Stilbene derivatives, their preparation and use

Abstract

The present disclosure provides stilbene derivatives and their preparation and use. Specifically, the present disclosure provides the use of a compound represented by Formula I-1, its stereoisomer, pharmaceutically acceptable salt, or prodrug as an aromatic hydrocarbon receptor (AHR) modulator. The compound represented by Formula I-1 has significantly improved photostability of its molecular structure compared to the commercially available drug benvitimod, thereby alleviating benvitimod's photoinstability and susceptibility to decomposition under light irradiation. Furthermore, it has significantly improved activity against the AHR protein. Finally, the compound represented by Formula I-1 can be produced by a simple method at gram or kilogram levels, and has better prospects for subsequent formulation development, safety, and clinical application. [Formula 1] JPEG2025533578000047.jpg26169

Description

Detailed Description of the Invention

[0001] This application claims priority to two prior applications: patent application number 202211170147.6, entitled "Stilbene Derivatives, Their Preparation and Use," filed with the State Intellectual Property Office of China on September 22, 2022, and patent application number 202310654162.6, entitled "Stilbene Derivatives, Their Preparation and Use," filed with the State Intellectual Property Office of China on June 2, 2023. Both applications are incorporated herein by reference in their entireties.

[0002] [Technical Field] The present disclosure belongs to the technical field of inflammation or immune-related drugs, and specifically relates to novel stilbene derivatives, methods for their preparation and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, particularly as Aryl Hydrocarbon Receptor (AHR) modulators.

[0003] [Background technology] The aromatic hydrocarbon receptor (AHR), also known as the dioxin receptor, is a member of the bHLH (basic helix-loop-helix)-PAS (Per-ARNT-Sim) family of transcriptional regulators. A unique feature of bHLH-PAS family members is the presence of a PAS domain, named after the first three proteins with this motif: Drosophila Per, human ARNT, and Drosophila Sim. The PAS domain consists of 260–310 amino acids and contains two highly conserved hydrophobic repeats, termed PAS-A and PAS-B, separated by a relatively poorly conserved repeat. The bHLH domain is responsible for DNA binding, while the tandem PAS domains (PAS-A and PAS-B) are involved in protein-protein interactions and ligand binding. In AHR, ligand binding occurs in the PAS-B domain. In bHLH-PAS family members, the N-terminal bHLH-PAS region is relatively well conserved. Most non-conservative changes in the AHR occur in the transcriptional activation domain, leading to different protein-protein interactions with other coactivators, corepressors, or nuclear receptors, and regulating differential gene expression.

[0004] In the absence of ligand, AHR resides in the cytosol and binds to multiple chaperonins, including a dimer of heat shock protein 90 (HSP90), the co-chaperonin p23, the AHR-interacting protein (AIP), and the protein kinase Src. Upon ligand binding, AHR changes its conformation, translocates to the nucleus, dissociates from the chaperone complex, and heterodimerizes with the AHR nuclear transporter (Aryl Hydrocarbon Receptor Nucleus Translocator, ARNT). The upstream regulatory region of AHR-regulated genes contains a DNA consensus sequence (5'-TNGCGTG-3'), known as the xenobiotic responsive element (XRE) or dioxin responsive element (DRE). This sequence acts as a transcriptional enhancer and is one of the sites where AHR binds. The AHR-ARNT heterodimer complex is recruited by the XRE and initiates transcription of target genes.

[0005] Studies have revealed that AHR is involved in physiological processes such as cell physiology, host defense, immune cell proliferation and differentiation, and detoxification. AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T cells, and NK cells.

[0006] The structural flexibility of the AHR ligand-binding site allows for a wide range of small molecules to act as ligands, including exogenous ligands such as polycyclic aromatic hydrocarbons, dioxins, and polychlorinated biphenyls, as well as endogenous ligands such as tryptophan degradation metabolites, food-derived ligands, and bacterial and microbial metabolic pathway products. For example, the AHR modulator benvitimod, a naturally occurring small molecule produced from the bacterial symbiont of an entomopathogenic nematode, is the world's first commercially available aromatic hydrocarbon receptor agonist and can be used to treat various autoimmune diseases such as psoriasis and eczema. However, its application is limited by its structural characteristics, including photoinstability and susceptibility to degradation under light irradiation. Therefore, the development of more photostable AHR modulators is of great significance for expanding its clinical application range and reducing potential side effects.

[0007] Summary of the Invention In order to improve the above-mentioned problems of the prior art, the present disclosure provides a compound represented by the following formula I-1, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof: [ka] wherein Ar is unsubstituted or optionally substituted with one, two or more Rs; 6-20 selected from an aryl group or a 5- to 20-membered heteroaryl group, Each Rs may be the same or different and independently represent a halogen, a cyano group, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 selected from alkoxy groups, Each R1 is the same or different and independently represents a halogen, a cyano group, or C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 alkoxy groups, and n is 1 or 2.

[0008] In some embodiments of the present disclosure, the present invention provides a compound represented by the above formula I-1, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein each R is the same or different and independently represents a halogen, a cyano group, C 2-6 Straight chain alkyl group, halo C 1-6 Alkyl group, -COC 2-6 Alkyl group or C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0009] In some embodiments of the present disclosure, the compound of formula I-1 above, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof: [ka] wherein Ar is unsubstituted or optionally substituted with one, two or more Rs; 6-20 selected from an aryl group or a 5- to 20-membered heteroaryl group, Each Rs may be the same or different and independently represent a halogen, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 selected from alkoxy groups, R1 is as defined in formula I-1.

[0010] The present disclosure further provides compounds of Formula I below, stereoisomers, pharmaceutically acceptable salts, or prodrugs thereof: [ka] wherein Ar is unsubstituted or optionally substituted with one, two or more Rs; 6-20 selected from an aryl group or a 5- to 20-membered heteroaryl group, Each Rs may be the same or different and independently represent a halogen, C 1-12 Alkyl group, halo C 1-12Alkyl group, -COC 1-12 Alkyl group or C 1-12 selected from alkoxy groups, R1 is a halogen, a cyano group, or C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 The alkoxy group is selected from the group consisting of alkoxy groups.

[0011] In some embodiments of the present disclosure, there is provided a compound represented by the above formula I-1 or formula I, a stereoisomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof, wherein Ar is selected from a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, which is unsubstituted or optionally substituted with one, two, or more Rs, and Rs is as defined in formula I-1 or formula I; preferably, Ar is selected from a phenyl group or a 5- to 10-membered heteroaryl group, which is unsubstituted or optionally substituted with one, two, or more Rs, and Rs is as defined in formula I-1 or formula I. more preferably, Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs, or a 5- to 6-membered heteroaryl group, where Rs is as defined in formula I-1 or formula I; most preferably, Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thienyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrazinyl or pyrimidinyl group, where Rs is as defined in formula I-1 or formula I.

[0012] In some embodiments of the present disclosure, there is provided a compound represented by the above formula I-1 or formula I, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein each R1 is the same or different and independently represents F, Cl, Br, a methyl group or a cyano group.

[0013] In some embodiments of the present disclosure, the compound represented by the above formula I-1 or formula I, its stereoisomer, pharmaceutically acceptable salt or prodrug, wherein each Rs is the same or different and independently represents a halogen, a cyano group, C 1-6 Alkyl group, halo C 1-6 Alkyl group, -COC 1-6 Alkyl group or C 1-6 Preferably, each Rs is the same or different and independently represents a halogen, a cyano group, a C 1-6 Alkyl group or C 1-6 More preferably, each Rs is the same or different and independently selected from halogen, C 1-6 Alkyl group or C 1-6 Preferably, each Rs is the same or different and is independently a halogen.

