Stilbene derivatives, processes for their preparation and uses thereof

Abstract

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

Description

Technical Field

[0001] This invention belongs to the field of inflammation or immune-related drug technology, specifically relating to a novel stilbene derivative, its preparation method, and pharmaceutical compositions containing the derivative, as well as their use as therapeutic agents, particularly as aryl hydrocarbon receptor (AHR) modulators. Background Technology

[0002] 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.

[0003] 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 upstream regulatory region 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 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.

[0004] 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.

[0005] 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 prone to degradation under light, limiting its application. Therefore, developing more stable AHR modulators is of great significance for expanding their clinical applications and reducing potential side effects. Summary of the Invention

[0006] To address the aforementioned problems of the prior art, the present invention provides compounds represented by Formula I, their stereoisomers, pharmaceutically acceptable salts, or prodrugs:

[0007]

[0008] Wherein, Ar is selected from unsubstituted groups, or optionally substituted by one, two or more Rs, of the following groups: C 6-20Aryl or 5-20 heteroaryl groups;

[0009] 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;

[0010] 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.

[0011] In one embodiment, Ar is selected from unsubstituted or optionally substituted C groups with one, two or more of the following groups. 6-14 Aryl or 5-14 heteroaryl: halogen or C 1-3 alkyl;

[0012] 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 Alkyl group.

[0013] In a preferred embodiment, Ar is selected from unsubstituted or optionally substituted groups of one, two or more Rs, including phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophene, for example, phenyl or pyridinyl groups substituted with one, two or more substituents selected from fluorine, chlorine or bromine, examples of which may be selected from 4-fluorophenyl, 2-fluorophenyl, ...

[0014] R1 is selected from F, Cl, Br, methyl, cyano, acetyl,

[0015] In one embodiment, R1 replaces the ortho position of the hydroxyl group on the benzene ring.

[0016] In one implementation, when Ar is a heteroaryl group, its 2-position is connected to an alkenyl group.

[0017] As an example, the compound represented by Formula I is selected from the following compounds:

[0018]

[0019]

[0020] According to embodiments of the present invention, the prodrug may be an ester formed by at least one hydroxyl group of a compound of Formula I and a pharmaceutically acceptable compound having at least one carboxyl group. As an example, the compound having at least one carboxyl 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, it may esterify 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.

[0021] The present invention also provides a method for preparing the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts, comprising the following steps:

[0022] 1) When R1 is a halogen, the compound of formula I is prepared by the following method:

[0023]

[0024] S5) Compound Id reacts with pyridine hydrochloride upon heating to give the compound shown in Formula I; or, compound Id is demethylated with boron tribromide followed by quenching with water to give the compound shown in Formula I.

[0025] 2) When R1 is methyl, the compound of formula I is prepared by the following method:

[0026]

[0027] The S5') compound Id' reacts with pyridine hydrochloride upon heating to give the compound shown in Formula I;

[0028] Ar and R1 are defined as described above.

[0029] In one embodiment, compound Id is prepared using the following method:

[0030]

[0031] 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;

[0032] S2) Compound Ia was added to a mixed solution of concentrated hydrochloric acid and n-hexane and heated to react and obtain compound Ib;

[0033] S3) Compound Ib reacts with triethyl phosphite upon heating to give compound Ic;

[0034] 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.).

[0035] compound Ar has the same definition as in Equation I above.

[0036] Optionally, the preparation method further includes the step of salting the compound represented by Formula I.

[0037] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0038] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers or excipients.

[0039] According to an embodiment of the present invention, the pharmaceutical composition is an aryl hydrocarbon receptor (AHR) modulator.

[0040] According to embodiments of the present invention, the aryl hydrocarbon receptor (AHR) modulator is used to alleviate and / or treat the following diseases or conditions: cancers, such as leukemia, prostate cancer, and colorectal cancer; ophthalmological diseases, such as uveitis, age-related macular degeneration, and dry eye; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; and other conditions or discomforts with immunological factors, such as asthma, allergies, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0041] The present invention also provides the use of compounds of Formula I, their stereoisomers, or pharmaceutically acceptable salts in the preparation of aromatic hydrocarbon receptor (AHR) modulators.

[0042] The present invention 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 a compound of Formula I, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition as described above.

