Stilbene derivatives, processes for their preparation and uses thereof

Abstract

The present disclosure provides a stilbene derivative, a preparation method and use thereof, in particular, the present disclosure provides a compound represented by formula (I-1), a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as an aromatic hydrocarbon receptor (AHR) modulator. The compound represented by formula I-1 greatly improves the light stability of the molecular structure compared with the marketed drug benvepick, improves the light instability of benvepick, and is easily degraded under light. In addition, the activity on AHR protein is also significantly improved. Finally, the preparation method of the compound represented by formula I-1 is simple, and can be prepared in kilograms or kilograms, which has a better prospect in subsequent preparation development, safety and clinical application.

Description

[0001] This application claims priority to two earlier applications: Patent Application No. 202211170147.6, filed with the China National Intellectual Property Administration on September 22, 2022, entitled "Stilbene Derivatives and Their Preparation Methods and Uses"; and Patent Application No. 202310654162.6, filed with the China National Intellectual Property Administration on June 2, 2023, also entitled "Stilbene Derivatives and Their Preparation Methods and Uses". The full text of both applications is incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the field of inflammation or immune-related pharmaceutical technology, specifically relating to a novel stilbene derivative, its preparation method, pharmaceutical compositions containing the derivative, and their use as therapeutic agents, particularly as aryl hydrocarbon receptor (AHR) modulators. Background Technology

[0003] 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 characteristic of the bHLH-PAS family members is the presence of a PAS domain, named after the three proteins first discovered to possess this motif: Drosophila Per, Human ARNT, and Drosophila Sim. The PAS domain consists of 260-310 amino acids and includes two highly conserved hydrophobic repeat sequences, PAS-A and PAS-B, separated by a less conserved sequence. 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 AHRs, ligand binding occurs within the PAS-B domain. The N-terminal bHLH-PAS region is relatively well conserved among bHLH-PAS family members. Most of the non-conserved changes in AHR occur in the transcriptional activation domain, leading to different protein-protein interactions with other coactivators, co-repressors, or nuclear receptors, regulating different gene expression.

[0004] In the absence of ligands, AHR exists in the cytosol and binds to various chaperone proteins, including a dimer of heat shock protein 90 (HSP90), the helper chaperone p23, the AHR-interacting protein (AIP), and the protein kinase Src. Upon ligand binding, AHR changes its conformation, translocates to the nucleus, separates from the chaperone complex, and then forms a heterodimer with the AHR nuclear translocator (ARNT). The regulatory region upstream of AHR-regulated genes contains a shared DNA sequence (5′-TNGCGTG-3′) called the Xenobiotic Responsive Element (XRE), also known as the Dioxin Responsive Element (DRE). This XRE acts as a transcriptional enhancer and is a binding site for AHR. The AHR-ARNT heterodimer complex is recruited by the XRE to initiate the transcription of the target gene.

[0005] Studies have shown 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] Because the ligand binding sites of AHRs are structurally flexible, many small molecules can serve as ligands, including exogenous ligands such as polycyclic aromatic hydrocarbons (PAHs), dioxins, and polychlorinated biphenyls (PCBs); endogenous ligands such as tryptophan degradation metabolites, food-derived ligands, and products of bacterial and microbial metabolic pathways. For example, the AHR modulator benvitimod is a naturally derived small molecule produced by the bacterial symbiont of entomopathogenic nematodes. It was the world's first marketed aryl hydrocarbon receptor agonist and can be used to treat various autoimmune diseases, such as psoriasis and eczema. However, benvitimod's structural characteristics, such as photostability, make it easily degraded under light, limiting its application. Therefore, developing more photostable AHR modulators is of great significance for expanding its clinical applications and reducing potential side effects. Summary of the Invention

[0007] To address the aforementioned problems of the prior art, this disclosure provides a compound represented by Formula I-1, its stereoisomers, pharmaceutically acceptable salts, or prodrugs:

[0008]

[0009] Wherein, Ar is selected from unsubstituted groups, or optionally substituted by one, two or more Rs, of the following groups: C6-20 Aryl or 5 to 20 heteroaryl groups;

[0010] Each Rs may be the same or different, and is independently selected from halogen, cyano, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 1-12 Alkoxy;

[0011] Each R1 may be the same or different, and is independently selected from halogen, cyano, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 1-12 alkoxy groups; and

[0012] n is 1 or 2.

[0013] In some embodiments of this disclosure, the compound represented by Formula I-1, its stereoisomers, pharmaceutically acceptable salts, or prodrugs, wherein each R1 is the same or different and is independently selected from halogens, cyano groups, C... 2-6 Straight-chain alkyl, halogenated C 1-6 Alkyl, -COC2-6 alkyl or C 1-6 Alkyl group.

[0014] In some embodiments of this disclosure, the compound represented by Formula I-1, its stereoisomers, pharmaceutically acceptable salts, or prodrugs are compounds represented by Formula I, their stereoisomers, pharmaceutically acceptable salts, or prodrugs:

[0015]

[0016] in:

[0017] Ar is selected from unsubstituted groups, or optionally substituted by one, two or more Rs, of the following groups: C 6-20 Aryl or 5 to 20 heteroaryl groups;

[0018] Each Rs may be the same or different, and is independently selected from halogens, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 1-12 Alkoxy;

[0019] R1 is defined as in equation I-1.

[0020] Furthermore, this disclosure provides compounds represented by Formula I, their stereoisomers, pharmaceutically acceptable salts, or prodrugs:

[0021]

[0022] Wherein, Ar is selected from unsubstituted groups, or optionally substituted by one, two or more Rs, of the following groups: C 6-20 Aryl or 5-20 heteroaryl groups;

[0023] Each Rs may be the same or different, and is independently selected from halogens, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 1-12 Alkoxy;

[0024] R1 is selected from halogen, cyano, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 1-12 Alkyl group.

[0025] In some embodiments of this disclosure, the compound of formula I-1 or formula I, its stereoisomers, pharmaceutically acceptable salts, or prodrugs, wherein Ar is selected from unsubstituted or optionally substituted with one, two, or more Rs: 6- to 10-membered aryl or 5- to 10-membered heteroaryl; Rs as defined in formula I-1 or formula I; preferably, Ar is selected from unsubstituted or optionally substituted with one, two, or more Rs: phenyl or 5- to 10-membered heteroaryl; Rs as defined in formula I-1 Or as defined in Formula I; more preferably, Ar is selected from unsubstituted or optionally substituted with one, two or more Rs, of the following groups: phenyl or 5 to 6-membered heteroaryl; Rs as defined in Formula I-1 or Formula I; most preferably, Ar is selected from unsubstituted or optionally substituted with one, two or more Rs, of the following groups: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophene, quinolinyl, isoquinolinyl, pyridazinyl, pyrazinyl or pyrimidinyl; Rs as defined in Formula I-1 or Formula I.

[0026] In some embodiments of this disclosure, the compound of formula I-1 or formula I, its stereoisomers, pharmaceutically acceptable salts or prodrugs, wherein each R1 is the same or different and is independently F, Cl, Br, methyl or cyano.