[0014] In some embodiments of the present disclosure, the compound of formula I above or a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein each Rs is the same or different and independently represents halogen, C 1-6 Alkyl group, halo C 1-6 Alkyl group, -COC 1-6 Alkyl group or C 1-6 alkoxy groups, preferably, each Rs is the same or different and independently selected from halogen, C 1-6 Alkyl group or C 1-6 More preferably, each Rs is the same or different and independently selected from halogen, C 1-6 Alkyl group or C 1-6 Preferably, each Rs is the same or different and is independently a halogen, for example, Rs is F, Cl, a methyl group or a methoxy group.

[0015] In some embodiments of the present disclosure, there is provided a compound of formula I-1 or formula I above, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein Ar is unsubstituted or optionally substituted with one, two or more halogens, C1-3 Alkyl group or C 1-3 Alkoxy-substituted C 6-14 aryl group or 5- to 14-membered heteroaryl group, R1 is F, Cl, Br, cyano group, C 1-3 Alkyl group, halo C 1-3 Alkyl group, -COC 1-3 Alkyl group or C 1-3 alkoxy groups, preferably F, Cl, Br, cyano groups, C 1-3 Alkyl or halo C 1-3 It is an alkyl group.

[0016] In some embodiments of the present disclosure, the present invention provides a compound represented by the above formula I-1 or formula I, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs, a pyridin-2-yl, a pyridin-3-yl, a pyridin-4-yl, a 2-thienyl group, a 2-pyridazinyl group, and a 2-quinolinyl group, and Rs is as defined in formula I-1 or formula I, and preferably, Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs, a pyridin-2-yl, a pyridin-3-yl, a pyridin-4-yl, a 2-thienyl group, a 2-pyridazinyl group, and a 2-quinolinyl group. Rs is a halogen, for example, Ar is selected from a phenyl group, a pyridinyl group, a thienyl group, a pyridazinyl group, or a quinolinyl group substituted with one, two or more substituents selected from fluorine, chlorine, bromine, a methyl group, or a methoxy group, examples of which include a 4-fluorophenyl group, a 2-fluorophenyl group, a 2-pyridazinyl group, a 2-thienyl group, a 2-quinolinyl group, a 2-pyridinyl group, a 3-pyridinyl group, a 4-pyridinyl group, [ka] may be selected from R1 is F, Cl, Br, a methyl group, a methoxy group, a cyano group, an acetyl group, [ka] Be chosen.

[0017] In one embodiment, R1 is substituted at the ortho position of one hydroxy group on the benzene ring, or simultaneously at the ortho positions of two hydroxy groups.

[0018] In one embodiment, when Ar is a heteroaryl group, it is linked at the 2-, 3-, or 4-position to an alkenyl group.

[0019] By way of example, compounds of Formula I-1 or Formula I include, but are not limited to, compounds selected from the following: [ka]

[0020] According to an embodiment of the present disclosure, the prodrug may be an ester formed from at least one hydroxy group of a compound represented by Formula I-1 or Formula I and a pharmaceutically acceptable compound having at least one carboxy group. Illustratively, the compound having at least one carboxy group may be a monobasic, dibasic, or polybasic organic acid (e.g., acetic acid, phosphoric acid). Alternatively, when the organic acid is a dibasic or polybasic organic acid, one carboxy group may form an ester with the compound represented by Formula I, and the other carboxy group may be a C substituted with a hydroxy group. 1-12 It can react with alkyl groups to form esters.

[0021] Another aspect of the present disclosure relates to a compound of formula I-1d or a salt thereof: [ka] Among them, R is selected from alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one, two, or more substituents selected from halogen, oxo group (=O), alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, nitro groups, cyano groups, amino groups, alkylamino groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; preferably, R is C 1-6 is an alkyl group, Each R1 is the same or different and independently represents a halogen, a cyano group, or C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 2-12 alkoxy groups, preferably F, Cl, Br, cyano groups, C 1-3 Alkyl or halo C 1-3 is an alkyl group, Ar and n are as defined in Formula I-1 or Formula I.

[0022] [ka]

[0023] Another aspect of the present disclosure relates to a method for preparing a compound of formula I-1, a stereoisomer, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] The compound of formula I-1d or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of formula I-1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Among them, R is selected from alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one, two, or more substituents selected from halogen, oxo group (=O), alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, nitro groups, cyano groups, amino groups, alkylamino groups, hydroxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; preferably, R is C 1-6 is an alkyl group, Each R1 is the same or different and independently represents a halogen, a cyano group, or C 2-6 Straight chain alkyl group, halo C 1-6 Alkyl group, -COC 2-6 Alkyl group or C 1-6 alkoxy groups, preferably F, Cl, Br, cyano groups or haloC 1-3 is an alkyl group, Ar and n are as defined in Formula I-1 or Formula I.

[0024] The present disclosure further provides a process for preparing a compound of Formula I, a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1) When R1 is halogen, the compound of formula I is [ka] S5) The compound represented by formula Id or a salt thereof is reacted with pyridine hydrochloride by heating to obtain the compound represented by formula I, or the compound represented by formula Id or a salt thereof is subjected to removal of the methyl group with boron tribromide, followed by quenching the reaction with water to obtain the compound represented by formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. It is manufactured by the method 2) When R1 is a methyl group, the compound of formula I is [ka] S5') Compound Id' is reacted with pyridine hydrochloride by heating to obtain the compound of formula I. It is manufactured by the method wherein Ar and R1 are as defined in formula I-1 or formula I.

[0025] In one embodiment, compound Id is [ka] S1) 3,5-dimethoxy-4-isopropylbenzyl alcohol is reacted with a halogenating reagent (e.g., N-chlorosuccinimide, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) or N-bromosuccinimide) to give compound Ia; S2) Compound Ia is added to a mixed solution of concentrated hydrochloric acid and n-hexane and reacted by heating to obtain compound Ib. S3) Compound Ib is reacted with triethyl phosphite by heating to obtain compound Ic; S4) Compound Ic and Compound [ka] in the presence of a basic compound (e.g., a basic compound such as potassium tert-butoxide or sodium tert-butoxide) to obtain compound Id; It is produced by the following method, but is not limited to these: compound [ka] The Ar group in has the same definition as in Formula I-1 or Formula I above.

[0026] Optionally, the above process further comprises preparing the compound of Formula I-1, Formula I or Table A as a salt.

[0027] The present disclosure further provides pharmaceutical compositions, which comprise a therapeutically effective amount of at least one of the compounds shown in Formula I-1, Formula I, or Table A, a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof.

[0028] According to an embodiment of the present disclosure, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

[0029] According to an embodiment of the present disclosure, the pharmaceutical composition is an aromatic hydrocarbon receptor (AHR) modulator.

[0030] According to an embodiment of the present disclosure, the aromatic hydrocarbon receptor (AHR) modulator is for alleviating and / or treating the following diseases or conditions: cancer, ophthalmological-related diseases, autoimmune diseases, and other diseases or conditions having an immunological factor; the cancer is preferably leukemia, prostate cancer, and intestinal cancer; the ophthalmological-related diseases are preferably uveitis, age-related macular degeneration, and dry eye; the autoimmune diseases are preferably rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; and the other diseases or conditions having an immunological factor are preferably asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0031] The present disclosure further provides the use of at least one of the compounds of Formula I-1, Formula I, or Table A, a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of an aromatic hydrocarbon receptor (AHR) modulator.

