CN108484491B

CN108484491B - Acrylate compound and application thereof

Info

Publication number: CN108484491B
Application number: CN201810481958.5A
Authority: CN
Inventors: 廖杰远; 陈先红; 邹德超; 孙志国; 王珂; 陈晓光; 谈敦潮; 杜立民; 季鸣
Original assignee: Beijing Micromedical Intelligence Information Technology Co ltd
Current assignee: Beijing Micromedical Intelligence Information Technology Co ltd
Priority date: 2018-05-18
Filing date: 2018-05-18
Publication date: 2020-09-29
Anticipated expiration: 2038-05-18
Also published as: WO2019218998A1; CN108484491A

Abstract

The invention relates to an acrylate compound shown in a formula I and application thereof in preparing a medicament for preventing or treating diseases or symptoms related to IL-17F.

Description

Acrylate compound and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an acrylate compound and application thereof.

Background

The interleukin 17 (IL-17) family includes 6 interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F) and their receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD, IL-17RE and IL-17RF) (Gaffen, S.L. et al, Immunology, 2009, (9): -. IF-17F is about 55% identical to IL-17A and is believed to share the same receptor as IL-17A (Kolls and Linden 2004, Immunity, 21, 467-. Both form homodimeric and heterodimeric proteins, both produced by activated human CD4+ T cells (Wright et al, J Biol chem.2007, 282(18), 13447-13455).

The prior art has shown that: IL-17F may be associated with the development of a variety of diseases, including diseases mediated by aberrant immune responses, such as rheumatoid arthritis and respiratory inflammation, as well as organ transplant rejection and tumors or cancers; accordingly, inhibitors of IL-17F are likely to be promising therapeutics for these diseases (Huichao Yan et al, Immuno-Gastroenterology, 2012, 1: 100-. The prior art has shown that IL-17F is associated with autoimmune diseases (Iwakura, Y., H. Ishigame et al, Immunity, 2011, 34 (2): 149-. IL-17F antagonism is associated with protection against asthma (Kawaguchi et al, 2006, J.allergy Clin.Immunol.117 (4); 795-.

Some IL-17F inhibitors have been reported in the prior art, for example, some WO2014065413 reports triazole derivatives and isoxazole derivatives as RORs_γReceptor inhibitor, so as to inhibit the differentiation and activation of Th17 cell and inhibit IL-17. WO201400944 and WO2016014918 report on aryl sultam derivatives and benzimidazole derivatives as RORc modulators, such compounds being mainly used for the treatment of autoimmune diseases.

WO2016213676 reports substituted 2, 3-dihydro-1H-inden-1-ones as ROR_γt/ROR_γReceptor antagonists, useful for modulating ROR_γt/ROR_γActivity and use for treating ROR_γt/ROR_γMediated diseases and conditions. WO2016072402 reports on the receptor ROR of TH17 cells by cyclic amine derivatives_γtHas inhibitory effect on TH17 cell differentiation and IL-17 secretion. WO2016120849 reports methoxy-substituted pyrrolopyridines for ROR_γReceptor inhibitor, thereby reducing the amount of I L-17. However, the inhibitory effects of these compounds are still not satisfactory or there is a problem in selectivity, and therefore, there is still an urgent need in the art to develop novel I L-17 inhibitors, particularly IL-17F inhibitors, for the prevention and/or treatment of related diseases.

Disclosure of Invention

The inventor unexpectedly finds that the compound shown in the formula I or the pharmaceutically acceptable salt thereof has unexpected IL-17F inhibition effect through research:

wherein Q is selected from O and N; x, Y, Z are each independently selected from C, O, S and N;

R₁and R₂The same or different, are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted acyl; or, R₁And R₂Oxygen adjacent thereto forms an acetal;

R₃selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted acyl;

R₄selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl;

R₅selected from hydrogen, halogen, cyano, nitro, unsubstituted or substituted hydroxy, unsubstituted or substituted alkyl.

In some preferred embodiments, at least one of X, Y, Z is N, but not both.

In some preferred embodiments, Q is selected from O, R₃And R₄The oxygen adjacent to it forms a lactone.

In some preferred embodiments, R₁And R₂The oxygen adjacent to it forms an acetal.

In some preferred embodiments, R₁And R₂The same is true.

In some preferred embodiments, R₁And R₂Independently selected from hydrogen, C1-C3 alkyl and C1-C5 alkylacyl.

In some preferred embodiments, R₁And R₂The oxygen adjacent to it forms an acetal of the formula:

wherein R is₆、R₇Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, and phenyl C2-C5 alkenyl.

In some preferred embodiments, R₆、R₇The adjacent C forms a 3-6 membered ring.

In some preferred embodiments, R₅Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, chloro, bromo and iodo.

In some preferred embodiments, X, Y, Z is C or N.

In some particularly preferred embodiments, the compounds of formula I of the present invention are specific compounds selected from the group consisting of:

accordingly, in a first aspect, the present invention provides a compound of formula I as described above, or a pharmaceutically acceptable salt thereof. For example, when QR4 is hydroxy, the salt may be a salt of a compound of formula I with an alkali metal, alkaline earth metal, transition metal or amine; when X, Y or Z has an N atom, the salt may be a salt of a compound of formula I with an organic or inorganic acid.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention also provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, of the invention in the manufacture of a medicament for inhibiting the secretion and activity of IL-17F.