[0027] In some embodiments of this disclosure, the compounds of Formula I-1 or Formula I, their stereoisomers, pharmaceutically acceptable salts, or prodrugs, wherein each Rs is the same or different and is independently selected from halogens, cyano groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, -COC 1-6 Alkyl or C 1-6 Alkyl groups; preferably, each Rs may be the same or different, and is independently selected from halogens, cyano groups, C... 1-6 Alkyl or C1-6 Alkyl groups; more preferably, each Rs may be the same or different, and is independently selected from halogens, C 1-6 Alkyl or C 1-6 Alkoxy groups; most preferably, each Rs is the same or different and is a halogen independently of each other.

[0028] In some embodiments of this disclosure, the compound of Formula I or the compound represented by Formula I, its stereoisomers, pharmaceutically acceptable salts or prodrugs, wherein each Rs is the same or different and is independently selected from halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, -COC 1-6 Alkyl or C 1-6 Alkoxy groups; preferably, each Rs may be the same or different, and is independently selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl groups; more preferably, each Rs may be the same or different, and is independently selected from halogens, C 1-6 Alkyl or C 1-6 Alkyl groups; most preferably, each Rs is the same or different and is a halogen independently of each other; for example, Rs is F, Cl, methyl or methoxy.

[0029] In some embodiments of this disclosure, the compound of formula I-1 or formula I, its stereoisomers, pharmaceutically acceptable salts or prodrugs, wherein Ar is selected from unsubstituted or optionally substituted C groups with one, two or more of the following groups: 6-14 Aryl or 5 to 14-membered heteroaryl: halogen, C 1-3 Alkyl or C 1-3 Alkyl group; R1 is selected from F, Cl, Br, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, -COC 1-3 Alkyl or C 1-3 Alkoxy groups, preferably F, Cl, Br, cyano, or C. 1-3 Alkyl or halogenated C 1-3 alkyl.

[0030] In some embodiments of this disclosure, the compound represented by Formula I-1 or Formula I, its stereoisomers, pharmaceutically acceptable salts, or prodrugs, wherein Ar is selected from unsubstituted or optionally substituted with one, two, or more Rs, of the following groups: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-thienyl, 2-pyridazinyl, 2-quinolinyl, and Rs as defined in Formula I-1 or Formula I; preferably, Ar is selected from unsubstituted or optionally substituted with one, two, or more Rs. The following substituent groups are used: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-thienyl, 2-pyridazinyl, 2-quinolinyl; Rs is a halogen; for example, Ar is selected from phenyl, pyridinyl, thienyl, pyridazinyl, or quinolinyl groups substituted with one, two, or more substituents selected from fluorine, chlorine, bromine, methyl, or methoxy, examples of which may be selected from 4-fluorophenyl, 2-fluorophenyl, 2-pyridazinyl, 2-thienyl, 2-quinolinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,

[0031] R1 is selected from F, Cl, Br, methyl, methoxy, cyano, acetyl.

[0032] In one embodiment, R1 substitutes for one of the hydroxyl groups on the benzene ring at the ortho position, or simultaneously substitutes for both hydroxyl groups at the ortho position.

[0033] In one embodiment, when Ar is a heteroaryl group, it is attached to an alkenyl group at positions 2, 3, or 4.

[0034] As an example, the compounds represented by Formula I-1 or Formula I are selected from, but not limited to:

[0035] Table A:

[0036]

[0037]

[0038] According to embodiments of this disclosure, the prodrug can be an ester formed by at least one hydroxyl group of a compound of Formula I-1 or Formula I with a pharmaceutically acceptable compound having at least one carboxyl group. As an example, the compound having at least one carboxyl group can 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, it can be esterified with a compound of Formula I via one carboxyl group, while other carboxyl groups are substituted with hydroxyl groups. 1-12 Alkyl groups react to form esters.

[0039] Another aspect of this disclosure relates to compounds of formula I-1d or salts thereof:

[0040]

[0041] in:

[0042] R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one, two, or more substituents selected from halogen, oxo (=O), alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, amino, alkylamino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; preferably, R is C 1-6 alkyl;

[0043] Each R1 may be the same or different, and is independently selected from halogen, cyano, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, -COC 1-12 Alkyl or C 2-12 Alkoxy groups, preferably F, Cl, Br, cyano, or C. 1-3 Alkyl or halogenated C 1-3 alkyl;

[0044] Ar and n are as defined in Equation I-1 or Equation I.

[0045] Table B lists typical intermediate compounds disclosed herein, including but not limited to:

[0046]

[0047] Another aspect of this disclosure relates to a method for preparing the compound of formula I-1, its stereoisomers, or pharmaceutically acceptable salts, the method comprising the following steps:

[0048]

[0049] The compound shown in Formula I-1d or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound shown in Formula I-1, its stereoisomers, or its pharmaceutically usable salts.

[0050] in:

[0051] R is selected from alkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one, two, or more substituents selected from halogen, oxo (=O), alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, amino, alkylamino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; preferably, R is C 1-6 alkyl;

[0052] Each R1 may be the same or different, and is independently selected from halogen, cyano, C2-6 Straight-chain alkyl, halogenated C 1-6 Alkyl, -COC 2-6 Alkyl or C 1-6 Alkoxy groups, preferably F, Cl, Br, cyano, or halogenated C. 1-3 alkyl;

[0053] Ar and n are as defined in Equation I-1 or Equation I.

[0054] This disclosure also provides a method for preparing the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts, comprising the following steps:

[0055] 1) When R1 is a halogen, the compound of formula I is prepared by the following method:

[0056]

[0057] S5) The compound of formula Id or its salt reacts with pyridine hydrochloride upon heating to give the compound of formula I; or, the compound of formula Id or its salt is demethylated with boron tribromide and then quenched with water to give the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt.

[0058] 2) When R1 is methyl, the compound of formula I is prepared by the following method:

[0059]

[0060] The S5') compound Id' reacts with pyridine hydrochloride upon heating to give the compound shown in Formula I;

[0061] Ar and R1 are as defined in Equation I-1 or Equation I.

[0062] In one embodiment, compound Id is prepared using the following method, but not limited to:

[0063]

[0064] S1) 3,5-Dimethoxy-4-isopropylbenzyl alcohol reacts with a halogenating agent (e.g., N-chlorosuccinimide, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt or N-bromosuccinimide) to give compound Ia;

[0065] S2) Compound Ia was added to a mixed solution of concentrated hydrochloric acid and n-hexane and heated to react and obtain compound Ib;

[0066] S3) Compound Ib reacts with triethyl phosphite upon heating to give compound Ic;

[0067] S4) Compound Ic and Compound The reaction yields compound Id in the presence of basic compounds (such as potassium tert-butoxide, sodium tert-butoxide, etc.).

[0068] compound The Ar group in it has the same definition as in Formula I-1 or Formula I above.

[0069] Optionally, the preparation method further includes the step of preparing a salt from the compound represented by Formula I-1, Formula I, or Table A.