[0032] The present disclosure further provides a method for alleviating and / or treating a disease or condition mediated by the aromatic hydrocarbon receptor (AHR), comprising administering to a patient a therapeutically effective amount of at least one of the compounds of Formula I-1, Formula I, or Table A, a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described above.

[0033] According to an embodiment of the present disclosure, the diseases or conditions mediated by the aromatic hydrocarbon receptor (AHR) include cancer, ophthalmological-related diseases, autoimmune diseases, and other diseases or disorders with immunological factors; the cancers are preferably leukemia, prostate cancer, and intestinal cancer; the ophthalmological-related diseases are preferably uveitis, age-related macular degeneration, and dry eye; the autoimmune diseases are preferably rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; and the other diseases or conditions with immunological factors are preferably asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0034] Beneficial effects The present disclosure improves the structure of benvitimod, thereby significantly improving the photostability of the molecular structure of the resulting compounds compared to the commercially available drug benvitimod, thereby alleviating the problems of benvitimod's photoinstability and susceptibility to decomposition under light irradiation. Furthermore, some compounds also exhibit significantly improved activity against the AHR protein, or have activity at least equal to or greater than that of benvitimod.

[0035] Finally, the resulting compounds are simple to prepare and can be produced at gram or kilogram levels, offering better prospects for subsequent formulation development, safety, and clinical application.

[0036] Definitions and Explanations of Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0037] Unless otherwise specified, the definitions of groups and terms in the specification and claims of this application, including their illustrative definitions, exemplary definitions, preferred definitions, definitions in tables, definitions of specific compounds in the examples, etc., may be arbitrarily combined or linked with each other. Such combined and linked group definitions and compound structures should be understood to be within the scope of the specification and / or claims of this application.

[0038] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to at least describing each specific integer value therein. For example, a numerical range of "1 to 10" is equivalent to describing each integer value in the numerical range "1 to 10," which are 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. When a numerical range is defined as a "number," it should be understood that the two endpoints of the range, each integer in the range, and each decimal point in the range are described. For example, a "number from 0 to 10" is understood to describe not only each integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also the sum of each integer and at least each of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0039] It should be understood that when referring to one, two or more herein, "more" should refer to an integer greater than two, such as 3 or greater, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0040] The "-*" used in conjunction with a chemical bond in a substituent indicates the point of attachment.

[0041] The term "halogen" includes F, Cl, Br or I.

[0042] The term "alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group, e.g., C 1-12 It should be understood to refer to an alkyl group.

[0043] "C1-12 The term "alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, 1-6 It should be understood that alkyl groups are preferred. 1-6 "Alkyl group" preferably denotes a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, C 2-6 Alkyl groups are preferred, and C 2-6 It should be understood that straight-chain alkyl groups are more preferred. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isoamyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, and the like, or isomers thereof. In particular, the groups are alkyl groups having 1, 2, or 3 carbon atoms ("C 1-3 alkyl group), such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0044] The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring group having 6 to 20 carbon atoms, including C 6-20 It should be understood that aryl groups are preferred.

[0045] "C 6-20 The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring group having 6 to 20 carbon atoms, and "C 6-14 It should be understood that "aryl groups" are preferred. 6-14The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 It is to be understood that the aryl group preferably represents a ring having 6 carbon atoms ("C6 aryl group") such as a phenyl group or a biphenyl group, or a ring having 9 carbon atoms ("C9 aryl group") such as an indanyl group or an indenyl group, or a ring having 10 carbon atoms ("C9 aryl group") such as a tetrahydronaphthyl group, a dihydronaphthyl group, or a naphthyl group. 10 aryl group), or a ring with 13 carbon atoms, such as a fluorenyl group ("C 13 aryl group), or a ring with 14 carbon atoms, such as an anthryl group ("C 14 When the aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and it may be substituted, for example, at the ortho-, para-, or meta-position.

[0046] The term "heteroaryl group" is to be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13... or 20 ring atoms, preferably 5-20 membered heteroaryl groups.

[0047] The term "5- to 20-membered heteroaryl group" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13... or 20 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms (e.g., preferably 5- to 10-membered heteroaryl groups), and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. Furthermore, in each case, they may also be benzo-fused. In particular, heteroaryl groups include thienyl, furan, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuran, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like. or pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, etc. and their benzo derivatives, for example, quinoline group, quinazolinyl group, isoquinoline group, etc.; azocine group, indolizinyl group, purine group, etc. and their benzo derivatives; or cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, naphthyridinyl group, pteridinyl group, carbazolyl group, acridinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, etc. When the 5- to 10-membered heteroaryl group is substituted, it may be mono- or polysubstituted. Furthermore, the substitution site is not limited, and for example, a hydrogen atom bonded to a carbon atom in the heteroaryl ring may be substituted, or a hydrogen atom bonded to a heteroatom in the heteroaryl ring may be substituted.

[0048] Unless otherwise specified, heteroaryl or heteroarylene groups include all possible isomeric forms, for example, their positional isomers.Thus, for some illustrative, non-limiting examples, they may include forms substituted or bonded to other groups at one, two or more positions, such as 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-positions (if present), and include pyridin-2-yl, pyridylidene-2-yl, pyridin-3-yl, pyridylidene-3-yl, pyridin-4-yl and pyridylidene-4-yl, thienyl or thienylene groups, including thien-2-yl, thien-3-yl and thienylen-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0049] The term "cycloalkyl group" refers to a saturated, monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring (also referred to as a fused ring hydrocarbon ring) having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include fused ring cycloalkyl groups, bridged cycloalkyl groups, and spirocycloalkyl groups. The fused ring is a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms (i.e., sharing one bond). The bridged ring is a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms. The spiro ring is a fused ring structure formed by two or more ring structures sharing one ring atom. For example, the cycloalkyl group may be a C group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group. 3-8 Monocyclic cycloalkyl groups or C groups such as decahydronaphthalene rings 7-12 It may also be a fused cyclic cycloalkyl group.

[0050] The term "heterocyclyl group" refers to a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O, and S. The heterocyclyl group can be linked to the remainder of the molecule through any one of the carbon atoms or, if present, a nitrogen atom. In particular, the heterocyclyl group may include, but is not limited to, 4- to 20-membered heterocyclyl groups, such as 4-membered rings such as azetidinyl and oxetanyl, 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, and pyrrolinyl, 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, and trithianyl, or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen atom-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydrooxazolyl group, or a 4H-[1,4]thiazinyl group, or it may be benzo-fused, for example, but not limited to, a dihydroisoquinolinyl group.

[0051] The term "haloalkyl group" refers to an alkyl group in which H is replaced with halogen, for example, when H in the alkyl group is optionally replaced with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 halogens, it is within the scope of the above-mentioned "halo", "alkyl group" and "C 1-12 "Alkyl group" has the definition as above. The above substitutions may be on the same carbon atom or on different carbon atoms. Optionally, "haloC 1-6 The above "halo C 1-12An example of the "alkyl group" is a trifluoromethyl group.

[0052] The definitions of the above terms apply equally to other terms that contain those terms. For example, the above "C 1-12 The definition of the term "alkyl group" is "C 1-12 Other terms containing "alkyl groups", e.g., "-COC 1-12 alkyl group," "-COC 2-12 alkyl group," "-COC 2-6 The same applies to "alkyl group" and the like.

[0053] For example, the term "alkoxy group" refers to an alkyloxy group, of which the alkyl group has the definition given above.

[0054] The term "haloalkoxy" refers to a haloalkyloxy group, in which the alkyl group has the definition above.

[0055] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group has the definition given above.

