> together with the intervening atom, the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> 8 carbocycle is monocyclic, such as C<com:Sub>4-6< / com:Sub> monocyclic carbocycle, for example, cyclopentane; (7) in the 3- to 8-membered heterocycle formed by <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> together with the intervening atom, the 3- to 8-membered heterocycle is monocyclic; (8) in the 3- to 8-membered heterocycle formed by R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup> together with the intervening atom, the 3- to 8-membered heterocycle is 4- to 6-membered heterocycle, preferably 4- to 6- [Image disponible dans le document PDF, Image available in the PDF document] membered monocyclic heterocycle, for example, (9) in the 3- to 8-membered heterocycle formed by R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup> together with the intervening atom, the number of heteroatoms is 1, and the heteroatom is preferably N; (10) in <com:Math><semantics>ℝ3<annotation encoding="application / x-tex">\mathbb{R}^3< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (11) in <com:Math><semantics>ℝ4<annotation encoding="application / x-tex">\mathbb{R}^4< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (12) in <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (13) in <com:Math><semantics>ℝ5<annotation encoding="application / x-tex">\mathbb{R}^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy is methoxy, ethoxy, <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-propoxy, isopropoxy, <com:Math><semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics>< / com:Math>-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, ethoxy, n-propoxy, or n-butoxy; (14) in R<com:Sup>5a< / com:Sup>, the halogen is fluorine, chlorine, bromine, or iodine; (15) in <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, for example, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl substituted with one hydroxyl; (16) in <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, for example, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one hydroxyl, and for another example, HO Or HO O (17) in <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (18) in <com:Math><semantics>ℝ2−1<annotation encoding="application / x-tex">\mathbb{R}^{2-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (19) in <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (20) in R<com:Sup>2-1< / com:Sup>, the halogen is fluorine, chlorine, bromine, or iodine; (21) the more than one refers to 2 or 3.

3. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein 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 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6- membered heteroarylene has 1 heteroatom, and the heteroatom is N; preferably, A is 6- to 10- membered arylene; more preferably, A is phenylene; (3) Y is -NR<com:Sup>1< / com:Sup>- or -CHR<com:Sup>1< / com:Sup>-; when Y is -CHR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably, when Y is <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the C<com:Sub>3-8< / com:Sub> carbocycle is monocyclic (for example, the <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> monocyclic carbocycle); more preferably, when Y is -CHR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic; (4) Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-; (5) <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; preferably, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a C<com:Sub>3-8< / com:Sub> carbocycle (for example, a C<com:Sub>4-6< / com:Sub> carbocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the C<com:Sub>3-8< / com:Sub> carbocycle is monocyclic; more preferably, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6- membered heterocycle) or a C<com:Sub>3-8< / com:Sub> carbocycle (for example, a C<com:Sub>4-6< / com:Sub> carbocycle); the 3- to 8- membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the C<com:Sub>3-8< / com:Sub> carbocycle is monocyclic; (6) X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; (7) <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; (8) <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; (9) <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, preferably, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> 6 alkoxy substituted with one R<com:Sup>5a< / com:Sup>; (10) R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl, preferably, R<com:Sup>5a< / com:Sup> is hydroxyl; (11) <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably, R<com:Sup>6< / com:Sup> is H; (12) Y is -NR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle has 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, wherein at least one of the heteroatoms is N; the 3- to 8-membered heterocycle is optionally substituted with one or more <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen; preferably, when Y is -NR<com:Sup>1< / com:Sup>-, R<com:Sup>1< / com:Sup> and R<com:Sup>2< / com:Sup>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the 3- to 8-membered heterocycle is optionally substituted with one or more <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math>; each <com:Math><semantics>R2−1<annotation encoding="application / x-tex">R^{2-1}< / annotation>< / semantics>< / com:Math> is independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy, or halogen.

4. The compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the compound of formula I satisfies one or more of the following conditions: [Image disponible dans le document PDF, Image available in the PDF document] b , wherein the a end is connected to phenylene, and the b end is connected to carbonyl).

5. The compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein 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 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is N; Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic; X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; when Y is -CHR<com:Sup>1< / com:Sup>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic (for example, <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> monocyclic carbocycle); Scheme 2: m is 0, 1, or 2; A is 6- to 10-membered arylene; Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; <com:Math><semantics>X is −CR3R4<annotation encoding="application / x-tex">X \text{ is } -CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; Scheme 3: m is 1; A is 6- to 10-membered arylene or 5- to 6-membered heteroarylene; the 5- to 6-membered heteroarylene has 1 heteroatom, and the heteroatom is N; Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CHR1<annotation encoding="application / x-tex">-CHR^1< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle) or a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic; X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; when Y is -CHR<com:Sup>1-< / com:Sup>, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle (for example, a <com:Math><semantics>C4−6<annotation encoding="application / x-tex">C_{4-6}< / annotation>< / semantics>< / com:Math> carbocycle), and the <com:Math><semantics>C3−8<annotation encoding="application / x-tex">C_{3-8}< / annotation>< / semantics>< / com:Math> carbocycle is monocyclic; Scheme 4: m is 1; A is 6- to 10-membered arylene; Y is <com:Math><semantics>−NR1<annotation encoding="application / x-tex">-NR^1< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