[0070] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of formula I-1, formula I or Table A, their stereoisomers, or pharmaceutically acceptable salts or prodrugs.

[0071] According to embodiments of this disclosure, the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients.

[0072] According to embodiments of this disclosure, the pharmaceutical composition is an aryl hydrocarbon receptor (AHR) modulator.

[0073] According to embodiments of this disclosure, the aryl hydrocarbon receptor (AHR) modulator is used to alleviate and / or treat the following diseases or conditions: cancer, ophthalmological diseases, autoimmune diseases, and other conditions or discomforts with immunological factors; the cancer is preferably leukemia, prostate cancer, and colorectal cancer; the ophthalmological diseases are preferably uveitis, age-related macular degeneration, and dry eye syndrome; the autoimmune diseases are preferably rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; other conditions or discomforts with immunological factors are preferably asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0074] This disclosure also provides the use of at least one of the compounds of formula I-1, formula I or Table A, their stereoisomers or pharmaceutically acceptable salts or prodrugs in the preparation of aromatic hydrocarbon receptor (AHR) modulators.

[0075] This disclosure also provides a method for alleviating and / or treating aryl hydrocarbon receptor (AHR) mediated diseases or conditions, 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, their stereoisomers or pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.

[0076] According to embodiments of this disclosure, the aryl hydrocarbon receptor (AHR)-mediated diseases or conditions include: cancer, ophthalmological diseases, autoimmune diseases, and other conditions or discomforts with immunological factors; the cancer is preferably leukemia, prostate cancer, and colorectal cancer; the ophthalmological diseases are preferably uveitis, age-related macular degeneration, and dry eye syndrome; the autoimmune diseases are preferably rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; other conditions or discomforts with immunological factors are preferably asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0077] Beneficial effects

[0078] This disclosure improves the structure of benvitimod, resulting in compounds that significantly enhance the photostability of the molecular structure compared to the marketed drug benvitimod, thus mitigating the photostability and degradation issues associated with benvitimod under light. Furthermore, some compounds also significantly improve activity against AHR proteins or achieve activity at least equal to or greater than that of benvitimod.

[0079] Finally, the obtained compound is simple to prepare and can be prepared in gram or dry gram quantities, showing better prospects in subsequent formulation development, safety and clinical application.

[0080] Terminology Definitions and Explanations

[0081] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains.

[0082] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0083] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when certain numerical ranges are defined as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "numbers from 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0084] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0085] The "-*" symbol used in combination with a chemical bond in a substituent indicates a linking site.

[0086] The term "halogen" includes F, Cl, Br, or I.

[0087] The term "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group, such as C 1-12 alkyl.

[0088] Term "C" 1-12 "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C12. 1-6 Alkyl group. "C" 1-6 "alkyl" should be understood to preferably represent a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, preferably C64. 2-6 Alkyl, more preferably C 2-6 A straight-chain alkyl group. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 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, or 1,2-dimethylbutyl, or isomers thereof. In particular, the group has 1, 2, or 3 carbon atoms (“C…”). 1-3 Alkyl), such as methyl, ethyl, n-propyl or isopropyl.

[0089] The term "aryl" should be understood to refer to a monocyclic, bicyclic, or tricyclic hydrocarbon ring group having 6 to 20 carbon atoms, preferably C14 or C24. 6-20 Aryl.

[0090] Term "C" 6-20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring group having 6 to 20 carbon atoms and possessing monovalent aromatic or partially aromatic properties, preferably "C". 6-14 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), preferably 6 to 10-membered aryl. Examples include a ring having 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring having 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring having 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), such as anthracene. When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on its substitution site; for example, it can be ortho, para, or meta substituted.

[0091] The term "heteroaryl" 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, preferably 5 to 20 membered heteroaryls.

[0092] The term "5 to 20-membered heteroaryl" 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, particularly 5, 6, 9, or 10 carbon atoms (preferably 5 to 10-membered heteroaryl), and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S. Furthermore, in each case, it may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc. When the 5-10 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, a hydrogen atom bonded to a carbon atom on the heteroaryl ring can be substituted, or a hydrogen atom bonded to a heteroatom on the heteroaryl ring can be substituted.

[0093] Unless otherwise stated, heteroaryl or heteroaryl includes all its possible isomers, such as its positional isomers. Thus, for some illustrative, non-limiting examples, it may include forms in which one, two, or more of its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, etc. (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0094] The term "cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic, or polycyclic hydrocarbon ring (also called a fused ring) having 3-20 carbon atoms, preferably having 3-12 carbon atoms. Bicyclic or polycyclic cycloalkyl includes fused cycloalkyl, bridged cycloalkyl, and spirocyclic cycloalkyl; fused cycloalkyl refers to a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). Bridged cycloalkyl refers to a fused ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Spirocyclic cycloalkyl refers to a fused ring structure formed by two or more cyclic structures sharing a single ring atom. For example, the cycloalkyl can be C10-2000. 3-8 Monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7-12 Circular alkyl groups, such as decahydronaphthalene rings.

[0095] The term "heterocyclic 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 heterocyclic group can be attached to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group can include, but is not limited to, 4-20 membered heterocyclic groups, such as: 4-membered rings, such as azirmonobutyl, oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-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-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzofused, such as, but not limited to, dihydroisoquinolinyl.

[0096] The term "halogenated alkyl" refers to a group in which the hydrogen atom on an alkyl group is replaced by a halogen, for example, where the hydrogen atom on an alkyl group is optionally replaced by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 halogens. The terms "halogenated," "alkyl," and "C" are used in this context. 1-12 "Alkyl" has the definition as described above. The substitution refers to substitution on the same carbon atom or on different carbon atoms. Optional "halogenated C" 1-6 Alkyl group. The "halogenated C" 1-12 "Alkyl" is, for example, trifluoromethyl.

[0097] The above definition of a term also applies to other terms containing that term. For example, the above definition of the term "C" 1-12 The definition of "alkyl" also applies to compounds containing "C". 1-12 Other terms for "alkyl", such as "-COC" 1-12 Alkyl group, -COC 2-12 Alkyl group, -COC 2-6 Alkyl groups, etc.

[0098] For example, the term "alkoxy" refers to an alkyloxy group, where alkyl has the definition described above.

[0099] The term "haloalkoxy" means haloalkyloxy, where the alkyl group has the definition as described above.

[0100] The term "hydroxyalkyl" refers to a hydroxyl-substituted alkyl group, wherein the alkyl group has the definition as described above.

[0101] The term "alkylamino" indicates that the alkyl group has the definition as described above.

[0102] 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 present invention in which one or more suitable groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversal is usually achieved by enzymes naturally present in such subjects, although a second agent may be administered with the prodrug to facilitate reversal in vivo. Examples of such modifications include pharmaceutically acceptable esters as described above, where such reversal can be achieved by esterases, etc. Detailed Implementation

[0103] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0104] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0105] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0106] The liquid chromatography-mass spectrometry (LC-MS) system used was Waters 2695+ZQ2000, Shimadzu MS-2020+LC-20AB, and Shimadzu LC-40D XR+MS-2020.