The present inventors have surprisingly found that the compounds of formula I and pharmaceutically acceptable salts thereof have the effect of inhibiting the secretion of interleukin 17F and are therefore capable of acting as modulators of interleukin 17F.

The application also proves that the compound shown in the formula I and the pharmaceutically acceptable salt thereof also have the effects of preventing and treating tumors, so that the compound can be applied as a medicine for preventing and treating tumors. In particular, the tumors include solid tumors and non-solid tumors, including but not limited to melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, stomach cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple myeloma, lymphoid cancer, leukemia, bladder cancer, prostate cancer, cholangiocarcinoma, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, head and neck cancer, gallbladder cancer, kidney cancer, and the like. Particularly preferably, the tumor is colorectal cancer, gastric cancer, bladder cancer and breast cancer.

On the other hand, the compound of formula I or the pharmaceutically acceptable salt thereof has the effect of preventing and treating autoimmune diseases, and therefore, can be used as a medicine for preventing and treating autoimmune diseases. In particular, the autoimmune diseases include, but are not limited to, lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like. Particularly preferably, the autoimmune disease is selected from lupus erythematosus and psoriasis.

In the present invention, pharmaceutically acceptable salts of the compounds of formula I are meant to be suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical sciences,1977,66,1-19, by s.m. berge et al, which is incorporated herein by reference. Salts of the compounds of the present invention include those derived from suitable inorganic and organic bases. Inorganic base salts include salts with ammonia, alkali metals, alkaline earth metals, or transition metals, such as ammonium salts, as well as lithium, sodium, potassium, calcium, zinc, iron, ferrous salts, and the like. Salts of organic bases include amine salts, including salts of compounds of formula I with primary, secondary or tertiary amines, and may be selected from salts with the following organic bases: such as arginine, ethylenediamine, triethylamine, caffeine, betaine, ethanolamine, trimethylamine, piperidine, and the like.

Detailed Description

In the present invention, the compounds of formula I are as follows:

in some preferred embodiments, Q is selected from O. In some preferred embodiments, X, Y, Z are selected from C or N.

In some preferred embodiments, R₁And R₂The same; particularly preferably, R₁And R₂Independently selected from hydrogen, C1-C3 alkyl or C1-C5 alkylacyl.

wherein R is₆、R₇Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, phenyl C2-C5 alkenyl; or, R₆、R₇The adjacent C forms a 3-6 membered ring.

In some preferred embodiments, R₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl.

In some preferred embodiments, R₄Selected from hydrogen, methyl, ethyl, propyl, isopropyl.

In some preferred embodiments, R₃And R₄The oxygen adjacent to it forms a lactone.

In some preferred embodiments, R₅Selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine and iodine.

In a preferred embodiment, there are provided compounds of formula I below:

wherein at least one of X, Y, Z is N, but not N at the same time; r₁Or R₂Is the same, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C1-C5 alkylacyl; r₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl; r₄Selected from hydrogen, methyl, ethyl, propyl, isopropyl; r₅Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, nitro, fluoro, chloro, bromo, and iodo. In the compounds of the formula I in the abovementioned cases, R₁And R₂Acetal is not formed and R₃And R₄Nor lactone is formed.

Typical compounds described above are shown in table 1.

TABLE 1

In some particular aspects, the compounds of formula I of the present invention have the following structure of formula I-2:

wherein R is₁And R₂May be the same, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or C1-C5 alkanoyl;

R₅selected from hydrogen, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine and iodine.

That is, in the compound of formula I in the above case, R₃And R₄A lactone is formed.

Typical compounds of formula I-2 are shown in Table 2.

TABLE 2

In some particular aspects, the compounds of formula I have the following structure of formula I-3:

wherein R is₆、R₇Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, substituted or unsubstituted phenyl, phenyl C2-C5 alkenyl;

R₃selected from hydrogen, methyl, ethyl, propyl, isopropyl;

R₄selected from hydrogen, methyl, ethyl, propyl, isopropyl.

R₅Selected from hydrogen, methyl, ethyl, propyl, isopropyl.

That is, in the compound of formula I in the above case, R₁And R₂An acetal is formed.

Typical compounds of formula I-3 are shown in Table 3.

TABLE 3

In some particular aspects, the compounds of formula I have the following structure of formula I-4:

wherein R is₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl;

R₄selected from hydrogen, methyl, ethyl, propyl, isopropyl;

R₅selected from hydrogen, methyl, ethyl, propyl, isopropyl;

n is selected from 1,2, 3 and 4.

That is, in the compound of formula I in the above case, R₁And R₂Forming an acetal, and the substituents thereon form a 3-6 membered ring.

Typical compounds of formula I-4 are shown in Table 4.

TABLE 4

In some particular aspects, the compounds of formula I have the following structure of formula I-5:

R₅selected from hydrogen, methyl, ethyl, propyl, isopropyl.

That is, in the compound of formula I in the above case, R₁And R₂Form an acetal, and R₃And R₄A lactone is formed.

Typical compounds of formula I-5 are shown in Table 5.

TABLE 5

In some particular aspects, the compounds of formula I have the following structure of formula I-6:

wherein R is₅Selected from hydrogen, methyl, ethyl, propyl, isopropyl;

n is selected from 1,2, 3 or 4.

That is, in the compound of formula I in the above case, R₁And R₂Forming an acetal, wherein the substituents thereon form a 3-6 membered ring, and R is₃And R₄A lactone is formed.

Typical compounds of formula I-6 are shown in Table 6.