6. The compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the compound of formula I is a compound of formula I-1 or a compound of formula I-2: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1 I-2 (for example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-2-a or I-2-b ); n is 0, 1, 2, or 3; m, A, R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, X, R<com:Sup>5< / com:Sup>, and R<com:Sup>6< / com:Sup> are as defined 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 6- to 10-membered arylene; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> 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; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (2) in the compound of formula I-2 (for example, compound of I-2-a or I-2-b), n is 0, 1, or 2; m is 0, 1, or 2; A is 6- to 10-membered arylene; X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-2 (for example, compound of I-2-a or I-2-b), n is 1; m is 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> 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: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-a I-1-b [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-c (for example, I-1-c-1 [Image disponible dans le document PDF, Image available in the PDF document] or I-1-c-2 ); t is 0, 1, 2, or 3; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; m, A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, X, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> are as defined in any one of claims 1-4; in <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; further 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 6- to 10-membered arylene; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> 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; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (2) in the compound of formula I-1-b, m is 0, 1, or 2; A is 6- to 10-membered arylene; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> 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; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (3) in the compound of formula I-1-c (for example, compound of I-1-c-1 or I-1-c-2), t is 0, 1, or 2; m is 0, 1, or 2; A is 6- to 10-membered arylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-1-c (for example, compound of I-1-c-1 or I-1-c- 2), t is 1 or 2; m is 0 or 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> 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 (for example, compound of I-1-c-1 or <com:Math><semantics>I−1−c−2),<annotation encoding="application / x-tex">I-1-c-2),< / annotation>< / semantics>< / com:Math> t is 1; m is 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

7. The compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the compound of formula I is a compound of formula I-1-1 or a compound of formula I-2-1: [Image disponible dans le document PDF, Image available in the PDF document] I-1-1 I-2-1 (for example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-2-1-a or I-2-1-b n is 0, 1, 2, or 3; A, R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, and X are as defined in any one of claims 1 to 4; preferably, the compound of formula I satisfies one or two of the following conditions: (1) in the compound of formula I-1-1, A is 6- to 10-membered arylene; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle (for example, a 4- to 6-membered heterocycle); the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; preferably, in the compound of formula I-1-1, A is phenylene; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; or, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, together with the intervening atom, form a 3- to 8-membered heterocycle; the 3- to 8-membered heterocycle is monocyclic and has 1 heteroatom, and the heteroatom is N; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; (2) in the compound of formula I-2-1 (for example, I-2-1-a, I-2-1-b), n is 0, 1, or 2; A is 6- to 10-membered arylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; preferably, in the compound of formula I-2-1 (for example, I-2-1-a, I-2-1-b), n is 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> 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: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-1 I-1-1-2 or , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-3 (for example, I-1-1-3-a or [Image disponible dans le document PDF, Image available in the PDF document] I-1-1-3-b ); t is 0, 1, 2, or 3; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, and X are as defined in any one of claims 1 to 4; in R<com:Sup>1-1< / com:Sup>, the C<com:Sub>1-6< / com:Sub> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, or tert-butyl, for example, methyl or ethyl; further 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 6- to 10-membered arylene; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; preferably, in the compound of formula I-1-1-1, A is phenylene; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; (2) in the compound of formula I-1-1-2, A is 6- to 10-membered arylene; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; preferably, in the compound of formula I-1-1-2, A is phenylene; <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; (3) in the compound of formula I-1-1-3 (for example, I-1-1-3-a, I-1-1-3-b), t is 0, 1, or 2; A is a 6- to 10-membered arylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; preferably, in the compound of formula I-1-1-3 (for example, I-1-1-3-a, I-1-1-3-b), t is 1 or 2; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; more preferably, in the compound of formula I-1-1-3 (for example, I-1-1-3-a, I-1-1-3-b), t is 1; A is phenylene; X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl.