[0107] High performance liquid chromatography (HPLC) analysis was performed using Shimadzu LC-20AB, Shimadzu LC-20ADXR, and Shimadzu LC-40D XR HPLC systems.

[0108] Chiral HPLC analysis was performed using a Shimadzu LC-30AD high-performance liquid chromatograph.

[0109] High performance liquid chromatography was performed using a Shimadzu LC-20AP and a Gilson GX-281 preparative chromatograph.

[0110] In the examples, if chiral molecules are prepared, the chiral preparation is performed using a Waters 150Mgm or Waters SFC 350 preparative chromatograph.

[0111] The CombiFlash rapid preparation system uses the CH-200P (Agela & Phenomenex).

[0112] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0113] Silica gel column chromatography typically uses 200-300 mesh silica gel from Yantai Huanghai or Titan Technology as the carrier.

[0114] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Titan Technologies, Energie Chemicals, Haohong Biotechnology, and Bid Pharmaceuticals.

[0115] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0116] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0117] In the examples, the reaction is described as being carried out under hydrogen conditions. A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 L. The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator. The hydrogenation reaction is typically performed under vacuum, followed by hydrogen filling, and repeated three times.

[0118] As illustrated in the examples, the reactions were carried out under microwave conditions using a CEM Discover-S908860 microwave reactor. Unless otherwise specified, "solution" in the examples refers to an aqueous solution.

[0119] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0120] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: petroleum ether / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0121] In some embodiments, the compound is purified using preparative HPLC.

[0122] Example 1

[0123] (E)-4-chloro-2-isopropyl-5-styrylbenzene-1,3-diol

[0124]

[0125] first step

[0126] 4-Isopropyl-3,5-Dimethoxybenzoic acid 1b

[0127] Water (98 g, 9.44 mol) was carefully added to concentrated sulfuric acid (1.087 kg, 11.007 mol), followed by compound 1a (250 g, 1.274 mol), with the internal temperature controlled to not exceed 40 °C. Isolactone (110 g, 1.835 mol) was added dropwise to the mixture, maintaining an internal temperature of 40–45 °C. After the addition was complete, the mixture was stirred overnight at 50 °C. The reaction mixture was cooled to room temperature and then 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 and dissolved in ethyl acetate (250 g), then heated under reflux for 1 h. Hexane (1 L) was added while maintaining an internal temperature of 65–70 °C, and stirring was continued for 0.5 h. The mixture was then cooled to 0 °C and stirred for another 1 h. The mixture was filtered, and the filter cake was washed with hexane and dried overnight at 40 °C to obtain the title product 1b.

[0128] Step 2

[0129] (4-Isopropyl-3,5-dimethoxyphenyl)methanol 1c

[0130] 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 protection, with the internal temperature controlled not to exceed 25 °C. Iodine (76.4 g, 0.301 mol) was dissolved in tetrahydrofuran (340 mL) and slowly added dropwise to the above mixture, with the internal temperature controlled at 35 °C. After the addition was complete, the reaction mixture was stirred overnight at 35 °C. The reaction solution was cooled to room temperature, poured into water (900 mL), and stirred at room temperature for 1 h, then filtered. The filtrate was concentrated to remove the organic solvent, and then added to a sodium bisulfite solution (9 g sodium bisulfite dissolved in 900 mL water), stirred at room temperature for 0.5 h, and filtered. The filter cake was washed with water and dried overnight at 40 °C to give the title product 1c.

[0131] Step 3

[0132] (2-chloro-4-isopropyl-3,5-dimethoxyphenyl)methanol 1d

[0133] Compound 1c (5 g, 23.8 mmol) was dissolved in tetrahydrofuran (50 mL), and then a solution of N-chlorosuccinimide (2.85 g, 21.3 mmol) in tetrahydrofuran (50 mL) was added at 0 °C. The reaction 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.

[0134] Step 4

[0135] 2-Chloro-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 1e

[0136] 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 of the filtrate was separated and washed with saturated brine (200 mL), saturated sodium bicarbonate solution (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.

[0137] Step 5

[0138] (2-chloro-4-isopropyl-3,5-dimethoxybenzyl) phosphate diethyl 1f

[0139] Compound 1e (3.2 g, 12.2 mmol) was added to triethyl phosphite (30 mL), and the mixture was heated to 160 °C and stirred for 5 h under nitrogen protection. After cooling to room temperature, the mixture was concentrated to give the crude product, titled 1f.

[0140] Step 6

[0141] (E)-2-chloro-4-isopropyl-3,5-dimethoxy-1-styrene 1g

[0142] 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 the mixture was heated to 50 °C and stirred for 2 h under nitrogen protection. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL), and then washed with water (50 mL) and saturated brine (50 mL). After separation of the organic phase, the mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 1 g of the title compound.

[0143] Step 7

[0144] (E)-4-chloro-2-isopropyl-5-styrylbenzene-1,3-diol

[0145] 1 g (1.3 g, 4.1 mmol) of the compound was mixed with pyridine hydrochloride (3 g) and heated to 180 °C under nitrogen protection, with stirring for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL), then washed with water (50 mL) and saturated brine (50 mL). After separation of the organic phase, the mixture was 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.

[0146] LCMS (ESI, m / z): 289.05 [M+H] + .

[0147] 1 H NMR (400MHz, CDCl3, ppm): δ7.54-7.51(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=6.8Hz, 6H).

[0148] Example 2

[0149] (E)-2-Isopropyl-4-methyl-5-styrylbenzene-1,3-diol 2

[0150]

[0151] (E)-2-Isopropyl-4-methyl-5-styrylbenzene-1,3-diol 2

[0152] Compound 2a (3.80 kg) and pyridine hydrochloride (11.15 kg) were added to a 100 L glass reactor under nitrogen protection. The reaction solution was heated to 165–175 °C with stirring until dissolved, and the reaction was maintained at this temperature for 5 h. After the reaction was complete, the reaction solution 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). The mixture was stirred, and methyl tert-butyl ether (14.05 kg) was added. The mixture was stirred for 15–20 min and allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure. Methyl tert-butyl ether (2.80 kg) was added to the concentrated residue and stirred until dissolved. Heptane (10.40 kg) was added dropwise, and the mixture was placed in an ice-water bath and stirred for 1 h. The mixture was then filtered. The filtrate was concentrated to obtain a brownish-black oil. The oil was purified by silica gel column chromatography and then by preparative HPLC to obtain the title product 2.

[0153] LCMS (ESI, m / z): 267.14 [MH] - .

[0154] 1 H NMR (400MHz, CDCl3, ppm): δ7.38 (d, J=7.4Hz, 2H), 7.26 (t, J=7.7Hz, 2H), 7.17-7.15 (m, 2H), 6.75 (d, J=1 6Hz, 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=7.2Hz, 6H).