TABLE 6

In the present invention, the compounds of formula I can be prepared according to the following method:

firstly, the initial raw material D- (-) -quinic acid is formed into lactone in the presence of a catalyst, meanwhile, protecting groups are introduced at the 3,4 positions to obtain an intermediate 1, the intermediate 1 and the intermediate 2 are subjected to esterification reaction to obtain an intermediate 3, the intermediate 3 is subjected to ester hydrolysis under the alkaline condition to obtain an intermediate 4, and the intermediate 4 is further subjected to deprotection under the acidic condition to obtain the compound shown in the formula I.

The reaction process is as follows:

wherein:

`R₁、`R₂、`R₃、`R₄、`R₅are each as defined for R in formula I₁、R₂、R₃、R₄、R_5、The same definition, the other variables X,Y, Z are as defined in formula I; l is halogen or hydroxyl selected from fluorine, chlorine, bromine and iodine.

In the synthetic route of the present invention, in preparing intermediate 3, there are generally two methods for forming an ester: when the intermediate 2 is a carboxylic acid, an ester may be formed in the presence of a conventional condensing agent (e.g., N' -Dicyclohexylcarbodiimide (DCC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), etc.); when intermediate 2 is the corresponding acid halide, it can be directly esterified under basic conditions (e.g., pyridine, triethylamine, N-diisopropylethylamine, 1, 8-diazacyclo [5,4,0] undecene-7, etc.).

In the synthesis method, the alkali used for ester hydrolysis of the intermediate 3 can be lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; the acid used for deprotection of the intermediate 4 may be aqueous hydrochloric acid, aqueous sulfuric acid, aqueous trifluoroacetic acid, or the like.

In the present invention, the term "alkyl" denotes a saturated straight-chain or branched-chain hydrocarbon group of 1 to 12 carbon atoms, preferably a saturated straight-chain or branched-chain hydrocarbon group of 1 to 6 carbon atoms, more preferably a saturated straight-chain or branched-chain hydrocarbon group of 1 to 5 carbon atoms, particularly preferably a saturated straight-chain or branched-chain hydrocarbon group of 1 to 4 carbon atoms, and particularly preferably methyl, ethyl, propyl, isopropyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, heptyl, octyl.

In the present invention, the term "alkenyl" denotes a monovalent group derived from a hydrocarbon moiety by removal of a single hydrogen atom, wherein the hydrocarbon moiety has at least one carbon-carbon double bond and contains 2 to 12 carbon atoms, respectively. Preferred alkenyl groups are C2-C6 alkenyl groups, more preferably C2-C5 alkenyl groups. Representative alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and the like.

In the present invention, the term "cycloalkyl" denotes a saturated carbocyclic compound having 3 to 12 ring atoms, preferably a cycloalkyl having 3 to 6 carbon atoms, more preferably a cycloalkyl having 3 to 5 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

In the present invention, the term "acyl" includes residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyl groups, aromatic carbonyl groups, and aliphatic sulfonic acid groups. Examples of aliphatic carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, and the like. Preferred acyl groups for use herein are alkylacyl groups, especially C1-C6 alkylacyl groups.

In the present invention, the term "halogen" means fluorine, chlorine, bromine, iodine.

In the present invention, the term "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system having 1 to 3 aromatic rings, preferably an aryl group having 6 to 14 carbon atoms, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, anthryl and the like.

In the present invention, the term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecule through an alkyl group, as defined herein. Examples include, but are not limited to, benzyl, phenethyl, and the like.

In the present invention, the term "substituted" means that one, two or three or more hydrogen atoms are independently substituted with substituents including, but not limited to, halogen, -OH, protected hydroxy, -NO₂、-CN、-NH₂Protected amino, alkoxy, and the like. Preferred substituents include halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, -NO₂And an acetyl group.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable adjuvant (excipient or diluent).

The term "pharmaceutical composition" is meant to encompass any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, e.w. maetin (Mack Publishing co., Easton, Pa.,1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces no biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention. Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer substances, for example: a phosphate salt; glycine; sorbic acid or potassium sorbate; a mixture of partial glyceride esters of saturated vegetable fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pyrogen-free water; isotonic saline; ethanol; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

The invention also provides a pharmaceutical preparation, which comprises the compound shown in the formula I or the pharmaceutically acceptable salt thereof and optionally pharmaceutically acceptable excipient or diluent, and the compound or the salt thereof can be prepared into conventional pharmaceutical preparations according to conventional preparation methods, such as capsules, tablets, pills, granules, emulsions, suspensions, injections, drops and the like.

The inventor finds that the compound shown in the formula I and the pharmaceutically acceptable salt thereof have the effect of inhibiting the secretion of interleukin 17, especially interleukin 17F, and can prevent and treat tumors. The experimental result shows that the inhibition rate of some compounds in the compound of the formula I to interleukin 17F is close to 70% when the concentration is 0.5 mu M/L; has better inhibiting effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors under the dosage of 20mg/kg, and all the inhibiting effect exceeds 50 percent.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: preparation of Compound 1-1

