CN110357789B - N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof - Google Patents

Abstract

The invention relates to N-substituted acrylamide derivatives as DHODH inhibitors, their preparation and use. Specifically, the invention discloses a compound shown in a general formula I, and preparation and application thereof. The compound of the present invention has excellent DHODH inhibitory activity, and thus can be used for treating or preventing DHODH-mediated diseases, including but not limited to cancer, autoimmune diseases such as rheumatoid arthritis, lupus erythematosus and organ transplant rejection, and inflammatory diseases such as colitis and rhinitis.

Description

N-substituted acrylamide derivatives as DHODH inhibitors and their preparation and use

technical field

The invention belongs to the field of medicinal chemistry and drug therapy, and particularly relates to N-substituted acrylamide derivatives as DHODH inhibitors and their preparation and use.

Background technique

Dihydroorotate dehydrogenase (DHODH) is an iron-containing flavin-dependent mitochondrial enzyme, an intracellular rate-limiting enzyme in nucleic acid pyrimidine synthesis, and catalyzes the fourth step in the de novo pyrimidine biosynthesis pathway. . Inhibition of DHODH can block the synthesis of nascent pyrimidines, resulting in obstacles to DNA and RNA synthesis. There are two ways of pyrimidine synthesis in most organisms: the salvage pathway and de novo synthesis from small molecules. The requirement of an organism for pyrimidine depends on the cell type and the stage of differentiation. Cells in the resting and differentiated stages obtain only a small part of pyrimidine through the de novo synthesis pathway, and mainly rely on the salvage pathway. In contrast, rapidly differentiating human cells such as activated T-lymphocytes, B-lymphocytes, and tumor cells rely on de novo synthesis of pyrimidines to satisfy the organism's requirement for nucleotide precursors and other cellular components. required for growth, which makes DHODH inhibitors useful as anti-proliferative agents in the treatment of tumors as well as certain immunosuppressive responses.

Leflunomide (LEF), which was launched in 1998, is a new type of isoxazole immunomodulator, which is mainly used for the treatment of rheumatoid arthritis, lupus erythematosus and other autoimmune diseases and acute and chronic diseases that resist organ transplantation. Prevention and treatment of rejection and xenogeneic rejection. It was later found that leflunomide is a prodrug, which is rapidly converted into the active metabolite A771726 (MI) by the cytoplasm and microsomes of the liver and intestinal wall after oral administration. MI is a good inhibitor of human dihydroorotate dehydrogenase, which can block the de novo biosynthesis of pyrimidine, thereby affecting the synthesis of DNA and RNA. Studies have shown that MI can be used to prevent, treat or inhibit a variety of autoimmune diseases, acute and chronic rejection of organ transplantation and xenogeneic rejection, skin diseases such as psoriasis, and multiple sclerosis.

Buquina, which was originally studied as an anticancer drug, is one of the most powerful DHODH inhibitors, but its antitumor effect was shown to be mediocre in phase II clinical trials, and the compound continued to be developed as an immunosuppressant. 4SC-101 has been shown to have a good inhibitory effect on lupus erythematosus and enteritis, and is in the clinical development stage.

Since the long-term use of leflunomide can cause drug resistance and side effects such as abnormal liver enzymes, hypertension or skin rash, the search for novel, highly effective DHODH inhibitors with less side effects is still a research hotspot in immune-related diseases and tumor treatment.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a class of compounds with novel structures that can be used as DHODH inhibitors and their preparation methods and uses.

The first aspect of the present invention provides a compound represented by formula I or its stereoisomer, its cis-trans isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or Crystal form:

In the formula,

A is unsubstituted or substituted C _3-7 cycloalkyl, unsubstituted or substituted C _5-7 cycloalkenyl, unsubstituted or substituted C ₆ -C ₁₀ aryl, or unsubstituted or substituted 5-10 Membered heterocyclyl; said substituted means substituted by a group selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy group, C ₆ -C ₁₀ aryl group -NH-CO-, -O-(CH ₂ )mO-, -(CH ₂ )n-; wherein, m or n is an integer of 1-4;

B is unsubstituted or substituted C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C ₆ -C ₁₀ aryl, 5-10 membered heterocyclic group; the substituted refers to being selected from the group The groups substituted by: halogen, cyano (-CN), nitro, carboxyl (-COOH), amide (-CONH ₂ ), sulfonic acid, sulfonamide, C _1-6 sulfonate, hydroxyl, C _1-6 alkanecarbonyl, C _1-6 haloalkanecarbonyl, C _1-6 aldehyde group, C _1-6 ester group, C _1-6 hydrazide, guanidino, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-7 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy , C ₆ -C ₁₀ aryl-NH-CO-, -O-CH ₂ -O-, -(CH ₂ )n-; wherein, n is an integer of 2 to 4;

R ₁ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl;

R ₂ is selected from the group consisting of hydrogen, halogen, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl.