[0155] Example 3

[0156] (E)-4-Fluoro-2-isopropyl-5-styrylbenzene-1,3-diol 3

[0157]

[0158] first step

[0159] (2-Fluoro-4-isopropyl-3,5-dimethoxyphenyl)methanol 3a

[0160] Compound 1c (25 g, 118.90 mmol) was dissolved in acetonitrile (250 mL) and placed in an ice-water bath. Under nitrogen protection, 1-chloromethyl-4-fluoro-1,4-diazobicyclo2,2,2-octanebis(tetrafluoroborate) salt (42.12 g, 118.90 mmol) was added in portions. The reaction mixture was stirred at 25 °C for 5 h. The reaction solution 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.

[0161] Step 2

[0162] 2-Fluoro-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 3b

[0163] The title product 3b was prepared from intermediate 3a by referring to the synthesis method in step 4 of Example 1.

[0164] Step 3

[0165] (2-Fluoro-4-isopropyl-3,5-dimethoxybenzyl) phosphate diethyl 3c

[0166] The title product 3c was prepared from intermediate 3b by referring to the synthesis method in step 5 of Example 1.

[0167] Step 4

[0168] (E)-2-Fluoro-4-isopropyl-3,5-dimethoxy-1-styrene-phenylene 3d

[0169] The title product 3d was prepared from intermediate 3c and benzaldehyde using the synthesis method described in step 6 of Example 1.

[0170] Step 5

[0171] (E)-4-Fluoro-2-isopropyl-5-styrylbenzene-1,3-diol 3

[0172] Title product 3 was prepared from intermediate 3d using the synthesis method described in step 7 of Example 1.

[0173] LCMS (ESI, m / z): 273.1 [M+H] + .

[0174] 1H NMR (400MHz, 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=6.4Hz, 1H), 5.22 (d, J=7.2Hz, 1H), 4.64 (s, 1H), 3.50-3.42 (m, 1H), 1.37 (d, J=7.2Hz, 6H). 19 FNMR (400MHz, CDCl3, ppm): δ-154.66 (1F).

[0175] Example 4

[0176] (E)-4-bromo-2-isopropyl-5-styrylphenyl-1,3-diol

[0177]

[0178] first step

[0179] (2-Bromo-4-isopropyl-3,5-dimethoxyphenyl)methanol 4a

[0180] Compound 1c (10 g, 47.6 mmol) was dissolved in tetrahydrofuran (100 mL), and then a solution of N-bromosuccinimide (7.62 g, 42.8 mmol) in tetrahydrofuran (30 mL) was added dropwise at room temperature. The reaction 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 give compound 4a.

[0181] Step 2

[0182] 2-Bromo-1-chloromethyl-4-isopropyl-3,5-dimethoxybenzene 4b

[0183] The title product 4b was prepared from intermediate 4a using the synthesis method described in step 4 of Example 1.

[0184] Step 3

[0185] (2-Bromo-4-isopropyl-3,5-dimethoxybenzyl) phosphate diethyl 4c

[0186] The title product 4c was prepared from intermediate 4b by referring to the synthesis method in step 5 of Example 1.

[0187] Step 4

[0188] (E)-2-bromo-4-isopropyl-3,5-dimethoxy-1-styrene-phenyl 4d

[0189] The title product 4d was prepared from intermediate 4c and benzaldehyde using the synthesis method described in step 6 of Example 1.

[0190] Step 5

[0191] (E)-4-bromo-2-isopropyl-5-styrylbenzene-1,3-diol

[0192] Title product 4 was prepared from intermediate 4d using the synthesis method described in step 7 of Example 1.

[0193] LCMS (ESI, m / z): 333.08 [M+H] + .

[0194] 1 H NMR (400MHz, CDCl3, ppm): δ7.54-7.51 (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=7.2Hz, 6H).

[0195] Example 5

[0196] (E)-4-fluoro-5-(4-fluorostyryl)-2-isopropylbenzene-1,3-diol 5

[0197]

[0198] first step

[0199] (E)-2-Fluoro-1-(4-fluorostyryl)-4-isopropyl-3,5-dimethoxybenzene 5a

[0200] The title product 5a was prepared from intermediate 3c and 4-fluorobenzaldehyde using the synthesis method described in step 6 of Example 1.

[0201] Step 2

[0202] (E)-4-fluoro-5-(4-fluorostyryl)-2-isopropylbenzene-1,3-diol 5

[0203] The title product 5 was prepared from intermediate 5a using the synthesis method described in step 7 of Example 1.

[0204] LCMS (ESI, m / z): 291.74 [M+H] + .

[0205] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.09 (d, J=2.8Hz, 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=6.0Hz, 1H), 3.49-3.41 (m, 1H), 1.27 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-114.09 (1F), -150.87 (1F).

[0206] Example 6

[0207] (E)-4-Fluoro-5-(2-fluorostyryl)-2-isopropylbenzene-1,3-diol 6

[0208]

[0209] first step

[0210] (E)-2-Fluoro-1-(2-fluorostyryl)-4-isopropyl-3,5-dimethoxybenzene 6a

[0211] The title product 6a was prepared from intermediate 3c and 2-fluorobenzaldehyde using the synthesis method described in step 6 of Example 1.

[0212] Step 2

[0213] (E)-4-Fluoro-5-(2-fluorostyryl)-2-isopropylbenzene-1,3-diol 6

[0214] Title product 6 was prepared from intermediate 6a using the synthesis method described in step 7 of Example 1.

[0215] LCMS (ESI, m / z): 291.26 [M+H] + .

[0216] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.15 (d, J=2.4Hz, 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=6.0Hz, 1H), 3.49-3.41 (m, 1H), 1.25 (d, J=7.2Hz, 6H); 19FNMR (400MHz, DMSO-d6, ppm): δ-118.95(1F), -150.76(1F).

[0217] Example 7

[0218] (E)-4-fluoro-5-[2-(3-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 7

[0219]

[0220] first step

[0221] (E)-3-fluoro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 7a

[0222] The title product 7a was prepared from intermediate 3c and 3-fluoro-2-pyridinecarboxaldehyde using the synthesis method described in step 6 of Example 1.

[0223] Step 2

[0224] (E)-4-fluoro-5-[2-(3-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 7

[0225] Compound 7a (100 mg, 0.31 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1.3 mL, 1.3 mmol, 1 M dichloromethane solution) was added dropwise at 0 °C under nitrogen protection. The reaction was then stirred at room temperature for 0.5 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and diluted with dichloromethane (50 mL). After separation of the organic phase, the mixture was 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 obtain compound 7.

[0226] LCMS (ESI, m / z): 292.42 [M+H] + .

[0227] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.23 (s, 1H), 9.15 (s, 1H), 8.48-8.45 (m, 1H), 7.79-7.71 (m, 2H), 7.4 1-7.36 (m, 1H), 7.26-7.19 (m, 1H), 6.60 (d, J=5.2Hz, 1H), 3.49-3.42 (m, 1H), 1.26 (d, J=6.4Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-127.60 (1F), -150.31 (1F).