Step A:

d- (-) -quinic acid (40.0g, 0.208mol,; p-toluenesulfonic acid monohydrate (0.8g, 4.16mmol), acetone (200.0ml), 2-dimethoxypropane (75.8g, 0.728mol) were put into a reaction flask, heated and refluxed for 4h, the reaction system started to be a solid-liquid mixed phase, and with the reaction going on, all dissolved, the reaction was completed, 40 ℃, concentrated under reduced pressure to dryness, and ethyl acetate (300.0ml) and 5% NaHCO were added to the remainder₃The aqueous solution (300.0ml) was stirred, the layers were separated, the aqueous phase was extracted with ethyl acetate (100.0ml), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and spin-dried to give a pale yellow solid. Recrystallization from ethyl acetate/petroleum ether system gave 36.2g of off-white solid 3, 4-oxo-isopropylidene quinic acid-1, 5-lactone (intermediate 1-1a), yield: 81.2 percent. mp: 131-133 ℃;

and B:

(E) -3 (3-pyridyl) enepropionic acid (20g, 0.134mol) was added to a reaction flask, methylene chloride (200.0ml) was added thereto so that the solid was not completely dissolved, thionyl chloride (40.0ml) was added thereto, and the mixture was refluxed for reaction for 3 hours. The raw materials are reacted completely, and the reaction system is directly decompressed and rotary distilled to obtain the white-like solid (E) -3- (3-pyridyl) acryloyl chloride hydrochloride (intermediate 1-1b) which is directly used for the next reaction.

And C:

adding the intermediate 1-1a (23.6g, 0.11mol), anhydrous dichloromethane (240.0ml), N, N-diisopropylethylamine (56.9g, 0.44mol) and 4-dimethylaminopyridine (4.0g, 0.033mol) into a reaction bottle in sequence, cooling the system to 0 ℃ by using an ice bath, dropwise adding a solution of (E) -3- (3-pyridyl) acryloyl chloride hydrochloride (intermediate 1-1b) (27.3g, 0.134mol) in N, N-dimethylacetamide (110.0ml), and heating the system to 25 ℃ for reaction for 1h to complete the reaction of the raw materials. Adding water into the system, separating liquid, extracting the water phase twice by using dichloromethane, combining organic phases, washing by using water and 1N HCl respectively, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, performing suction filtration, decompressing and rotary evaporating filtrate to remove the solvent to obtain a light yellow oily substance. Crystallization from dichloromethane/petroleum ether and filtration gave 31.5g (intermediate 1-1c) as a pale yellow solid, yield: 82.8 percent. MS (ESI)⁺)：m/z＝345.2

Step D:

intermediate 1-1c (4.0g, 11.58mmol) was added to a reaction flask, followed by tetrahydrofuran (80.0ml) and H₂Cooling to 0 deg.C with ice bath, adding 1mol/L LiOH aqueous solution (17.4ml, 17.4mmol), stirring at room temperature for 1h, reacting for 1h, adjusting pH to about 6 with 0.5N citric acid aqueous solution, concentrating under reduced pressure, extracting the obtained solid with tetrahydrofuran (60.0ml × 3), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, rotary evaporating the filtrate to obtain 2.41g solid (intermediate 1-1d), and obtaining yield 57.3% MS (ESI)⁺)：m/z＝363.1

Step E:

intermediate 1-1d (1.0g, 2.75 mmol)) Adding the mixture into a reaction bottle, adding dichloromethane (20.0ml) for dissolving, adding water (1.0ml), cooling the system to 0 ℃ by using an ice bath, dropwise adding trifluoroacetic acid (2.0ml), after the dropwise adding is finished, heating the system to 25 ℃ for reacting for 0.5h, completely reacting the raw materials, directly concentrating the system under reduced pressure to obtain 0.77g of off-white solid (compound 1-1), wherein the yield is as follows: 86.5 percent. MS (ESI)⁺)：m/z＝323.3。

Example 2: preparation of Compounds 1-5

Step E:

add intermediate 1-1c (10.0g, 28.96mmol), DCM (100.0mL) to a three-necked flask in sequence, stir to dissolve, add H₂O (10.0ml), cooling the system to 0 ℃ by using an ice bath, slowly dropwise adding trifluoroacetic acid (20.0ml), after dropwise adding, heating the system to 25 ℃ for reacting for 0.5h, completely reacting the raw materials, and concentrating the reaction system at room temperature by using an oil pump under reduced pressure to obtain 7.2g of white foam-like solid 1-5e, wherein the yield is as follows: 81.5 percent. MS (ESI)⁺)：m/z＝305.1。

Step F:

under the protection of nitrogen, adding the intermediate 1-5e (5.0g, 16.38mmol) into a reaction bottle, adding anhydrous DMF (50.0ml) for dissolving, cooling the system to 0 ℃, adding sodium hydride (1.64g, 40.95mmol, 60% mineral oil) in batches, stirring for 30min, slowly dropwise adding a DMF solution (10.0ml) containing bromoethane (3.9g, 35.79mmol), and naturally raising the temperature to room temperature for reaction for 2 h. Adding a saturated ammonium chloride aqueous solution into a reaction system, extracting with ethyl acetate for three times, combining organic phases, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, performing suction filtration, performing rotary evaporation under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain 1.3g of the title compound 1-5f, wherein the yield is as follows: 22.0 percent. MS (ESI)⁺)：m/z＝361.2。

Step G:

intermediate 1-5f (1.0g, 2.77mmol) was added to a reaction flask, methanol (10.0ml) was added, and the solution was stirred at room temperature. Sodium methoxide (0.18g, 3.33mmol) was added to the reaction system, and the reaction was stirred at room temperature for 1 h. The raw materials are reacted completely. Adding into a reaction systemSaturated aqueous ammonium chloride (10.0ml), concentrated under reduced pressure, the residue was extracted three times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, rotary evaporated under reduced pressure to give a crude product, which was purified by column chromatography to give 0.35g of the title compound 1-5, yield: 32.1 percent. MS (ESI)⁺)：m/z＝393.3。

Example 3: preparation of Compounds 1-8

And B:

(E) -3- (6-methyl-3-pyridyl) enepropionic acid (15g, 0.092mol) was charged into a reaction flask, methylene chloride (150.0ml) was added thereto so that the solid was not completely dissolved, and thionyl chloride (30.0ml) was added thereto and the mixture was heated under reflux for 3 hours. The raw materials are reacted completely, and the reaction system is directly decompressed and steamed to obtain the white-like solid (E) -3- (6-methyl-3-pyridyl) acryloyl chloride hydrochloride (the intermediate 1-8b) which is directly used for the next reaction.