[0056] The term "alkylamino group" refers to the alkyl group having the definition given above.

[0057] The term "prodrug compound" refers to a covalently bonded compound that releases an active parent drug according to Formula (I) in vivo. Such prodrugs are typically compounds of the invention that have been modified at one or more suitable groups such that the modifications are reversible after administration to a human or mammalian subject. While a second agent can be administered with such a prodrug for in vivo reversal, reversal is typically accomplished by an enzyme naturally present in such a subject. Examples of such modifications include the pharmaceutically acceptable esters mentioned above, of which reversal can be accomplished by esterases, etc.

[0058] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0059] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0060] The structures of the compounds in this disclosure are confirmed by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shifts (δ) are -6 The concentration is expressed in ppm (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0061] The liquid chromatograph mass spectrometers used were Waters 2695+ZQ2000, Shimadzu MS-2020+LC-20AB, and Shimadzu LC-40D XR+MS-2020.

[0062] For high performance liquid chromatography (HPLC) analysis, Shimadzu LC-20AB, Shimadzu LC-20ADXR and Shimadzu LC-40D XR high performance liquid chromatographs were used.

[0063] A Shimadzu LC-30AD high performance liquid chromatograph was used for chiral HPLC analytical measurements.

[0064] For preparative high performance liquid chromatography, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

[0065] Where chiral molecular separations are present in the examples, a Waters 150 Mgm, Waters SFC 350 preparative chromatograph was used for the chiral separations.

[0066] CombiFlash high-speed preparative chromatograph CH-200P (Agela & Phenomenex) was used.

[0067] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used for thin-layer chromatography. The silica gel plates used for thin-layer chromatography (TLC) had a diameter of 0.15 mm to 0.2 mm, and those for separating and purifying products by thin-layer chromatography had a diameter of 0.4 mm to 0.5 mm.

[0068] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai or Taitan Technology was generally used as the carrier.

[0069] Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Taitan Technology, Ananji Chemical, Shanghai Haohong Biotechnology, and BiDe Pharmaceutical.

[0070] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0071] An argon or nitrogen atmosphere refers to an argon or nitrogen gas balloon with a volume of approximately 1 L connected to the reaction flask.

[0072] In the examples, when a reaction is described as being carried out under hydrogen gas conditions, the hydrogen atmosphere refers to a reaction flask connected to a hydrogen gas balloon with a volume of approximately 1 L. For pressurized hydrogenation reactions, a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen gas generator or an HC2-SS hydrogenator were used. The hydrogenation reaction typically involved three cycles of evacuation and refilling with hydrogen gas.

[0073] In the examples, where it is stated that a reaction is carried out under microwave conditions, a CEM Discover-S 908860 microwave reactor was used for the microwave reaction. Unless otherwise specified in the examples, solutions refer to aqueous solutions.

[0074] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0075] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvents used in the reaction, the eluent system for column chromatography to purify the compounds, and the developing solvent system for thin layer chromatography comprised A: petroleum ether / ethyl acetate system and B: dichloromethane / methanol system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds, and may be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0076] In some examples, preparative HPLC was used to purify the compounds.

[0077] Example 1 (E)-4-Chloro-2-isopropyl-5-styrylbenzene-1,3-diol 1 [ka]

[0078] Step 1 4-Isopropyl-3,5-dimethoxybenzoic acid 1b Water (98 g, 9.44 mol) was carefully added to concentrated sulfuric acid (1.087 kg, 11.007 mol), and then compound 1a (250 g, 1.274 mol) was added while controlling the internal temperature below 40°C. Isopropanol (110 g, 1.835 mol) was added dropwise to the mixture, and the internal temperature was controlled at 40-45°C. After the addition was complete, the reaction mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature and slowly poured into ice water (1 kg) and stirred at 40°C for 1 h. The mixture was filtered, and the filter cake was washed with water. It was then dissolved in ethyl acetate (250 g) and heated to reflux for 1 h. The internal temperature was controlled at 65-70°C, and n-hexane (1 L) was added. The mixture was stirred for 0.5 h, then cooled to 0°C and stirred for 1 h. The mixture was filtered, and the filter cake was washed with n-hexane and dried at 40° C. overnight to give the title product 1b.

[0079] Step 2 (4-Isopropyl-3,5-dimethoxyphenyl)methanol 1c Compound 1b (150 g, 0.669 mol) was dissolved in tetrahydrofuran (1 L) and sodium borohydride (39.5 g, 1.037 mol) was added in portions under nitrogen gas protection while controlling the internal temperature below 25 °C. Iodine (76.4 g, 0.301 mol) was dissolved in tetrahydrofuran (340 mL) and slowly added dropwise to the mixture while controlling the internal temperature at 35 °C. After the addition was completed, the reaction mixture was stirred at 35 °C overnight. The reaction mixture was cooled to room temperature and poured into water (900 mL). The mixture was stirred at room temperature for 1 h and then filtered. The filtrate was concentrated to remove the organic solvent and added to a sodium bisulfite solution (9 g of sodium bisulfite dissolved in 900 mL of water). The mixture was stirred at room temperature for 0.5 h and then filtered. The filter cake was washed with water and dried at 40 °C overnight to obtain the title product 1c.

[0080] Step 3 (2-chloro-4-isopropyl-3,5-dimethoxyphenyl)methanol 1d Compound 1c (5 g, 23.8 mmol) was dissolved in tetrahydrofuran (50 mL). A solution of N-chlorosuccinimide (2.85 g, 21.3 mmol) in tetrahydrofuran (50 mL) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and saturated brine (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 1d.

[0081] Step 4 2-Chloro-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 1e Compound 1d (5.2 g, 21.3 mmol) was added in portions to a mixture of concentrated hydrochloric acid (60 mL) and n-hexane (50 mL) and the mixture was stirred at 55 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and filtered through diatomaceous earth. The organic phase was separated from the filtrate and washed with saturated brine (200 mL), saturated aqueous sodium bicarbonate (200 mL), and water (200 mL), respectively. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title product 1e.

[0082] Step 5 (2-chloro-4-isopropyl-3,5-dimethoxybenzyl)diethyl phosphate 1f Compound 1e (3.2 g, 12.2 mmol) was added to triethyl phosphite (30 mL), and the mixture was heated to 160° C. under nitrogen gas protection and stirred for 5 h. After cooling to room temperature, the mixture was concentrated to give the crude title product 1f.

[0083] Step 6 (E)-2-chloro-4-isopropyl-3,5-dimethoxy-1-styrylbenzene 1g Compound 1f (4.5 g, crude), benzaldehyde (1.2 g, 11.3 mol), and potassium tert-butoxide (1.6 g, 14.3 mol) were added to tetrahydrofuran (50 mL) and heated to 50 °C under nitrogen gas protection for 2 h with stirring. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound 1g.

[0084] Step 7 (E)-4-Chloro-2-isopropyl-5-styrylbenzene-1,3-diol 1 Compound 1g (1.3 g, 4.1 mmol) and pyridine hydrochloride (3 g) were mixed and heated to 180 °C under nitrogen gas protection and stirred for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 1. LCMS (ESI, m / z): 289.05 [M+H] + . 1 H NMR (400 MHz, CDCl3, ppm): δ 7.54-7.51 (m, 2H), 7.39-7.34 (m, 2H), 7.31-7.25 (m, 2H), 7.01-6.96 (m, 1H), 6.68 (s, 1H), 4.82 (s, 1H), 4.64 (s, 1H), 3.53-3.48 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H).