[0228] Example 8

[0229] (E)-5-[2-(3-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylphenyl-1,3-diol 8

[0230]

[0231] first step

[0232] (E)-3-chloro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 8a

[0233] Title product 8a was prepared from intermediate 3c and 3-chloro-2-pyridinecarboxaldehyde using the synthesis method described in step 6 of Example 1.

[0234] Step 2

[0235] (E)-5-[2-(3-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylphenyl-1,3-diol 8

[0236] The title product 8 was prepared from intermediate 8a by referring to the synthesis method in step 2 of Example 7.

[0237] LCMS (ESI, m / z): 308.28 [M+H] + .

[0238] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.25 (d, J=2.4Hz, 1H), 9.18 (s, 1H), 8.56 (dd, J=4.4Hz, 1.2Hz, 1H), 7.94 (dd, J=8.0Hz, 1.2Hz, 1H), 7. 84-7.80 (m, 1H), 7.48-7.43 (m, 1H), 7.33 (dd, J=8.0Hz, 4.4Hz, 1H), 6.61 (d, J=6.0Hz, 1H), 3.50-3.42 (m, 1H), 1.26 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-149.99 (1F).

[0239] Example 9

[0240] (E)-4-fluoro-5-[2-(5-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 9

[0241]

[0242] first step

[0243] (E)-5-fluoro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 9a

[0244] The title product 9a was prepared from intermediate 3c and 5-fluoro-2-pyridinecarboxaldehyde using the synthesis method described in step 6 of Example 1.

[0245] Step 2

[0246] (E)-4-fluoro-5-[2-(5-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 9

[0247] The title product 9 was prepared from intermediate 9a by referring to the synthesis method in step 2 of Example 7.

[0248] LCMS (ESI, m / z): 292.34 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.17 (d, J=2.4Hz, 1H), 9.12 (s, 1H), 8.56 (d, J=2.8Hz, 1H), 7.75-7.64 (m, 2H ), 7.58-7.53 (m, 1H), 7.11-7.06 (m, 1H), 6.54 (d, J=6.0Hz, 1H), 3.49-3.41 (m, 1H), 1.26 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-128.86 (1F), -150.44 (1F).

[0250] Example 10

[0251] (E)-5-[2-(5-chloropyridin-2-yl)vinyl]-4-fluoro-2-isopropylbenzene-1,3-diol 10

[0252]

[0253] first step

[0254] (E)-5-chloro-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 10a

[0255] Title product 10a was prepared from intermediate 3c and 5-chloro-2-pyridinecarboxaldehyde using the synthesis method described in step 6 of Example 1.

[0256] Step 2

[0257] (E)-5-[2-(5-chloropyridin-2-yl)vinyl-1-4-fluoro-2-isopropylphenyl-1,3-diol 10]

[0258] The title product 10 was prepared from intermediate 10a by referring to the synthesis method in step 2 of Example 7.

[0259] LCMS (ESI, m / z): 308.05 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.19 (d, J=2.0Hz, 1H), 9.14 (s, 1H), 8.60 (d, J=2.4Hz, 1H), 7.91 (dd, J=8.4Hz, 2.4 Hz, 1H), 7.66-7.60 (m, 2H), 7.10-7.06 (m, 1H), 6.56 (d, J=5.6Hz, 1H), 3.79-3.39 (m, 1H), 1.25 (d, J=7.2Hz, 6H). 19 FNMR (400MHz, DMSO-d6, ppm): δ-150.19(1F).

[0261] Example 11

[0262] (E)-4-fluoro-2-isopropyl-5-[2-(pyridazin-3-yl)vinyl]benzene-1,3-diol 11

[0263]

[0264] first step

[0265] 2-Fluoro-4-isopropyl-3,5-dimethoxybenzaldehyde 11a

[0266] Compound 3a (15 g, 65.71 mmol) was dissolved in dichloromethane (300 mL), and then Dys-Martin reagent (30.66 g, 72.29 mmol) was added. The mixture was stirred at 20–25 °C for 16 h. A saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture. 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 11a.

[0267] Step 2

[0268] (E)-3-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridazine 11b

[0269] 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), followed by the addition of potassium hydroxide (59.6 mg, 1.0 mmol). The mixture was heated to 120 °C and stirred for 0.5 h. After cooling to room temperature, saturated ammonium chloride aqueous solution (100 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted 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.

[0270] Step 3

[0271] (E)-4-fluoro-2-isopropyl-5-[2-(pyridazin-3-yl)vinyl]benzene-1,3-diol 11

[0272] Title product 11 was prepared from intermediate 11b by referring to the synthesis method in step 2 of Example 7.

[0273] LCMS (ESI, m / z): 275.1 [M+H] + .

[0274] 1 H NMR (400MHz, 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=8.4Hz, 1.6Hz, 1H), 7.73 (d, J=1 6.4Hz, 1H), 7.68 (dd, J=8.4Hz, 4.8Hz, 1H), 7.23 (d, J=16.4Hz, 1H), 6.60 (d, J=5.6Hz, 1H), 3.51-3.42 (m, 1H), 1.26 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-149.71 (1F).

[0275] Example 12

[0276] (E)-4-fluoro-2-isopropyl-5-[2-(thien-2-yl)vinyl]benzene-1,3-diol 12

[0277]

[0278] first step

[0279] (E)-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)thiophene 12a

[0280] Title product 12a was prepared from intermediate 11a and diethyl (thiophen-2-ylmethyl)phosphate using the synthesis method described in step 6 of Example 1.

[0281] Step 2

[0282] (E)-4-fluoro-2-isopropyl-5-[2-(thien-2-yl)vinyl]benzene-1,3-diol 12

[0283] The title product 12 was prepared from intermediate 12a by referring to the synthesis method in step 2 of Example 7.

[0284] LCMS (ESI, m / z): 279.0 [M+H] + .

[0285] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.14 (s, 1H), 9.11-9.05 (m, 1H), 7.48 (d, J = 5.2Hz, 1H), 7.25 (d, J = 3.2Hz, 1H), 7.19 (d, J = 16.4Hz , 1H), 7.07 (dd, J=5.2Hz, 3.6Hz, 1H), 6.83 (d, J=16.4Hz, 1H), 6.46 (d, J=6.0Hz, 1H), 3.47-3.40 (m, 1H), 1.24 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-151.18(1F).

[0286] Example 13

[0287] (E)-4-fluoro-2-isopropyl-5-[2-(6-methylpyridin-2-yl)vinyl]benzene-1,3-diol 13

[0288]

[0289] first step

[0290] (E)-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)-6-methylpyridine 13a

[0291] Title product 13a was prepared from intermediate 11a and [(6-methylpyridin-2-yl)methyl]triphenylphosphonium bromide, following the synthetic method in step 6 of Example 1.

[0292] Step 2

[0293] (E)-4-fluoro-2-isopropyl-5-[2-(6-methylpyridin-2-yl)vinyl]benzene-1,3-diol 13

[0294] Title product 13 was prepared from intermediate 13a by referring to the synthesis method in step 2 of Example 7.