And C:

adding the intermediate 1-1a (16.5g, 0.077mol), anhydrous dichloromethane (170.0ml), N, N-diisopropylethylamine (39.8g, 0.308mol) and 4-dimethylaminopyridine (2.8g, 0.023mol) into a reaction bottle in sequence, cooling the system to 0 ℃ by using an ice bath, dropwise adding a solution of (E) -3- (6-methyl-3-pyridyl) acryloyl chloride hydrochloride (intermediate 1-8b) (20.1g, 0.092mol) in N, N-dimethylacetamide (80.0ml), dropwise adding, heating the system to 25 ℃ for reaction for 1h, and completely reacting the raw materials. Adding water into the system, separating liquid, extracting the water phase twice by using dichloromethane, combining organic phases, washing by using water and 1N HCl respectively, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, performing suction filtration, decompressing and rotary evaporating filtrate to remove the solvent to obtain a light yellow oily substance. Crystallization from dichloromethane/petroleum ether and filtration gave 21.80g (intermediates 1-8c) of a pale yellow solid, yield: 78.8 percent. MS (ESI)⁺)：m/z＝359.2

Step D:

to a reaction flask, intermediate 1-8c (10.0g, 0.028mol) was added, and tetrahydrofuran (200.0ml), H, and₂o (50.0ml), and the solution was dissolved by stirring at room temperature. BodyCooling to 0 ℃ with ice bath, dropping 1mol/L LiOH aqueous solution (42.0ml, 0.042mol), stirring at room temperature for 1h, reacting completely, adjusting pH to about 6 with 0.5N citric acid aqueous solution, concentrating under reduced pressure to dryness, extracting with tetrahydrofuran (80.0ml × 3), mixing organic phases, drying with anhydrous sodium sulfate, filtering, rotary evaporating filtrate to obtain 6.48g solid (intermediate 1-8d), and recovering yield 61.7% MS (ESI)⁺)：m/z＝377.1

Step E:

adding the intermediate 1-8d (1.0g, 2.65mmol) into a reaction bottle, adding dichloromethane (20.0ml) for dissolving, adding water (1.0ml), cooling the system to 0 ℃ by using an ice bath, dropwise adding trifluoroacetic acid (2.0ml), after dropwise adding, heating the system to 25 ℃ for reacting for 0.5h, completely reacting the raw materials, and directly concentrating the system under reduced pressure to obtain 0.69g of off-white solid (compound 1-8), wherein the yield is as follows: 77.2 percent. MS (ESI)⁺)：m/z＝337.3。

Example 4: preparation of Compounds 1-9

Prepared according to the operating conditions described for the process of example 1, intermediate 1-9b is obtained by first substituting (E) -3- (2-chloro-3-pyridyl) allylic acid for (E) -3- (3-pyridyl) enepropionic acid to the acid chloride, then esterification of intermediate 1-9b with 1-1a under basic conditions, followed by hydrolysis and deprotection to give the title compounds 1-9. MS (ESI)⁺)：m/z＝357.0。

Example 5: preparation of Compounds 1-10

Prepared according to the operating conditions described for the process of example 1, first by substituting (E) -3- (5-nitro-3-pyridyl) allylic acid for (E) -3- (3-pyridyl) enepropionic acid to the acid chloride to give intermediates 1-10b, then by esterification of intermediates 1-10b with 1-1a under basic conditions, followed by hydrolysis and deprotection to give the title compounds 1-10. MS (ESI)⁺)：m/z＝368.1。

Example 6: preparation of Compounds 1-11

Prepared according to the operating conditions described for the process of example 1, intermediate 1-11b was obtained by first substituting (E) -3- (2-pyridyl) acrylic acid for (E) -3- (3-pyridyl) enepropionic acid to the acid chloride, and then intermediate 1-11b was esterified with 1-1a under basic conditions, followed by hydrolysis and deprotection to give the title compounds 1-11.

MS(ESI⁺)：m/z＝323.1。

Example 7: preparation of Compounds 1-14

And B:

(2E) -3- (2-pyrimidinyl) acrylic acid (18.0g, 0.12mol) was added to a reaction flask, methylene chloride (200.0ml) was added, the solid was not completely dissolved, thionyl chloride (40.0ml) was added, and the reaction was refluxed for 3 hours. The raw materials are reacted completely, and the reaction system is directly decompressed and rotary distilled to obtain the off-white solid (2E) -3- (2-pyrimidinyl) acryloyl chloride hydrochloride (the intermediate 1-14b) which is directly used for the next reaction.