[0043] According to embodiments of the present invention, the diseases or conditions mediated by the aryl hydrocarbon receptor (AHR) include: cancers such as leukemia, prostate cancer, and colorectal cancer; ophthalmological diseases such as uveitis, age-related macular degeneration, and dry eye; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, and psoriasis; and other conditions or discomforts with immunological factors such as asthma, allergic reactions, infections, osteoporosis, atherosclerosis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

[0044] Beneficial effects

[0045] This invention improves the structure of benvitimod, resulting in a compound with significantly enhanced photostability compared to the marketed drug benvitimod, thus mitigating the photostability and degradation issues associated with benvitimod under light. Furthermore, it significantly improves activity against AHR proteins.

[0046] Finally, the preparation method of the obtained compound is simple and can be carried out at the gram or kilogram level, showing better prospects in subsequent formulation development, safety and clinical application.

[0047] Terminology Definitions and Explanations

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] The "—*" symbol used in combination with a chemical bond in a substituent indicates a linking site.

[0053] The term "halogen" includes F, Cl, Br, or I.

[0054] 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. 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 their isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C..."). 1-3 Alkyl), such as methyl, ethyl, n-propyl or isopropyl.

[0055] Term "C" 6-20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms that is monovalent and partially aromatic, preferably "C". 6-14 "Aromatic". 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), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 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.

[0056] "5-20 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 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and in each case 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.

[0057] 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.

[0058] 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 the term "C". 1-12 Alkoxy group, -COC 1-12 Alkyl or halogenated C 1-12 Alkyl groups, etc.

[0059] 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

[0060] 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.

[0061] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0062] Example 1

[0063]

[0064] first step:

[0065] 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. Isopropanol (110 g, 1.835 mol) was added dropwise to the mixture, with the internal temperature controlled at 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 controlling the internal temperature at 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 compound 1b.

[0066] Step Two:

[0067] 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 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 obtain compound 1c.

[0068] Step 3:

[0069] 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 (petroleum ether:ethyl acetate = 3:1) to give compound 1d.

[0070] Step 4:

[0071] 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 compound 1e.

[0072] Step 5:

[0073] 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 crude compound 1f.

[0074] Step 6:

[0075] 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), 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 =10:1) Purification yielded 1g of compound.

[0076] Step 7:

[0077] 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 subjected to silica gel column chromatography (V) 石油醚：乙酸乙酯 Compound 1 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 289.05 [M+H] + .

[0078] 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).

[0079] Example 2

[0080]

[0081] 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 completed, the reaction solution was cooled to 80–90 °C and poured into dilute hydrochloric acid (prepared 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, allowed to stand and separate into layers, and the organic and aqueous phases were retained. Dilute hydrochloric acid (prepared by mixing 15.20 kg of water and 0.94 kg of concentrated hydrochloric acid) was added to the organic phase. The mixture was stirred for 15–20 min, allowed to stand and separate into layers, and the organic and aqueous phases were retained. The two aqueous phases were combined, and methyl tert-butyl ether (5.63 kg) was added. The mixture was stirred for 15–20 min, allowed to stand and separate into layers, and the organic phase was retained. Combine the two organic phases, add water (15.20 kg), stir for 15–20 min, and allow to stand for separation. After separating the organic phases, add activated carbon (0.038 kg), stir at room temperature for 1 h, filter, and concentrate the filtrate under reduced pressure at 40–50 °C.

[0082] Add 2.80 kg of methyl tert-butyl ether to the concentrated residue, heat to 35–45 °C and stir until dissolved. Add 10.40 kg of n-heptane dropwise, maintaining the temperature at 30–45 °C. After the addition is complete, maintain the temperature at 35–45 °C and continue stirring for 0.5 h. Cool to 0–10 °C, maintain the temperature and stir for 1 h, filter, and wash the filter cake with a pre-cooled mixed solvent (obtained by mixing 0.60 kg of methyl tert-butyl ether and 2.10 kg of n-heptane). Collect the filter cake and vacuum dry at 40–50 °C for 46 h to obtain compound 2b. Concentrate the filtrate, add 500 mL of methyl tert-butyl ether to the residue, and stir for 3 h. Filter, collect the filtrate, and concentrate the filtrate to obtain a brownish-black oil. Perform silica gel column chromatography (V) on the above oil. 石油醚：乙酸乙酯 Purified with a ratio of 40:1, and then subjected to silica gel column chromatography (V 石油醚：乙酸乙酯 The mixture was purified twice (90:1 to 70:1) to obtain a reddish-brown solid. A mixed solvent of n-heptane (10 mL) and petroleum ether (10 mL) was added to this solid, and the mixture was stirred for 1 hour and then filtered. The filter cake was further purified by preparative liquid chromatography (pre-HPLC) to obtain compound 2. MS (ESI, m / z): 267.14 [MH]-.