In another preferred embodiment, the compound is selected from the compounds shown in formula II:

In the formula,

A and R ₂ are as defined above;

X represents a nitrogen atom or a group CY, wherein Y is selected from the group consisting of carboxyl, amide, sulfonic acid, sulfonamide, C _1-6 sulfonate, hydroxyl, C _1-6 alkylcarbonyl, C _{1- 6} haloalkanecarbonyl, C _1-6 aldehyde group, C _1-6 ester group, C _1-6 hydrazide group, cyano group, nitro group, guanidino group;

R ₃ , R ₄ , R ₅ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _{2 -6} alkenyl, C _1-6 alkoxy, hydroxyl, C _1-6 haloalkoxy, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy, C ₆ -C ₁₀ aryl-NH- CO-, -O-CH ₂ -O-, -(CH ₂ )n-; wherein, n is an integer of 2-4.

In another preferred embodiment, the Y is selected from the group consisting of carboxyl group, amide group, and cyano group.

In another preferred embodiment, A is unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolyl, unsubstituted or substituted naphthyl, unsubstituted or substituted thienyl, Unsubstituted or substituted benzothienyl, unsubstituted or substituted furyl, unsubstituted or substituted benzofuryl, unsubstituted or substituted quinoline or unsubstituted or substituted isoquinolinyl.

In another preferred embodiment, A is selected from the following group:

In another preferred embodiment, R ₂ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl, and cyclopropyl.

In another preferred example, R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkane, C _3-7 cycloalkane group, C _1-4 alkoxy group, hydroxyl group.

In another preferred example, R ₃ , R ₄ , and R ₅ are each independently hydrogen, fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, methoxy, cyclopropyl, and hydroxyl.

In another preferred embodiment, the compound is selected from the compound shown in formula III:

In the formula,

B and R ₂ are as defined above;

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ are each independently selected from hydrogen, halogen, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkane, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C ₆ -C ₁₀ aryl, C ₆ - C ₁₀ aryloxy, 5- or 6-membered heterocyclic group, hydroxyl, C ₆ -C ₁₀ aryl-NH-CO-;

Or any two of R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ can be connected to form -O-(CH ₂ )mO-, -(CH ₂ )n-, -CH=CH-; wherein, m Or n is an integer of 1-4.

In another preferred embodiment, B is selected from unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heterocyclyl, or unsubstituted or substituted C _5-7 cycloalkenyl.

In another preferred embodiment, the 5-membered or 6-membered heterocyclic group is selected from the group consisting of pyridyl, thienyl, and furyl.

In another preferred embodiment, B is selected from the following group:

In another preferred example, R ₈ and R ₉ can be connected to form -O-(CH ₂ )mO-, -(CH ₂ )n-, -CH=CH-; wherein, m or n is an integer from 1 to 4 .

The second aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition contains the compound described in the first aspect or its stereoisomer, cis-trans isomer, its tautomer, its prodrug or A pharmaceutically acceptable salt or solvate or crystal form thereof; and a pharmaceutically acceptable carrier or excipient.

In another preferred embodiment, the pharmaceutical composition is an injection, a capsule (such as hard and soft gelatin capsules), a tablet, a coated tablet, a pill, a powder, a granule, a sugar-coated tablet, a solution, a syrup doses, emulsions, suspensions, aerosols, suppositories, infusions, ointments, creams and tinctures.

The third aspect of the present invention provides the compound of the first aspect or its stereoisomer, its cis-trans isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal Type or use of the pharmaceutical composition of the second aspect, for the preparation of a dihydroorotate dehydrogenase inhibitor; for the preparation of a pyrimidine biosynthetic enzyme inhibitor; and/or for the preparation of a prophylactic or therapeutic Inhibition of hydroorotate dehydrogenase and/or inhibition of pyrimidine biosynthetic enzymes to ameliorate pathological conditions or diseases.

In another preferred embodiment, the pathological condition or disease is selected from the group consisting of cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular disease, anti-organ transplant rejection, melanoma, psoriasis disease, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia and malaria.

The fourth aspect of the present invention provides the compound of the first aspect or its stereoisomer, its cis-trans isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal type of preparation method,

The method is method 1, comprising the steps:

(1) in an inert solvent, compound 1 and compound 2 are reacted to form compound 3;

(2) in an inert solvent, compound 3 is hydrolyzed to form compound 4;

(3) in an inert solvent, compound 4 reacts with oxalyl chloride and compound 5 successively, thereby forming compound 6;

Or the method is method 2, comprising the steps:

(1) In an inert solvent, compound 7 and TsCl react to form compound 8;

(2) In an inert solvent, compound 8 and compound 5 are reacted to form compound 6;

Or the method is method 3, comprising the steps:

(1) In an inert solvent, compound 1 and compound 9 are reacted to form compound 10;

(2) in an inert solvent, compound 10 reacts with oxalyl chloride and compound 5 successively, thereby forming compound 6;

Or the method is method 4, comprising the steps:

(1) In an inert solvent, compound 1 reacts with compound 11 and NCS or NBS to form compound 12;

(2) in an inert solvent, compound 12 undergoes a hydrolysis reaction to form compound 13;