[0085] Example 2 (E)-2-Isopropyl-4-methyl-5-styrylbenzene-1,3-diol 2 [ka]

[0086] (E)-2-Isopropyl-4-methyl-5-styrylbenzene-1,3-diol 2 Compound 2a (3.80 kg) and pyridine hydrochloride (11.15 kg) were added to a 100 L glass reactor under nitrogen gas protection. The reaction mixture was heated to 165-175°C with stirring to dissolve the mixture, and the temperature was maintained for 5 h. After completion of the reaction, the reaction mixture was cooled to 80-90°C and poured into dilute hydrochloric acid (obtained by mixing 19.00 kg of water and 0.94 kg of concentrated hydrochloric acid) and stirred. Methyl tert-butyl ether (14.05 kg) was added, and the mixture was stirred for 15-20 min and allowed to stand for phase separation. The organic phase was separated and concentrated under reduced pressure. Methyl tert-butyl ether (2.80 kg) was added to the concentrated residue, which was then stirred to clarify. n-Heptane (10.40 kg) was added dropwise, the mixture was placed in an ice-water bath, stirred for 1 h, and filtered. The filtrate was concentrated to obtain a dark brown oil. The above oil was purified by silica gel column chromatography and by preparative HPLC to give the title product 2. LCMS (ESI, m / z): 267.14 [MH] - . 1 H NMR (400 MHz, CDCl3, ppm): δ7.38 (d, J = 7.4 Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.17-7.15 (m, 2H), 6.75 (d, J = 16 Hz, 1H), 6.49 (s, 1H), 4.74 (s, 1H), 4.68 (s, 1H), 3.43-3.34 (m, 1H), 2.13 (s, 3H), 1.30 (d, J = 7.2 Hz, 6H).

[0087] Example 3 (E)-4-Fluoro-2-isopropyl-5-styrylbenzene-1,3-diol 3 [ka]

[0088] Step 1 (2-Fluoro-4-isopropyl-3,5-dimethoxyphenyl)methanol 3a Compound 1c (25 g, 118.90 mmol) was dissolved in acetonitrile (250 mL) and placed in an ice-water bath. Under nitrogen gas protection, 1-chloromethyl-4-fluoro-1,4-diazobicyclo-2.2.2octane bis(tetrafluoroborate) salt (42.12 g, 118.90 mmol) was added in several portions. The reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into ethyl acetate (300 mL) and washed with water (300 mL) and saturated brine (300 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 3a.

[0089] Step 2 2-Fluoro-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 3b The title product 3b was prepared from the intermediate 3a according to the synthesis method of Step 4 in Example 1.

[0090] Step 3 (2-Fluoro-4-isopropyl-3,5-dimethoxybenzyl)diethyl phosphate 3c The title product 3c was prepared from the intermediate 3b according to the synthesis method of Step 5 in Example 1.

[0091] Step 4 (E)-2-Fluoro-4-isopropyl-3,5-dimethoxy-1-styrylbenzene 3d Following the synthesis method of Step 6 in Example 1, the title product 3d was prepared from intermediate 3c and benzaldehyde.

[0092] Step 5 (E)-4-Fluoro-2-isopropyl-5-styrylbenzene-1,3-diol 3 The title product 3 was prepared from intermediate 3d according to the synthesis method of Step 7 in Example 1. LCMS (ESI, m / z): 273.1 [M+H] + . 1 H NMR (400 MHz, CDCl3, ppm): δ7.52-7.49 (m, 2H), 7.38-7.34 (m, 2H), 7.29-7.25 (m, 1H), 7.16-7.03 (m, 2H), 6.49 (d, J = 6.4 Hz, 1H), 5.22 (d, J = 7.2Hz, 1H), 4.64 (s, 1H), 3.50-3.42 (m, 1H), 1.37 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, CDCl3, ppm): δ -154.66 (1F).

[0093] Example 4 (E)-4-Bromo-2-isopropyl-5-styrylbenzene-1,3-diol 4 [ka]

[0094] Step 1 (2-Bromo-4-isopropyl-3,5-dimethoxyphenyl)methanol 4a Compound 1c (10 g, 47.6 mmol) was dissolved in tetrahydrofuran (100 mL) and a solution of N-bromosuccinimide (7.62 g, 42.8 mmol) in tetrahydrofuran (30 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and saturated brine (50 mL), respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4a.

[0095] Step 2 2-Bromo-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 4b The title product 4b was prepared from the intermediate 4a according to the synthesis method of Step 4 in Example 1.

[0096] Step 3 (2-Bromo-4-isopropyl-3,5-dimethoxybenzyl)diethyl phosphate 4c The title product 4c was prepared from the intermediate 4b according to the synthesis method of Step 5 in Example 1.

[0097] Step 4 (E)-2-Bromo-4-isopropyl-3,5-dimethoxy-1-styrylbenzene 4d Following the synthesis method of Step 6 in Example 1, the title product 4d was prepared from intermediate 4c and benzaldehyde.

[0098] Step 5 (E)-4-Bromo-2-isopropyl-5-styrylbenzene-1,3-diol 4 The title product 4 was prepared from the intermediate 4d according to the synthesis method of Step 7 in Example 1. LCMS (ESI, m / z): 333.08 [M+H] + . 1 H NMR (400 MHz, CDCl3, ppm): δ 7.54-7.51 (m, 2H), 7.39-7.34 (m, 2H), 7.32-7.25 (m, 2H), 6.97-6.92 (m, 1H), 6.69 (s, 1H), 5.80 (s, 1H), 4.85 (s, 1H), 3.57-3.49 (m, 1H), 1.36 (d, J = 7.2 Hz, 6H).

[0099] Example 5 (E)-4-Fluoro-5-(4-fluorostyryl)-2-isopropylbenzene-1,3-diol 5 [ka]

[0100] Step 1 (E)-2-Fluoro-1-(4-fluorostyryl)-4-isopropyl-3,5-dimethoxybenzene 5a Following the synthesis method of Step 6 in Example 1, the title product 5a was prepared from intermediate 3c and 4-fluorobenzaldehyde.

[0101] Step 2 (E)-4-Fluoro-5-(4-fluorostyryl)-2-isopropylbenzene-1,3-diol 5 The title product 5 was prepared from the intermediate 5a according to the synthesis method of Step 7 in Example 1. LCMS (ESI, m / z): 291.74 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.09 (d, J = 2.8 Hz, 1H), 9.05 (s, 1H), 7.67-7.62 (m, 2H), 7.22-7.17 (m, 2H), 7.14-6.99 (m, 2H), 6.51 (d, J = 6.0 Hz, 1H), 3.49-3.41 (m, 1H), 1.27 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ-114.09 (1F), -150.87 (1F).

[0102] Example 6 (E)-4-Fluoro-5-(2-fluorostyryl)-2-isopropylbenzene-1,3-diol 6 [ka]

[0103] Step 1 (E)-2-Fluoro-1-(2-fluorostyryl)-4-isopropyl-3,5-dimethoxybenzene 6a Following the synthesis method of Step 6 in Example 1, the title product 6a was prepared from intermediate 3c and 2-fluorobenzaldehyde.

[0104] Step 2 (E)-4-Fluoro-5-(2-fluorostyryl)-2-isopropylbenzene-1,3-diol 6 The title product 6 was prepared from the intermediate 6a according to the synthesis method of Step 7 in Example 1. LCMS (ESI, m / z): 291.26 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.15 (d, J = 2.4 Hz, 1H), 9.09 (s, 1H), 7.83-7.78 (m, 1H), 7.37-7.31 (m, 1H), 7.28-7.21 (m, 3H), 7.14-7.09 (m, 1H), 6.54 (d, J = 6.0 Hz, 1H), 3.49-3.41 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H); 19 F NMR (400 MHz, DMSO-d6, ppm): δ -118.95 (1F), -150.76 (1F).