[0083] 1H 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=16Hz ,1H),6.49(s,1H),4.74(s,1H),4.68(s,1H),3.39(sept,J=7.1Hz,1H),2.13(s,3H),1.30(d,J=7.2Hz,6H).

[0084] Example 3

[0085]

[0086] first step:

[0087] Compound 1c (10.5 g, 50 mmol) was dissolved in acetonitrile (120 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (21.2 g, 60 mmol) was added in portions at 0 °C, followed by stirring 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), respectively. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 3a was obtained by purification at a ratio of 3:1.

[0088] Step Two:

[0089] Compound 3a (6 g, 26.3 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 compound 3b.

[0090] Step 3:

[0091] Compound 3b (5.6 g, 22.7 mmol) was added to triethyl phosphite (50 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 obtain compound 3c.

[0092] Step 4:

[0093] Compound 3c (2.1 g, 6 mmol), benzaldehyde (0.7 g, 6.6 mol), and potassium tert-butoxide (0.874 g, 7.8 mmol) were added to tetrahydrofuran (40 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), 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 =10:1) Purification yielded compound 3d.

[0094] Step 5:

[0095] Compound 3d (0.8 g, 2.7 mmol) and pyridine hydrochloride (2.5 g) were mixed 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 3 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 273.1 [M+H] + .

[0096] 1 H 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 F NMR (400MHz, CDCl3, ppm): δ-154.66 (1F).

[0097] Example 4

[0098]

[0099] first step:

[0100] 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 (petroleum ether:ethyl acetate = 10:1) to give compound 4a.

[0101] Step Two:

[0102] Compound 4a (17 g, 59 mmol) was added in portions to a mixture of concentrated hydrochloric acid (220 mL) and n-hexane (120 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 compound 4b.

[0103] Step 3:

[0104] Compound 4b (33.58 g, 109 mmol) was added to triethyl phosphite (167.75 g), and the mixture was heated to 160 °C and stirred for 5 h under nitrogen protection. After cooling to room temperature, the reaction mixture was concentrated. Hexane (70 mL) was added to the residue, and the mixture was stirred at 0 °C for 1 h and filtered. The filter cake was washed with cold hexane and dried overnight at room temperature to give compound 4c.

[0105] Step 4:

[0106] Compound 4c (12.24 g, 30 mmol), benzaldehyde (3.5 g, 33 mmol), and potassium tert-butoxide (4.4 g, 39 mmol) were added to tetrahydrofuran (150 mL), and the mixture was heated to 35 °C and stirred for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (150 mL) and dilute hydrochloric acid (150 mL, 1 M). The organic phase was separated, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 =10:1) Purification yielded compound 4d.

[0107] Step 5:

[0108] Compound 4d (1.08 g, 3 mmol) was dissolved in dichloromethane (20 mL), and boron tribromide (7.2 mL, 7.2 mmol, 1 M dichloromethane solution) was added dropwise at 0 °C under nitrogen protection. The reaction was then stirred at room temperature for 3 h. The reaction was quenched with water (50 mL), and the organic phase was separated and washed with water (50 mL) and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 4 was obtained after purification at a ratio of 5:1. LCMS (ESI, m / z): 333.08 [M+H] + .

[0109] 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).

[0110] Example 5

[0111]

[0112] first step:

[0113] Compound 3c (1 g, 3 mmol), p-fluorobenzaldehyde (409 mg, 3.3 mmol), and potassium tert-butoxide (437 mg, 3.9 mmol) were added to tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 5a was obtained by purification at a ratio of 10:1.