And C:

adding the intermediate 1-1a (21.4g, 0.1mol), anhydrous dichloromethane (220.0ml), N, N-diisopropylethylamine (51.7g, 0.4mol) and 4-dimethylaminopyridine (3.7g, 0.03mol) into a reaction bottle in sequence, cooling the system to 0 ℃ by using an ice bath, dropwise adding a solution of (2E) -3- (2-pyrimidinyl) acryloyl chloride hydrochloride (intermediate 1-14b) (24.6g, 0.12mol) in N, N-dimethylacetamide (100.0ml), and heating the system to 25 ℃ for reaction for 1h to complete the reaction of the raw materials. Adding water into the system, separating liquid, extracting the water phase twice by using dichloromethane, combining organic phases, washing by using water and 1N HCl respectively, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, performing suction filtration, decompressing and rotary evaporating filtrate to remove the solvent to obtain a light yellow oily substance. Crystallizing with dichloromethane/petroleum ether, filtering to obtain light yellow solidBody 24.2g (intermediates 1-14c), yield: 69.9 percent. MS (ESI)⁺)：m/z＝346.2

Step E:

to a three-necked flask were added intermediates 1-14c (10.0g, 28.87mmol), DCM (100.0ml) in order, followed by H₂O (10.0ml), trifluoroacetic acid (20.0ml) was slowly added dropwise to the ice-water bath, and after completion of the addition, the mixture was stirred at room temperature for 0.5h, and the reaction was monitored by sampling TLC for completion. The reaction system was concentrated under reduced pressure at room temperature using a vacuum oil pump to obtain 6.6g of a pale yellow foamy solid 1-14e, yield: 74.6 percent. MS (ESI)⁺)：m/z＝306.0。

Step F:

under the protection of nitrogen, adding the intermediates 1-14e (6.0g, 19.59mmol) into a reaction bottle, adding anhydrous DMF (60.0ml) to dissolve, cooling the system to 0 ℃, adding sodium hydride (2.0g, 48.98mmol, 60% mineral oil) in batches, stirring for 30min, slowly dropwise adding methyl iodide (6.2g, 43.68mmol), and naturally heating to room temperature for reaction for 1 h. Adding 2N ammonium chloride aqueous solution into a reaction system, extracting with ethyl acetate for three times, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, performing suction filtration, performing rotary evaporation on filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain 2.4g of the title compounds 1-14f, wherein the yield is as follows: 36.6 percent. MS (ESI)⁺)：m/z＝334.2。

Step G:

intermediate 1-14f (1.5g, 4.49mmol) was added to the reaction flask, methanol (15.0ml) was added, and the solution was stirred at room temperature. Sodium methoxide (0.3g, 5.55mmol) was added to the reaction system, and the reaction was stirred at room temperature for 0.5 h. The raw materials are reacted completely. To the reaction system was added a saturated aqueous ammonium chloride solution (15.0ml), concentrated under reduced pressure, the residue was extracted three times with ethyl acetate, the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered under suction, rotary-evaporated under reduced pressure to give a crude product, which was purified by column chromatography to give 0.57g of the title compounds 1 to 14, yield: 34.7 percent. MS (ESI)⁺)：m/z＝366.3。

Example 8: preparation of Compound 2-1

Compounds 1-5e, compound 2-1, prepared in example 2.

Example 9: preparation of Compounds 2-3

Step F:

compound 2-3 was prepared according to the procedure described for step F, example 2. MS (ESI)⁺)：m/z＝485.3。

Example 10: preparation of Compound 3-1 Compound 1-1d prepared in example 1 was Compound 3-1.

Example 11: preparation of Compounds 3-4

Step A:

d- (-) -quinic acid (20.0g, 0.10mol), toluene (120ml), methyl isobutyl ketone (100.0ml) and p-toluenesulfonic acid monohydrate (2.0g, 0.01mol) are sequentially added into a 500ml single-mouth bottle, after the addition is finished, the temperature is raised to reflux, a water separator is erected, the system is yellow turbid liquid, water is divided for 2 hours after the reflux, and the reflux reaction is continued for 2 hours. The system became clear, a small amount of yellow insoluble was stuck to the wall of the flask and the reaction was monitored by TLC to be complete. Concentrating under reduced pressure at 50 deg.C, adding H into the residue₂O (80.0ml), saturated NaHCO₃Adjusting the pH value to 7-8, extracting the water phase with dichloromethane (100.0ml × 2), combining the organic phases, washing with bromine (100.0ml), and removing anhydrous Na₂SO₄Drying, filtration and concentration gave 23.70g of a yellow solid. Recrystallizing with ethyl acetate \ petroleum ether system, crystallizing overnight, crystallizing at 0 deg.C for 2h, vacuum filtering, and vacuum drying the filter cake to obtain 13.71g white crystal, i.e. intermediate 3-4 a. Yield: 53.92 percent. MS (ESI)⁺)：m/z＝254.1。

And C:

the procedure is as in step C of example 1, wherein 1-1a is replaced by 3-4 a.

Step D:

the procedure is as in step D of example 1, replacing 1-1c with 3-4 c. MS (ESI)⁺)：m/z＝403.2。

Example 12: preparation of Compounds 4-8

Step A: the procedure is as in step A of example 11, wherein methyl isobutyl ketone is replaced by cyclohexanone.

And C: following the procedure of step C of example 1, wherein esterification was carried out using 1-14b instead of 1-1b, intermediates 4-8C were obtained.

Step D: the procedure is as in step D of example 1, replacing 1-1c with 4-8 c. MS (ESI)⁺)：m/z＝404.1。

Example 13: preparation of Compound 5-1

Compound 1-1c, Compound 5-1, prepared in example 1.