[0105] Example 7 (E)-4-Fluoro-5-[2-(3-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 7 [ka]

[0106] Step 1 (E)-3-Fluoro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 7a Following the synthesis method of Step 6 in Example 1, the title product 7a was prepared from intermediate 3c and 3-fluoro-2-pyridineformaldehyde.

[0107] Step 2 (E)-4-Fluoro-5-[2-(3-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 7 Compound 7a (100 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL) and, under nitrogen gas protection, boron tribromide (1.3 mL, 1.3 mmol, 1 M dichloromethane solution) was added dropwise at 0 °C. The reaction was stirred at room temperature for 0.5 h. The mixture was quenched with saturated sodium bicarbonate solution (50 mL) and diluted with dichloromethane (50 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 7. LCMS (ESI, m / z): 292.42 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.23 (s, 1H), 9.15 (s, 1H), 8.48-8.45 (m, 1H), 7.79-7.71 (m, 2H), 7.41-7.36 (m, 1H), 7.26-7.19 (m, 1H), 6.60 (d, J = 5.2 Hz, 1H), 3.49-3.42 (m, 1H), 1.26 (d, J = 6.4 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -127.60 (1F), -150.31 (1F).

[0108] Example 8 (E)-5-[2-(3-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylbenzene-1,3-diol 8 [ka]

[0109] Step 1 (E)-3-Chloro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 8a Following the synthesis method of Step 6 in Example 1, the title product 8a was prepared from intermediate 3c and 3-chloro-2-pyridineformaldehyde.

[0110] Step 2 (E)-5-[2-(3-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylbenzene-1,3-diol 8 The title product 8 was prepared from the intermediate 8a according to the synthesis method of Step 2 in Example 7. LCMS (ESI, m / z): 308.28 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.25 (d, J = 2.4 Hz, 1H), 9.18 (s, 1H), 8.56 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 7.94 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.48-7.43 (m, 1H), 7.33 (dd, J = 8.0 Hz, 4.4 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 3.50-3.42 (m, 1H), 1.26 (d, J = 7.2Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -149.99 (1F).

[0111] Example 9 (E)-4-Fluoro-5-[2-(5-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 9 [ka]

[0112] Step 1 (E)-5-Fluoro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 9a Following the synthesis method of Step 6 in Example 1, the title product 9a was prepared from intermediate 3c and 5-fluoro-2-pyridineformaldehyde.

[0113] Step 2 (E)-4-Fluoro-5-[2-(5-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 9 The title product 9 was prepared from the intermediate 9a according to the synthesis method of Step 2 in Example 7. LCMS (ESI, m / z): 292.34 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.17 (d, J = 2.4 Hz, 1H), 9.12 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 7.75-7.64 (m, 2H), 7.58-7.53 (m, 1H), 7.11-7.06 (m, 1H), 6.54 (d, J = 6.0 Hz, 1H), 3.49-3.41 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -128.86 (1F), -150.44 (1F).

[0114] Example 10 (E)-5-[2-(5-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylbenzene-1,3-diol 10 [ka]

[0115] Step 1 (E)-5-Chloro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 10a Following the synthesis method of Step 6 in Example 1, the title product 10a was prepared from intermediate 3c and 5-chloro-2-pyridineformaldehyde.

[0116] Step 2 (E)-5-[2-(5-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylbenzene-1,3-diol 10 The title product 10 was prepared from the intermediate 10a according to the synthesis method of Step 2 in Example 7. LCMS (ESI, m / z): 308.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.19 (d, J = 2.0 Hz, 1H), 9.14 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.66-7.60 (m, 2H), 7.10-7.06 (m, 1H), 6.56 (d, J = 5.6 Hz, 1H), 3.79-3.39 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -150.19 (1F).

[0117] Example 11 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridazin-3-yl)vinyl]benzene-1,3-diol 11 [ka]

[0118] Step 1 2-Fluoro-4-isopropyl-3,5-dimethoxybenzeneformaldehyde 11a Compound 3a (15 g, 65.71 mmol) was dissolved in dichloromethane (300 mL) and Dess-Martin reagent (30.66 g, 72.29 mmol) was added. The mixture was stirred at 20-25 °C for 16 h. Saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture. The organic phase was separated and washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 11a.

[0119] Step 2 (E)-3-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridazine 11b Compound 11a (240.3 mg, 1.0 mmol) and 3-methylpyridazine (100 mg, 1.0 mmol) were dissolved in 2-methyl-2-butanol (1.5 mL), and potassium hydroxide (59.6 mg, 1.0 mmol) was added. The mixture was heated to 120 °C and stirred for 0.5 h. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution (100 mL) and water (100 mL) were added to the mixture, followed by extraction with ethyl acetate (100 mL). The organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 11b.

[0120] Step 3 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridazin-3-yl)vinyl]benzene-1,3-diol 11 The title product 11 was prepared from intermediate 11b according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 275.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm): δ9.29-9.26 (m, 1H), 9.24-9.21 (m, 1H), 9.11-9.08 (m, 1H), 8.03 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.73 (d, J = 16.4 Hz, 1H), 7.68 (dd, J = 8.4 Hz, 4.8 Hz, 1H), 7.23 (d, J = 16.4 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 3.51-3.42 (m, 1H), 1.26 (d, J = 7.2Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -149.71 (1F).

[0121] Example 12 (E)-4-Fluoro-2-isopropyl-5-[2-(thiophen-2-yl)vinyl]benzene-1,3-diol 12 [ka]

[0122] Step 1 (E)-2-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)thiophene 12a Following the synthesis method of Step 6 in Example 1, the title product 12a was prepared from the intermediate 11a and diethyl (thiophen-2-ylmethyl)phosphate.

[0123] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(thiophen-2-yl)vinyl]benzene-1,3-diol 12 The title product 12 was prepared from the intermediate 12a according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 279.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm): δ9.14 (s, 1H), 9.11-9.05 (m, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.19 (d, J = 16.4 Hz, 1H), 7.07 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 6.83 (d, J = 16.4 Hz, 1H), 6.46 (d, J = 6.0 Hz, 1H), 3.47-3.40 (m, 1H), 1.24 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -151.18 (1F).

[0124] Example 13 (E)-4-Fluoro-2-isopropyl-5-[2-(6-methylpyridin-2-yl)vinyl]benzene-1,3-diol 13 [ka]

[0125] Step 1 (E)-2-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)-6-methylpyridine 13a Following the synthesis method of Step 6 in Example 1, the title product 13a was prepared from the intermediate 11a and [(6-methylpyridin-2-yl)methyl]triphenylphosphonium bromide.

[0126] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(6-methylpyridin-2-yl)vinyl]benzene-1,3-diol 13 The title product 13 was prepared from intermediate 13a according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 288.1 [M+H] + . 1H NMR (400 MHz, CDCl3, ppm): δ7.64-7.53 (m, 2H), 7.27-7.25 (m, 1H), 7.16 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 6.4 Hz, 1H), 3.52-3.45 (m, 1H), 2.60 (s, 3H), 1.38 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, CDCl3, ppm): δ -153.59 (1F).