8. The compound of formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein 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 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-A I-B (for example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-B-1 or I-B-2 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-C I-D (for example, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] I-D-1 or I-D-2 ); <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; X, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> are as defined in any one of claims 1 to 4; in <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; preferably, the compound of formula I satisfies one or more of the following conditions: (1) in the compound of formula I-A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (2) in the compound of formula I-B (for example, I-B-1, I-B-2), <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-B (for example, I-B-1, I-B-2), <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (3) in the compound of formula I-C, <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-C, <com:Math><semantics>R1−1<annotation encoding="application / x-tex">R^{1-1}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; (4) in the compound of formula I-D (for example, I-D-1, I-D-2), X is <com:Math><semantics>−NR3<annotation encoding="application / x-tex">-NR^3< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one or more <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math> is fluorine, chlorine, bromine, or hydroxyl; R<com:Sup>6< / com:Sup> is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; preferably, in the compound of formula I-D (for example, I-D-1, I-D-2), X is <com:Math><semantics>−CR3R4<annotation encoding="application / x-tex">-CR^3R^4< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkoxy substituted with one <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>; R<com:Sup>5a< / com:Sup> is hydroxyl; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H.

9. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is any one of the following compounds: HO HO HO. HO [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 10. A pharmaceutical composition comprising (i) the compound of formula I or the pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 9; and (ii) a pharmaceutically acceptable carrier.

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

12. Use of the compound of formula I or the pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 9, or the pharmaceutical composition as defined in claim 10, in the manufacture of a medicament for treating and / or preventing a disease associated with retinoic acid receptor γ; preferably, the disease associated with retinoic acid receptor γ may be acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

13. Use of the compound of formula I or the pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 9, or the pharmaceutical composition as defined in claim 10, in the manufacture of a medicament; preferably, the medicament is used for treating and / or preventing acne (including acne vulgaris, rosacea, nodulocystic acne, acne conglobata, and secondary acne caused by sunlight or medication), comedo, psoriasis, ichthyosis, cutaneous keratinization disorder, pigmentation, or dry eye syndrome.

14. A compound of formula II or a salt thereof [Image disponible dans le document PDF, Image available in the PDF document] II <com:Math><semantics>R6<annotation encoding="application / x-tex">R^{6}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl; A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^{2}< / annotation>< / semantics>< / com:Math>, X, and Y are as defined in any one of claims 1 to 9; in <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>ℂ1−6<annotation encoding="application / x-tex">\mathbb{C}_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, or tert-butyl, for example, methyl; in <com:Math><semantics>R6<annotation encoding="application / x-tex">R^{6}< / annotation>< / semantics>< / com:Math>, the <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, ethyl; preferably, the compound of formula II is any one of the following compounds: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 15. A method for preparing a compound of formula I, comprising the following step: subjecting a compound of formula II to a hydrolysis reaction as shown below (for example, at 50-70°C, further for example, at 60°C) in an organic solvent (for example, an alcohol solvent, further for example, methanol) in the presence of a base (for example, an alkali metal hydroxide, further for example, sodium hydroxide, still further for example, 1 mol / L aqueous sodium hydroxide solution) to obtain the compound of formula I; [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> is attached at the para position of A, m is 1; A, X, Y, and R<com:Sup>2< / com:Sup> are as defined in any one of claims 1 to 9, and R<com:Sup>6< / com:Sup> and R<com:Sup>7< / com:Sup> are as defined in claim 14; preferably, the method for preparing the compound of formula I further comprises the following step: subjecting a compound of formula III and a compound of formula IV to a coupling reaction as shown in the following scheme (for example, at 100-120°C, further for example, at 110°C) in a solvent (for example, a mixed solvent of water and a cyclic ether solvent, further for example, a mixed solvent of water and dioxane, still further for example, dioxane and water in a volume ratio of 20:3 or 4:1) in the presence of a catalyst (for example, a palladium catalyst, further for example, Pd(dppf)Cl<com:Sub>2< / com:Sub>) and an alkali metal halide salt (for example, an alkali metal fluoride salt, further for example, KF) to obtain the compound of formula II; [Image disponible dans le document PDF, Image available in the PDF document] R<com:Sup>8< / com:Sup> is a boronate ester group ); R<com:Sup>9< / com:Sup> is halogen (for example, bromine); A, X, Y, and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> are as defined in any one of claims 1 to 9; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined in claim 14.

16. A method for preparing a compound of formula II, comprising the following step: subjecting a compound of formula III and a compound of formula IV to a coupling reaction as shown in the following scheme (for example, at 100-120°C, further for example, at 110°C) in a solvent (for example, a mixed solvent of water and a cyclic ether solvent, further for example, a mixed solvent of water and dioxane, still further for example, dioxane and water in a volume ratio of 20:3 or 4:1) in the presence of a catalyst (for example, a palladium catalyst, further for example, Pd(dppf)Cl<com:Sub>2< / com:Sub>) and an alkali metal halide salt (for example, an alkali metal fluoride salt, further for example, KF) to obtain the compound of formula II; [Image disponible dans le document PDF, Image available in the PDF document] , R<com:Sup>8< / com:Sup> is a boronate ester group ); R<com:Sup>9< / com:Sup> is halogen (for example, bromine); A, X, Y, and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> are as defined in any one of claims 1 to 9; <com:Math><semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> are as defined in claim 14.