[0114] Step Two:

[0115] Compound 5a (730 mg, 2.3 mmol) and pyridine hydrochloride (2.5 g) were heated to 180 °C and stirred for 4 h under nitrogen protection. After cooling, the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) and saturated brine (50 mL), respectively. The organic phase was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 5 was obtained after purification at a ratio of 4:1. LCMS (ESI, m / z): 291.74 [M+H] + .

[0116] 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).

[0117] Example 6

[0118]

[0119] first step:

[0120] Compound 3c (800 mg, 2.6 mmol), o-fluorobenzaldehyde (400 mg, 3.2 mmol), and potassium tert-butoxide (400 mg, 3.6 mmol) were added to tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 6a was obtained by purification at a ratio of 10:1.

[0121] Step Two:

[0122] Compound 6a (500 mg, 1.6 mmol) and pyridine hydrochloride (5 g) were heated to 180 °C and stirred for 4 h under nitrogen protection. After cooling, the mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL) and saturated brine (50 mL), respectively. The organic phase was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 6 was obtained after purification at a ratio of 4:1. LCMS (ESI, m / z): 291.26 [M+H] + .

[0123] 1H 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); 19 F NMR (400MHz, DMSO-d6, ppm): δ-118.95(1F),-150.76(1F).

[0124] Example 7

[0125]

[0126] first step:

[0127] Compound 3c (1 g, 3 mmol), 3-fluoropyridine-2-carboxaldehyde (413 mg, 3.3 mmol), and potassium tert-butoxide (437 mg, 3.9 mmol) were added to tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 7a was obtained by purification at a ratio of 5:1.

[0128] Step Two:

[0129] 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 7 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 292.42 [M+H] + .

[0130] 1H 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).

[0131] Example 8

[0132]

[0133] first step:

[0134] Compound 3c (1 g, 3 mmol), 3-chloropyridin-2-carboxaldehyde (465 mg, 3.3 mmol), and potassium tert-butoxide (437 mg, 3.9 mmol) were added to tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 8a was obtained by purification at a ratio of 5:1.

[0135] Step Two:

[0136] Compound 8a (180 mg, 0.54 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (2.2 mL, 2.2 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 8 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 308.28 [M+H] + .

[0137] 1H 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).

[0138] Example 9

[0139]

[0140] first step:

[0141] Compound 3c (1 g, 3 mmol), 5-fluoropyridine-2-carboxaldehyde (413 mg, 3.3 mmol), and potassium tert-butoxide (437 mg, 3.9 mmol) were added to tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 9a was obtained by purification at a ratio of 5:1.

[0142] Step Two:

[0143] Compound 9a (180 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (2.3 mL, 2.3 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 9 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 292.34 [M+H] + .

[0144] 1H 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).

[0145] Example 10

[0146]

[0147] first step:

[0148] Compound 3c (800 mg, 2.6 mmol), 5-chloropyridin-2-carboxaldehyde (400 mg, 2.8 mmol), and potassium tert-butoxide (437 mg, 3.9 mmol) were added to tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 =5:1) Purification yielded compound 10a.

[0149] Step Two:

[0150] Compound 10a (80 mg, 0.24 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (2.3 mL, 2.3 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 subjected to silica gel column chromatography (V... 石油醚：乙酸乙酯 Compound 10 was obtained after purification at a ratio of 3:1. LCMS (ESI, m / z): 308.05 [M+H] + .

[0151] 1H 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 F NMR (400MHz, DMSO-d6, ppm): δ-150.19 (1F).

[0152] Test Example 1: Luciferase Reporter Gene Assay Experiment

[0153] This test case demonstrates a luciferase reporter gene assay to test the agonistic activity of the compound of the present invention on the AHR protein.

[0154] Test cells

[0155] HepG2-Lucia, a human liver cancer cell line expressing AHR and luciferase, was purchased from InvivoGen, catalog number hpgl-ahr;

[0156] Main instruments

[0157] Biosafety cabinet, model 307, ThermoFisher;

[0158] CO2 incubator, model CLM-240B-8-CN, ESCO;

[0159] Cell counter, model EVE-MC2, NanoEnTeK Corporation;

[0160] ECHO (Nano-Level Acoustic Plugging System), Model 655, LabCyte Corporation;

[0161] Microplate centrifuge, model PlatePro 3200, Monad Corporation;

[0162] Multifunctional microplate reader, model PHERAstar FSX, BMG LRBTECH.