Example 14: preparation of Compound 6-3

And C: the procedure of step C in example 1 was followed, wherein intermediates 1-1a were replaced with 4-8 a. MS (ESI)⁺)：m/z＝385.4。

EXAMPLE 15 biological Activity assays of Compounds provided by the invention

1. In vitro activity studies: the effect of 24h action of the compound shown in the formula I on IL17F secretion of U87-Luc cells is detected by an ELISA method by using an interleukin 17F (IL17F) detection kit.

The operation steps are as follows:

(1) and sample adding: blank wells (blank control wells are identical to the standard wells and the sample wells to be detected except for no sample and enzyme labeled reagent), standard wells, and sample wells to be detected. And accurately adding the standard sample on the enzyme-labeled coating plate, adding a sample diluent in the sample hole to be detected, and then adding the sample to be detected. And adding the sample to the bottom of the hole of the enzyme label plate during sample adding, slightly shaking and mixing the sample and the hole wall to the greatest extent.

(2) And incubation: the plates were sealed with a sealing plate and incubated at 37 ℃ for 30 minutes.

(3) And liquid preparation: and diluting the 30 times of concentrated washing liquid by 30 times of distilled water for later use.

(4) And washing: carefully uncovering the sealing plate membrane, discarding liquid, spin-drying, filling washing liquid in each hole, standing for 30 seconds, then discarding, and lightly tapping the enzyme labeling plate on absorbent paper to remove all liquid in the holes. Repeating the above steps for 5 times, sucking or pouring out the residual washing buffer solution after the last washing, reversely buckling the enzyme label plate on the water absorption paper, and sucking all the liquid remained in the holes.

(5) And adding enzyme: enzyme labeling reagent is added into each hole except for blank holes.

(6) And color development: adding the color developing agent A and the color developing agent B into each hole, shaking gently, mixing uniformly, and developing for 10 minutes in a dark place at 37 ℃.

(7) And terminating: stop solution was added to each well to stop the reaction (blue color turned immediately yellow).

(8) And (3) measuring: the blank wells were zeroed and the absorbance (OD value) of each well was measured sequentially at a wavelength of 450 nm. The measurement should be performed within 15 minutes after the addition of the stop solution.

The calculation method comprises the following steps:

GI (growth inhibition rate) ═ 1-OD_{Drug group}/OD_{Control group}) × 100%, the results are shown in table 7, table 7 is the results of in vitro activity tests for the compounds provided by the present invention.

TABLE 7 in vitro Activity test results for Compounds of the invention

2. In vivo efficacy studies:

2.1 in vivo model of mouse melanoma

Sterile mixing of 1 × 10⁷A B16-F10 cell was inoculated to the axilla of C57BL/6 mice10 days later, tumor tissue was taken under aseptic conditions, and the homogenate was diluted with physiological saline and counted to make a concentration of 1 × 10⁶one/mL tumor cell suspension, 0.2 mL/mouse right axilla. Animals were randomly assigned the next day after inoculation (after 24 hours), weighed and dosed, with test compound 1 time a day and 13 consecutive intraperitoneal doses. The positive control drug cyclophosphamide is administrated in the abdominal cavity for 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped off, weighed and photographed. And finally, calculating the tumor proliferation inhibition rate, and evaluating the anti-tumor effect strength by using the tumor inhibition rate.

2.2 in vivo model of mouse pancreatic cancer PAN02

Inoculating PAN02 tumor solution of pancreatic cancer of mouse to right axilla of C57BL/6 mouse under aseptic condition, taking well-grown tumor tissue under aseptic condition after 10 days, cutting, grinding, filtering, diluting with normal saline, counting, and making into 1.2 × 10⁷one/mL tumor cell suspension was inoculated to the right underarm of C57BL/6 mice at a rate of 0.2 mL/mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, and the test compound was administered after weighing for 13 consecutive doses. The positive control drug cyclophosphamide is administrated in the abdominal cavity for 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.

2.3 mouse colorectal cancer MC38 in vivo model

The mouse colorectal cancer MC38 tumor fluid is inoculated to the right armpit of a C57BL/6 mouse under a sterile condition. After 10 days, well-grown tumor tissues were aseptically harvested, minced, ground, filtered, diluted with physiological saline and counted to prepare a tumor cell suspension with a concentration of 1.2X 107 cells/mL, and 0.2 mL/mouse was inoculated to the right underarm of C57BL/6 mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, and the test compound was administered after weighing for 13 consecutive doses. The positive control drug cyclophosphamide is administrated in the abdominal cavity for 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.

2.4 mouse Lewis Lung cancer in vivo model

Inoculating Lewis lung cancer solution of mouse to right axilla of C57BL/6 mouse under aseptic condition, taking well-grown tumor tissue under aseptic condition 10 days later, shearing, grinding, filtering, diluting with normal saline, counting, and making into 1.2 × 10⁷one/mL tumor cell suspension was inoculated to the right underarm of C57BL/6 mice at a rate of 0.2 mL/mouse. Animals were randomly grouped the day after inoculation, 6 animals per group, and the test compound was administered after weighing for 13 consecutive doses. Cyclophosphamide was administered intraperitoneally 1 time. On day 14, the weight was weighed, the animals were sacrificed, tumor tissue was stripped and weighed, and photographed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor effect intensity by using the tumor inhibition rate.

The calculation method comprises the following steps:

tumor proliferation inhibition ratio TGI (%): TGI ═ 1-T/C) × 100. (T: tumor weight in treatment group; C: tumor weight in negative control group). The test results are shown in Table 8.