[0295] LCMS (ESI, m / z): 288.1 [M+H] + .

[0296] 1 H NMR (400MHz, CDCl3, ppm): δ7.64-7.53 (m, 2H), 7.27-7.25 (m, 1H), 7.16 (d, J=16.4Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.54 (d, J=6.4Hz, 1H), 3.52-3.45 (m, 1H), 2.60 (s, 3H), 1.38 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, CDCl3, ppm): δ-153.59 (1F).

[0297] Example 14

[0298] (E)-4-Fluoro-5-[2-(6-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 14

[0299]

[0300] first step

[0301] 2-Fluoro-4-isopropyl-3,5-dimethoxy-1-vinylbenzene 14a

[0302] The compound methyltriphenylphosphine bromide (4.7 g, 13.2 mmol) was dissolved in dioxane (30 mL), followed by the addition of potassium carbonate (3.6 g, 26.5 mmol) and 11a (3 g, 13.2 mmol). The mixture was heated to 110 °C and stirred for 6 h. The system was cooled to room temperature, and water (50 mL) was added. 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.

[0303] Step 2

[0304] (E)-2-fluoro-6-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 14b

[0305] 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), and the mixture was purged with nitrogen three times. Then, triethylamine (1.35 g, 13.3 mmol) and (1,1′-bis(diphenylphosphine)ferrocene)palladium dichloride (326 mg, 445 μmol) were added, and the mixture was heated to 95 °C and stirred for 16 h. The system was cooled to room temperature, and water (50 mL) was added. 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.

[0306] Step 3

[0307] (E)-4-Fluoro-5-[2-(6-fluoropyridin-2-yl)vinyl]-2-isopropylphenyl-1,3-diol 14

[0308] Title product 14 was prepared from intermediate 14b using the synthesis method described in step 2 of Example 7.

[0309] LCMS (ESI, m / z): 292.1 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.23 (d, J=2.4Hz, 1H), 9.17 (s, 1H), 8.01-7.94 (m, 1H), 7.59 (d, J=16.0Hz, 1 H), 7.50-7.46 (m, 1H), 7.10-7.00 (m, 2H), 6.55 (d, J=6.0Hz, 1H), 3.49-3.42 (m, 1H), 1.26 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-66.80 (1F), -150.07 (1F).

[0311] Example 15

[0312] (E)-4-fluoro-2-isopropyl-5-[2-(quinolin-2-yl)vinyl]benzene-1,3-diol 15

[0313]

[0314] first step

[0315] (E)-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)quinoline 15a

[0316] Compound 2-methylquinoline (300 mg, 2.10 mmol) and 11a (474 ​​mg, 2.10 mmol) were dissolved in acetic anhydride (5 mL), and the mixture was heated to 130 °C and stirred for 12 h. The system was cooled to room temperature, and water (50 mL) was added. 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.

[0317] Step 2

[0318] (E)-4-fluoro-2-isopropyl-5-[2-(quinolin-2-yl)vinyl]benzene-1,3-diol 15

[0319] Title product 15 was prepared from intermediate 15a using the synthesis method described in step 2 of Example 7.

[0320] LCMS (ESI, m / z): 324.1 [M+H] + .

[0321] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.27 (d, J=1.6Hz, 1H), 9.23 (s, 1H), 8.35 (d, J=8.4Hz, 1H), 8.00-7.94 (m, 2H), 7.87 (d, J=8.4Hz, 1H ), 7.80-7.73 (m, 2H), 7.58-7.54 (m, 1H), 7.25 (d, J = 16.4Hz, 1H), 6.63 (d, J = 6.0Hz, 1H), 3.48-3.45 (m, 1H), 1.27 (d, J = 6.8Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-149.88 (1F).

[0322] Example 16

[0323] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-2-yl)vinyl]benzene-1,3-diol 16

[0324]

[0325] first step

[0326] (E)-2-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 16a

[0327] Title product 16a was prepared from intermediate 11a and [(pyridin-2-yl)methyl]triphenylphosphonium bromide, following the synthetic method in step 6 of Example 1.

[0328] Step 2

[0329] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-2-yl)vinyl]benzene-1,3-diol 16

[0330] Title product 16 was prepared from intermediate 16a using the synthesis method described in step 2 of Example 7.

[0331] LCMS (ESI, m / z): 274.0 [M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.20 (s, 1H), 9.15 (s, 1H), 8.58 (d, J=4.4Hz, 1H), 7.86-7.78 (m, 1H), 7.66 (d, J=16.0Hz, 1H), 7. 62-7,59 (m, 1H), 7.33-7.26 (m, 1H), 7.08 (d, J = 16.0Hz, 1H), 6.56 (d, J = 6.0Hz, 1H), 3.49-3.43 (m, 1H), 1.26 (d, J = 7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-150.29 (1F).

[0333] Example 17

[0334] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-3-yl)vinyl]benzene-1,3-diol 17

[0335]

[0336] first step

[0337] (E)-3-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 17a

[0338] The title product 17a was prepared from 3-bromopyridine and intermediate 14a using the synthesis method in step 2 of Example 14.

[0339] Step 2

[0340] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-3-yl)vinyl]benzene-1,3-diol 17

[0341] Title product 17 was prepared from intermediate 17a using the synthesis method described in step 2 of Example 7.

[0342] LCMS (ESI, m / z): 274.0 [M+H] + .

[0343] 1 H NMR (400MHz, 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 = 16.4Hz, 1H), 7.11 (d, J = 16.4Hz, 1H), 6.54 (d, J = 6.0Hz, 1H), 3.50-3.42 (m, 1H), 1.26 (d, J = 7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-149.83 (1F).

[0344] Example 18

[0345] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-4-yl)vinyl]benzene-1,3-diol 18

[0346]

[0347]

[0348] first step

[0349] (E)-4-(2-fluoro-4-isopropyl-3,5-dimethoxystyryl)pyridine 18a

[0350] Title product 18a was prepared from 4-methylpyridine and intermediate 11a, following the synthetic method in the first step of Example 15.

[0351] Step 2

[0352] (E)-4-fluoro-2-isopropyl-5-[2-(pyridin-4-yl)vinyl]benzene-1,3-diol 18

[0353] Title product 18 was prepared from intermediate 18a using the synthesis method described in step 2 of Example 7.

[0354] LCMS (ESI, m / z): 274.0 [M+H] + .

[0355] 1H NMR (400MHz, DMSO-d6, ppm): δ9.24 (d, J=2.4Hz, 1H), 9.19 (s, 1H), 8.56 (d, J=5.6Hz, 2H), 7.65-7.61 (m, 2H), 7. 47 (d, J=16.4Hz, 1H), 7.02 (d, J=16.4Hz, 1H), 6.55 (d, J=6.0Hz, 1H), 3.49-3.43 (m, 1H), 1.26 (d, J=7.2Hz, 6H). 19 F NMR (400MHz, DMSO-d6, ppm): δ-149.61 (1F).

[0356] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0357] This test case demonstrates a luciferase reporter gene assay to test the agonistic activity of the disclosed compound on the AHR protein.