[0163] Main reagents

[0164] Please provide streptomycin, Gibco, catalog number 15140-122;

[0165] EMEM culture medium, ATCC, catalog number 30-2003;

[0166] Fetal bovine serum, Ausgenex, catalog number FBS500-S;

[0167] NEAA medium, Gibco, catalog number 11140-050;

[0168] Phosphate buffer, Gibco, catalog number 14190250;

[0169] DMSO (dimethyl sulfoxide), Solarbio, product number D8371;

[0170] FICZ (6-formylindolo[3,2-B]carbazole), MCE Corporation, catalog number HY-12451;

[0171] Zeocin (bleomycin), InvivoGen, catalog number ant-zn-1;

[0172] QUANTI-Luc Gold, InvivoGen, product number rep-qlcg5.

[0173] Experimental steps

[0174] 1. HepG2-Lucia AHR cells were cultured in EMEM medium containing 10% inactivated fetal bovine serum, 1×NEAA, penicillin, streptomycin, and 100 μg / ml Zeocin (bleomycin). The culture temperature was 37℃, and the carbon dioxide concentration was 5%.

[0175] 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.

[0176] 3. Add different concentrations of the test compound using ECHO, 40 nL per well.

[0177] 4. Continue to incubate the 384-well plate containing the compound in an incubator for 24 hours.

[0178] 5. Take the supernatant, add QUANTI-Luc Gold detection reagent, and read the luminescence signal value using a multi-functional microplate reader.

[0179] Test results

[0180] The compound of this invention and the activity of benvitimil against AHR protein EC 50 The data is summarized in Table 1 below:

[0181] Table 1: Effects of compounds on AHR-activated EC 50

[0182]

[0183] The above results indicate that the compounds in the embodiments of the present invention have good activation activity against AHR protein, and at least compound 5 has significantly better activity than benvitide.

[0184] Test Example 2: Light Stability Experiment

[0185] This test case compares the stability of the compound of this invention and benvitimod under light conditions.

[0186] Main instruments

[0187] Stability test chamber, model ICH-110L, Memert Corporation;

[0188] High performance liquid chromatograph (HPLC), model 1260, Agilent Technologies.

[0189] Analytical methods

[0190] Detection wavelengths: 220 nm, 254 nm

[0191] Column: Agilent ZORBAX SB-C8 4.6×250mm, 5μm

[0192] Mobile phase A: Water

[0193] Mobile phase B: Acetonitrile

[0194] Flow rate: 1.0 mL / min

[0195] Column temperature: 35℃

[0196] Injection volume: 10 μL

[0197] Experimental steps

[0198] 1. Weigh the compound to be tested and place it in a stability chamber;

[0199] 2. Turn on the light source: visible light 5000±500 lx, ultraviolet light 250 μW / cm². 2 ;

[0200] 3. Samples were taken at 0h, 8h, 24h and 72h respectively, and dissolved in 50% acetonitrile aqueous solution;

[0201] 4. The content was determined by HPLC, and the content was analyzed using the area normalization method.

[0202] Test results

[0203] The stability data of the compounds of this invention and benvitimod under light conditions are summarized in Table 2 below:

[0204] Table 2: Stability of compounds under light conditions

[0205]

[0206] The above results indicate that the compounds of the present invention are stable under light conditions. Specifically, the concentrations of compound 3, as determined by HPLC at 8, 24, and 72 h, were significantly higher than those of benvimod, indicating that the photostability of the compounds of the present invention is significantly improved compared to benvimod.

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof, 。 2. A process for the preparation of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, comprising the following steps: S5) reacting compound Id with pyridine hydrochloride under heating to obtain a compound of the formula I; or, removing the methyl group of compound Id with boron tribromide and quenching the reaction with water to obtain a compound of the formula I; Ar and R1 are defined as in claim 1.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

5. The pharmaceutical composition according to claim 3 or 4, wherein, The pharmaceutical composition is an arenavirus receptor modulator.

6. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an arenavirus receptor modulator.

7. Use according to claim 6, wherein, The arenavirus receptor modulator is used for the alleviation and / or treatment of uveitis, age-related macular degeneration, dry eye, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, vitiligo, atopic dermatitis, psoriasis, type 2 diabetes, graft-versus-host disease, and transplant rejection.

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