TABLE 8 in vivo Activity test results for part of the Compounds of the invention

As can be seen from Table 7, the compound 1-1 has an inhibitory effect on interleukin 17F, and the inhibition rate is close to 70%; the compound 1-1 has better inhibition effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors with the dosage of 20mg/kg, and the inhibition effect is more than 50 percent. The derivative has good inhibition effect on melanoma, pancreatic cancer, colorectal cancer, lung cancer and other tumors.

Example 16 animal models of autoimmune diseases

1. Mouse psoriasis model induced by imiquimod

1.1 animal groups

	Imiquimod fabrication	Dosage to be administered	Mode of administration	Number of animals
					Control group	-	-	-	10
Model set	+	-	-	10
					Imiquimod group	+	1.5mg/kg	Gavage stomach	10
Compound 1-1	+	20mg/kg	Tail vein injection	8

1.2 Molding and evaluation method

Depilating the back of the mouse with pet electric hair clipper and depilatory cream, and the area of the depilatory cream is about 1.5 × 2cm². Except that it is negativeAnimals of control group each group was modeled with imiquimod cream, i.e. 50mg of imiquimod cream was applied to the skin of the dehaired area of the back of the mice daily, 1 time daily for 7 consecutive days. Animals were treated on day 8 with intraperitoneal injections of compound 1 time a day for molding. Animals were scored daily for psoriasis-like lesion area and disease severity (PASI) starting the day of first molding. According to the PASI scoring standard, 0-4 points are respectively given to erythema, scales and infiltration thickening degree of the skin lesion of the mouse, and the total points are obtained by adding the points of the erythema, the scales and the infiltration thickening degree.

PASI scoring criteria: 0, none; 1, light; 2, moderate; 3, severe; 4, very severe. At the end of the experiment (day 7), the mice were sacrificed by cervical dislocation, skin thickness was measured with a vernier caliper, and the skin of the animal on the dorsal part where the hair was removed, fixed with 4% paraformaldehyde, and subjected to pathological analysis. The PASI scoring results are shown in table 1.3 below, with the results expressed as mean ± standard deviation.

1.3 PASI score

Erythema

Scale and chip

Number of days	Control group	Molding set	MTX	Compound 1-1
					0	0±0	0±0	0±0	0±0
1	0±0	0±0	0±0	0±0
					2	0±0	0.4±0.5	0.2±0.3	0.1±0
3	0±0	1.5±0.5	1.9±0.3	1.5±0.5
					4	0±0	1.9±0.4	1.6±0.7	1.6±0.4
5	0±0	2.4±0.7	1.7±0.7	1.8±0.5
					6	0±0	2.5±0.5	2.4±1.0	2.4±0.9

Increase in thickness

Total score

Number of days	Control group	Molding set	MTX	Compound 1-1
					0	0±0	0±0	0±0	0±0
1	0±0	0±0	0±0	0±0
					2	0±0	2.5±0.5	1.9±0.6	1.7±0.5
3	0±0	6±0.6	6.2±0.5	5.0±0.5
					4	0±0	6.3±0.7	5.7±1.0	5.4±0.6
5	0±0	7.3±0.8	5.1±1.2	5.4±0.5
					6	0±0	7.3±1.1	6.8±1.9	6.7±1.5

From the PASI score, the compound 1-1 improves pathological erythema to a better extent than scales and thickening. At different time of the disease, the compound has certain improvement effect on different pathological conditions, and is basically equivalent to positive compound MTX.

2. Lupus erythematosus animal model

The compound is injected into MRL/lpr spontaneous lupus mice of 10 weeks old by intragastric or intraperitoneal injection for 1 time every day for 3 months. Skin pathology, degree and pathology of joint swelling, blood/urine creatinine urea nitrogen, and blood dsDNA and ANA antibodies were observed and examined during dosing and at the end of the experiment. The result shows that the compound of the invention has obvious improvement on lupus erythematosus.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof:

wherein Q is O; x, Y, Z are each independently selected from CH and N, and wherein at least one of X, Y, Z is N, but not both;

R₁and R₂The same or different, are independently selected from hydrogen, C1-C6 alkyl, C6-C14 aryl C1-C6 alkyl, C1-C6 alkylacyl; or, R₁And R₂The oxygen adjacent to it forms an acetal of the formula:

wherein R is₆、R₇Independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, or R₆、R₇C adjacent to the C forms a 3-6 membered ring;

R₃selected from hydrogen, C1-C6 alkyl;

R₄selected from hydrogen, C1-C6 alkyl;

R₅selected from hydrogen, halogen, cyano, nitro, hydroxy, C1-C6 alkyl.

2. A compound having the structure:

wherein R is₁、R₂、R₅X, Y and Z are as defined in claim 1.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁And R₂The oxygen adjacent to it forms an acetal.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁And R₂The same is true.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁And R₂Independently selected from hydrogen, C1-C3 alkyl and C1-C5 alkylacyl.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₅Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, nitro, cyano, fluoro, chloro, bromo, and iodo.

7. A compound having the structure:

8. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a transition metal salt, or an ammonium salt.

9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or diluent.

10. Use of a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the secretion and activity of IL-17F.

11. The use according to claim 10, wherein the medicament is for the prevention or treatment of tumors.

12. The use according to claim 10, wherein the medicament is for the prevention or treatment of an inflammatory disease or an autoimmune disease.