[0358] Test cells:

[0359] HepG2-Lucia, a human liver cancer cell line expressing AHR and luciferase, was purchased from InvivoGen, catalog number hpgl-ahr;

[0360] Main instruments:

[0361] Biosafety cabinet, model 307, ThermoFisher;

[0362] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0363] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0364] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte Corporation;

[0365] Made a perforated plate centrifuge, model PlatePro 3200, from Monad.

[0366] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0367] Main reagents:

[0368] Penicillin-streptomycin, Gibco, catalog number 15140-122;

[0369] EMEM culture medium, ATCC, catalog number 30-2003;

[0370] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0371] NEAA medium, Gibco, catalog number 11140-050;

[0372] Phosphate buffer, Gibco, catalog number 14190250;

[0373] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0374] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0375] Zeocin (bleomycin), from LnvivoGen, catalog number ant-zn-1;

[0376] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0377] Experimental steps:

[0378] 1. HepG2-LuciaAHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1×NEAA, penicillin, streptomycin, and 100 μg / mL Zeocin. The culture temperature was 37℃, and the carbon dioxide concentration was 5%.

[0379] 2. Once cells have grown to approximately 80% confluence, digest the cells, centrifuge, resuspend, and count them. Seed the cells into 384-well plates, 40 μL per well.

[0380] 3. Add different concentrations of the test compound using ECHO, 40 nL per well.

[0381] 4. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours.

[0382] 5. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0383] Experimental results:

[0384] This disclosure describes the compound and the activity of benvitimide against AHR protein. 50 The data is summarized in Table 1 below:

[0385] Table 1: Effects of the compounds disclosed herein on AHR-activated EC 50

[0386]

[0387] The above results indicate that the compounds of the present invention have good activating activity against AHR protein, and at least compounds 5-9 and 14 have significantly better activity than benvimod.

[0388] Test Example 2: Light Stability Experiment

[0389] This test case examines the stability of the compounds in the embodiments of this disclosure, benvitide, and the compound of Control Example 1 under light conditions.

[0390] Main instruments:

[0391] Stability test chamber, model ICH-110L, Memert Corporation;

[0392] High performance liquid chromatograph (HPLC), model 1260, Agilent Technologies.

[0393] Analysis method:

[0394] Detection wavelengths: 220 nm, 254 nm

[0395] Column: Agilent ZORBAX SB-C8 4.6×250mm, 5μm

[0396] Mobile phase A: Water

[0397] Mobile phase B: Acetonitrile

[0398] Flow rate: 1.0 mL / min

[0399] Column temperature: 35℃

[0400] Injection volume: 10 μL

[0401] Experimental steps:

[0402] 1. Weigh the compound to be tested and place it in a stability chamber;

[0403] 2. Turn on the light source: visible light 5000±500 lx, ultraviolet light 250 μW / cm². 2 ;

[0404] 3. Samples were taken at 0h, 8h, 24h and 72h respectively, and dissolved in 50% acetonitrile aqueous solution;

[0405] 4. The content was determined by HPLC, and the content was analyzed using the area normalization method.

[0406] Experimental results:

[0407] The stability data of the disclosed compound and different batches of benvimod under light conditions are summarized below:

[0408] Table 2: Stability of the compounds disclosed herein under light conditions (batch 1)

[0409]

[0410] Table 3: Stability of other compounds disclosed herein under light conditions (batch 2)

[0411]

[0412] Among them, the compound in Comparative Example 1 was a compound synthesized by the inventor himself.

[0413] The above results indicate that the compounds of the present invention are more stable under light conditions: the compound content and / or the degree of change in content of the compounds of the present invention at 8, 24 and 72 h are significantly better than those of the compounds of Benvimod and / or Control Example 1, indicating that the photostability of the compounds of the present invention is significantly improved.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof: ， in, Ar is selected from unsubstituted groups, or optionally substituted by one, two or more Rs, such as phenyl or hexa-aryl groups; Each Rs may be the same or different, and is selected independently from halogens; The six-membered heteroaryl group is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thienyl, quinolinyl, or isoquinolinyl; R1 is selected from halogens.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 can be F, Cl, or Br.

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ar is selected from unsubstituted groups, or optionally substituted with one, two or more Rs, of the following groups: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl or thiophen-3-yl; Rs is as defined in claim 1; R1 is selected from F, Cl, Br.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ar is selected from 4-fluorophenyl, 2-fluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiophenyl, quinolinyl, isoquinolinyl, , , , or R1 is selected from F, Cl, and Br.

5. The compound of formula I as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by Formula I is selected from the following compounds: , , , , , , , and .

6. A compound represented by general formula I-1d or a salt thereof: in: R is C 1-6 alkyl; R1 is selected from halogens; Ar is as defined in claim 1; n is 1.

7. The compound of general formula I-1d as claimed in claim 6, or a salt thereof, wherein the compound is selected from the following compounds: , , , , , , , , , , , , , and .

8. A method for preparing a compound of formula I as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein, The steps include the following: When R1 is a halogen, the compound of formula I is prepared by the following method: The compound of Formula Id or its salt is reacted with pyridine hydrochloride by heating to give the compound of Formula I or its pharmaceutically acceptable salt; or, the compound of Formula Id or its salt is demethylated with boron tribromide and then quenched with water to give the compound of Formula I or its pharmaceutically acceptable salt.

9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of Formula I as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 9, wherein, The pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients.

11. The pharmaceutical composition of claim 9 or 10, wherein, The pharmaceutical composition is an aryl hydrocarbon receptor (AHR) modulator.

12. The pharmaceutical composition of claim 11, wherein, The pharmaceutical composition is used to relieve and / or treat the following diseases or conditions: cancer, eye-related diseases, autoimmune diseases, asthma, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, or transplant rejection.

13. The pharmaceutical composition of claim 12, wherein, The cancers mentioned are leukemia, prostate cancer, or colorectal cancer; the ophthalmological diseases mentioned are uveitis, age-related macular degeneration, or dry eye syndrome; the autoimmune diseases mentioned are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, or psoriasis.

14. Use of at least one of the compounds of Formula I as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of claims 9 to 10, in the preparation of an aryl hydrocarbon receptor (AHR) modulator.

15. The use as described in claim 14, wherein the aromatic receptor modulator is used to alleviate and / or treat the following diseases or conditions: uveitis, age-related macular degeneration, dry eye syndrome, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, psoriasis, type 2 diabetes, graft-versus-host disease, or transplant rejection.

16. Use of a pharmaceutical composition in the preparation of an aryl hydrocarbon receptor (AHR) modulator, said pharmaceutical composition comprising any of the following compounds or a pharmaceutically acceptable salt thereof: , , , , and ; The pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients.

17. The use as described in claim 16, wherein the aromatic receptor modulator is used to alleviate and / or treat the following diseases or conditions: uveitis, age-related macular degeneration, dry eye syndrome, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, psoriasis, type 2 diabetes, graft-versus-host disease, or transplant rejection.

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