[0127] Example 14 (E)-4-Fluoro-5-[2-(6-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 14 [ka]

[0128] Step 1 2-Fluoro-4-isopropyl-3,5-dimethoxy-1-vinylbenzene 14a Methyltriphenylphosphonium bromide (4.7 g, 13.2 mmol) was dissolved in dioxane (30 mL), and potassium carbonate (3.6 g, 26.5 mmol) and 11a (3 g, 13.2 mmol) were added. The mixture was heated to 110 °C and stirred for 6 h. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 14a.

[0129] Step 2 (E)-2-Fluoro-6-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 14b Compound 14a (1.00 g, 4.46 mmol) and 2-bromo-6-fluoropyridine (1.18 g, 6.69 mmol) were dissolved in dioxane (10 mL), purged with nitrogen gas three times, and then triethylamine (1.35 g, 13.3 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (326 mg, 445 μmol) were added. The mixture was heated to 95 °C and stirred for 16 h. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 14b.

[0130] Step 3 (E)-4-Fluoro-5-[2-(6-fluoropyridin-2-yl)vinyl]-2-isopropylbenzene-1,3-diol 14 The title product 14 was prepared from intermediate 14b according to the synthesis method in Step 2 of Example 7.

[0131] LCMS (ESI, m / z): 292.1 [M+H] + .

[0132] 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.23 (d, J = 2.4 Hz, 1H), 9.17 (s, 1H), 8.01-7.94 (m, 1H), 7.59 (d, J = 16.0 Hz, 1H), 7.50-7.46 (m, 1H), 7.10-7.00 (m, 2H), 6.55 (d, J = 6.0 Hz, 1H), 3.49-3.42 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -66.80 (1F), -150.07 (1F).

[0133] Example 15 (E)-4-Fluoro-2-isopropyl-5-[2-(quinolin-2-yl)vinyl]benzene-1,3-diol 15 [ka]

[0134] Step 1 (E)-2-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)quinoline 15a Compound 2-methylquinoline (300 mg, 2.10 mmol) and 11a (474 ​​mg, 2.10 mmol) were dissolved in acetic anhydride (5 mL), heated to 130 °C, and stirred for 12 h. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title product 15a.

[0135] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(quinolin-2-yl)vinyl]benzene-1,3-diol 15 The title product 15 was prepared from the intermediate 15a according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 324.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.27 (d, J = 1.6 Hz, 1H), 9.23 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.00-7.94 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.80-7.73 (m, 2H), 7.58-7.54 (m, 1H), 7.25 (d, J = 16.4 Hz, 1H), 6.63 (d, J = 6.0 Hz, 1H), 3.48-3.45 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H).19 F NMR (400 MHz, DMSO-d6, ppm): δ -149.88 (1F).

[0136] Example 16 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-2-yl)vinyl]benzene-1,3-diol 16 [ka]

[0137] Step 1 (E)-2-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 16a Following the synthesis method of Step 6 in Example 1, the title product 16a was prepared from the intermediate 11a and [(pyridin-2-yl)methyl]triphenylphosphonium bromide.

[0138] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-2-yl)vinyl]benzene-1,3-diol 16 The title product 16 was prepared from intermediate 16a according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 274.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.20 (s, 1H), 9.15 (s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 7.86-7.78 (m, 1H), 7.66 (d, J = 16.0 Hz, 1H), 7.62-7.59 (m, 1H), 7.33-7.26 (m, 1H), 7.08 (d, J = 16.0 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 3.49-3.43 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H). 19F NMR (400 MHz, DMSO-d6, ppm): δ -150.29 (1F).

[0139] Example 17 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-3-yl)vinyl]-benzene-1,3-diol 17 [ka]

[0140] Step 1 (E)-3-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 17a The title product 17a was prepared from 3-bromopyridine and intermediate 14a according to the synthesis method in Step 2 of Example 14.

[0141] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-3-yl)vinyl]-benzene-1,3-diol 17 The title product 17 was prepared from intermediate 17a according to the synthesis method in Step 2 of Example 7. LCMS (ESI, m / z): 274.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.36-9.05 (m, 2H), 9.00-8.90 (m, 1H), 8.62-8.58 (m, 1H), 8.51-8.38 (m, 1H), 7.75-7.62 (m, 1H), 7.41 (d, J = 16.4 Hz, 1H), 7.11 (d, J = 16.4 Hz, 1H), 6.54 (d, J = 6.0 Hz, 1H), 3.50-3.42 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ-149.83 (1F).

[0142] Example 18 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-4-yl)vinyl]benzene-1,3-diol 18 [ka]

[0143] Step 1 (E)-4-(2-Fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 18a The title product 18a was prepared from 4-methylpyridine and intermediate 11a according to the synthesis method of Step 1 in Example 15.

[0144] Step 2 (E)-4-Fluoro-2-isopropyl-5-[2-(pyridin-4-yl)vinyl]benzene-1,3-diol 18 The title product 18 was prepared from intermediate 18a according to the synthesis method of Step 2 in Example 7. LCMS (ESI, m / z): 274.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm): δ9.24 (d, J = 2.4 Hz, 1H), 9.19 (s, 1H), 8.56 (d, J = 5.6 Hz, 2H), 7.65-7.61 (m, 2H), 7.47 (d, J = 16.4 Hz, 1H), 7.02 (d, J = 16.4 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 3.49-3.43 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6, ppm): δ -149.61 (1F).

[0145] Measurement example 1: Luciferase reporter gene measurement experiment In this measurement example, a luciferase reporter gene measurement experiment was carried out to measure the agonistic activity of the compound according to the present disclosure against the AHR protein.

[0146] Test cells: Human liver cancer cells HepG2-Lucia expressing AHR and luciferase were purchased from InvivoGen, product number hpgl-ahr.

[0147] Main equipment: Biological safety cabinet, model number 307, ThermoFisher, CO2 incubator, model number CLM-240B-8-CN, ESCO Cell counter, model number EVE-MC2, NanoEnTeK, ECHO (nanoliter level ultrasonic dispensing system), model number 655, LabCyte, Inc. Microplate centrifuge, model number PlatePro 3200, Monad, Multifunctional microplate reader, model number PHERAstar FSX, BMG LRBTECH.

[0148] Key Reagents: Mycilin, Gibco, product number 15140-122; EMEM medium, ATCC, product number 30-2003; Fetal bovine serum, Ausgenex, product number FBS500-S, NEAA medium, Gibco, product number 11140-050; Phosphate buffer solution, Gibco, product number 14190250; DMSO (dimethyl sulfoxide), Solarbio, product number D8371; FICZ (6-formylindolo[3,2-b]carbazole), MCE, product number HY-12451; Zeocin (bleomycin), InvivoGen, product number ant-zn-1; QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0149] Experimental Procedure: 1. HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1x NEAA, mycilin, and 100 μg / mL Zeocin (bleomycin) at 37°C and 5% carbon dioxide. 2. Cells were grown to approximately 80% confluence, digested, centrifuged, resuspended, and counted. Cells were seeded into 384-well plates, 40 μL per well. 3. Add different concentrations of compounds to be tested by ECHO, 40 nL per well. 4. The 384-well plate to which the compound was added was cultured in an incubator for 24 hours. 5. The supernatant was collected, QUANTI-Luc Gold assay reagent was added, and the luminescence signal value was read using a multi-function microplate reader.

[0150] Test results: Activity EC of compounds of the present disclosure and benvitimod against AHR protein 50 The data is summarized in Table 1 below. [Table 1]

[0151] As is clear from the above results, the compounds according to the examples of the present disclosure have relatively good activation activity against the AHR protein, and the activity of at least compounds 5 to 9 and 14 is significantly superior to that of benvitimod.

[0152] Experimental Example 2: Photostability experiment In this measurement example, the stability of the compounds according to the examples of the present disclosure, benvitimod, and the compound according to Comparative Example 1 under light irradiation conditions was compared.

[0153] Main equipment: Stability chamber, model number ICH-110L, Memmert, High-performance liquid chromatograph (HPLC), model number 1260, Agilent.

[0154] Analysis method: Detection wavelength: 220 nM, 254 nM Column: Agilent ZORBAX SB-C8 4.6 x 250 mm, 5 μm Mobile phase A: water Mobile phase B: acetonitrile Flow rate: 1.0 mL / min Column temperature: 35℃ Sample injection volume: 10 μL

[0155] Experimental Procedure: 1. Weigh the compound to be tested into the stability chamber. 2. Turn on the light source and set the visible light to 5000±500 lx and the ultraviolet light to 250 μW / cm 2 and 3. Samples were taken at 0 h, 8 h, 24 h and 72 h, and dissolved in a 50% volumetric acetonitrile aqueous solution. 4. HPLC was used to measure the content, and the area normalization method was used.

[0156] Test results: The stability data of different batches of the compounds of the present disclosure and benvitimod under light irradiation conditions are summarized below. [Table 2] [Table 3]

[0157] Among them, the compound of Comparative Example 1 is a compound synthesized by the inventors themselves.

[0158] As is clear from the above results, the compounds according to the examples of the present disclosure are more stable under light irradiation conditions, and the compound content and / or the degree of change in content of the compounds according to the examples of the present disclosure are significantly superior to those of benvitimod and / or the compound of Comparative Example 1 at 8, 24, and 72 hours, indicating that the photostability of the compounds according to the present disclosure is significantly improved.

Claims

1. A compound of formula I-1, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, 【Chemical 1】 wherein Ar is unsubstituted or optionally substituted with one, two or more Rs; 6-20 selected from an aryl group or a 5- to 20-membered heteroaryl group; Each Rs may be the same or different and independently represent a halogen, a cyano group, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 selected from alkoxy groups, Each R 1 are the same or different and independently represent a halogen, a cyano group, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 alkoxy groups, and n is 1 or 2; A compound of formula I-1, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof.

2. Each R 1 are the same or different and independently represent a halogen, a cyano group, C 2-6 Straight chain alkyl group, halo C 1-6 Alkyl group, -COC 2-6 Alkyl group or C 1-6 alkoxy groups, A compound of formula I-1 according to claim 1, its stereoisomer, pharmaceutically acceptable salt or prodrug.

3. A compound of formula I below, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, 【Chemistry 2】 Among them, Ar is unsubstituted or optionally substituted with one, two or more Rs. 6-20 selected from an aryl group or a 5- to 20-membered heteroaryl group; Each Rs may be the same or different and independently represent a halogen, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 1-12 selected from alkoxy groups, R 1 is as defined in claim 1, A compound of formula I-1 according to claim 1 or 2, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

4. Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs or a 5- to 6-membered heteroaryl group, wherein Rs is as defined in claim 1, preferably Ar is selected from a phenyl group unsubstituted or optionally substituted with one, two or more Rs, a pyridin-2-yl, a pyridin-3-yl, a pyridin-4-yl, a thienyl group, a quinolinyl group, an isoquinolinyl group, a pyridazinyl group, a pyrazinyl group or a pyrimidinyl group, wherein Rs is as defined in claim 1, A compound of formula I-1 according to any one of claims 1 to 3, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

5. Each R 1 are identical or different and independently represent F, Cl, Br, a methyl group or a cyano group; A compound of formula I-1 according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

6. Ar is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3, pyridin-4-yl, 2-thienyl, 2-pyridazinyl, and 2-quinolinyl, unsubstituted or optionally substituted with one, two, or more Rs, and Rs is as defined in claim 1; R 1 is F, Cl, Br, cyano group, C 1-3 Alkyl group, halo C 1-3 Alkyl group, -COC 1-3 Alkyl group or C 1-3 alkoxy groups, preferably F, Cl, Br, cyano groups, C 1-3 Alkyl or halo C 1-3 alkyl group, A compound of formula I-1 according to any one of claims 1 to 5, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

7. Ar is a 4-fluorophenyl group, a 2-fluorophenyl group, a 2-pyridazinyl group, a 2-thienyl group, a 2-quinolinyl group, a 2-pyridinyl group, a 3-pyridinyl group, a 4-pyridinyl group, 【Chemistry 3】 Selected from R 1 is F, Cl, Br, methyl group, methoxy group, cyano group, acetyl group, 【Chemistry 4】 Preferably selected from F, Cl, Br, a cyano group, 【Chemistry 5】 characterized in that A compound of formula I-1 according to any one of claims 1 to 6, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

8. Each Rs may be the same or different and independently represent a halogen, C 1-6 Alkyl group or C 1-6 alkoxy groups, A compound of formula I-1 according to any one of claims 1 to 7, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

9. The compound of formula I-1 is 【Chemistry 6】 The compound is selected from the group consisting of: A compound of formula I-1 according to any one of claims 1 to 8, a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof.

10. A compound represented by general formula I-1d or a salt thereof, 【Chemistry 7】 Among them, R is selected from alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogen, oxo group, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, nitro group, cyano group, amino group, alkylamino group, hydroxy group, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; preferably, R is C 1-6 is an alkyl group, Each R 1 are the same or different and independently represent a halogen, a cyano group, C 1-12 Alkyl group, halo C 1-12 Alkyl group, -COC 1-12 Alkyl group or C 2-12 alkoxy groups, preferably F, Cl, Br, cyano groups, C 1-3 Alkyl or halo C 1-3 is an alkyl group, Ar and n are as defined in claim 1. A compound represented by general formula I-1d or a salt thereof.

11. [Chemical 8] is selected from the compounds A compound represented by the general formula I-1d according to claim 10 or a salt thereof.

12. A method for preparing a compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, comprising the steps of: 1) R 1 is a halogen, the compound of formula I is 【Chemistry 9】 S5) A compound represented by formula Id or a salt thereof is reacted with pyridine hydrochloride by heating to obtain a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a compound represented by formula Id or a salt thereof is reacted with boron tribromide to remove the methyl group, followed by quenching the reaction with water to obtain a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 2) R 1 is a methyl group, the compound of formula I is 【Chemistry 10】 S5') compound Id' is reacted with pyridine hydrochloride by heating to obtain the compound of formula I; Ar is as defined in claim 1, Manufacturing method.

13. A therapeutically effective amount of at least one of the compounds of formula I-1 according to any one of claims 1 to 9, its stereoisomers, pharmaceutically acceptable salts or prodrugs. Pharmaceutical compositions.

14. The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition of claim 13.

15. The pharmaceutical composition is an aromatic hydrocarbon receptor (AHR) modulator.

15. The pharmaceutical composition according to claim 13 or 14.

16. Use of at least one of the compounds of formula I-1 as defined in any one of claims 1 to 9, or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition as defined in any one of claims 13 to 15 in the manufacture of an aryl hydrocarbon receptor (AHR) modulator, wherein the aryl hydrocarbon receptor (AHR) modulator is for alleviating and / or treating the following diseases or conditions: cancer, ophthalmologically related diseases, autoimmune diseases, and other diseases or disorders having an immunological factor. wherein the cancer is preferably leukemia, prostate cancer, or intestinal cancer; the ophthalmological disease is preferably uveitis, age-related macular degeneration, or dry eye; the autoimmune disease is preferably rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, or psoriasis; and the other diseases or disorders having immunological factors are preferably asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, or transplant rejection. use.

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