(3) in an inert solvent, compound 13 reacts with oxalyl chloride and compound 5 successively to form compound 6;

Or the method is method 5, comprising the steps:

(1) In an inert solvent, compound 15 and compound 16 are reacted to form compound 17;

(2) in an inert solvent, compound 17 undergoes a hydrolysis reaction, thereby forming compound 18;

(3) In an inert solvent, compound 18 reacts with oxalyl chloride and compound 5 successively, thereby forming compound 19;

Or the method is method 6, comprising the steps:

(1) In an inert solvent, compound 1 and compound 20 are reacted to form compound 21;

(2) in an inert solvent, compound 21 reacts with oxalyl chloride and compound 5 successively, thereby forming compound 22;

Or the method is method 7, comprising the steps:

(1) In an inert solvent, compound 1 and compound 23 are reacted to form compound 24;

(2) in an inert solvent, compound 24 is hydrolyzed to form compound 25;

(3) in an inert solvent, compound 25 reacts with oxalyl chloride and compound 5 successively, thereby forming compound 26;

In the above formulas, except for the groups given definitions, other groups are as defined above.

The present invention provides a method of treatment or prevention, the method comprising administering to a subject in need thereof the compound of the present invention or a stereoisomer thereof, a cis-trans isomer thereof, a tautomer thereof, a prodrug thereof or A pharmaceutically acceptable salt or solvate or crystal form thereof or the pharmaceutical composition of the present invention.

In another preferred embodiment, the compound is a compound of formula I, formula II, or formula III.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

Through extensive and in-depth research, the inventors have unexpectedly discovered a class of DHODH inhibitors with novel structure and excellent performance for the first time. The present invention has been completed on this basis.

the term

The term "C _1-6 alkyl" as used herein refers to a straight or branched chain alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

The term "C _2-6 alkenyl" refers to a straight or branched chain alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2- Butenyl, or similar groups.

The term "C _2-6 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, or the like.

The term " _{C3-7cycloalkyl} " refers to a cyclic alkyl group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.

The term "C _5-7 cycloalkenyl" refers to a cyclic alkenyl group having 5-7 carbon atoms having one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1 ,3-cyclohexadienyl, 1,4-cyclohexadienyl, or similar groups.

As used herein, the term "C _1-6 alkoxy" refers to a straight or branched chain alkoxy group having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups.

The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

The term "C _1-6 halogenated alkane" refers to a straight or branched chain alkane having 1-6 carbon atoms substituted by the same or different one or more of the above-mentioned halogen atoms, such as trifluoromethyl, pentafluoroethyl, Heptafluoroisopropyl, or similar groups.

The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthracenyl, indenyl, indenyl, tetrahydronaphthyl, Indenyl, etc. Herein, aryl groups can be optionally substituted with one or more substituents described herein.

曲线标记处为取代位，上下同)。The term "aryloxy" refers to aryl-O-, such as phenoxy (

The position marked by the curve is the substitution position, the same as above and below).

The term "heterocyclyl" refers to a single or fused ring structure, which may be aromatic and non-aromatic in nature, and which preferably contains 3-20 ring-forming atoms, more preferably 5-14 or 5-10 ring atoms, of which at least 1 and preferably up to 4 are heteroatoms selected from nitrogen, oxygen or sulfur. Herein, examples of heterocyclic groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridine base, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuran base, morpholinyl, carbazolyl, dibenzothienyl, 1,2-methylenedioxyphenyl, indolyl, indazolyl, benzimidazolyl, benzo[d][1,2 ,3]thiadiazolyl, imidazo[1,2-a]pyridyl, cinnoline, phthalazinyl, 1,8-naphthyridinyl, or benzo[d][1,2,3]tris oxazin-4(3H)-3-yl and the like. Herein, a heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "5- or 6-membered heterocyclyl" refers to a five- or six-membered ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, eg, pyridyl, thiazolyl, thienyl, furanyl, pyrrolyl , pyrazolyl, pyrimidinyl, tetrahydrofuranyl, oxazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl and the like.

The term "C _1-6 sulfonate group" as used herein refers to a sulfonate group (C _1-6 alkyl-S(=O) ₂ O-) having 1-6 carbon atoms.

The term "C _1-6 alkylcarbonyl" as used herein refers to C _1-6 alkyl-C=O-.

The term "C _1-6 ester group" as used herein refers to C _1-5 alkyl-C(=O)O-).

The term "C _1-6 hydrazide" as used herein refers to -C _1-6 alkyl-C=O- _NHNH2 or C _1-6 alkyl-C=O-NHNH-.

The term "C _1-6 aldehyde" as used herein refers to -C _1-5 alkyl-CHO.

The group described in the present invention can be 0 to multiple (usually 0, 1, 2 or 3 ) is substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, carboxyl, mercapto, hydroxyl, methylol, C _1-4 aldehyde, C _1-6 alkyl, C _1-6 Haloalkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _{5- 7} cycloalkenyl, C _1-6 alkoxy (such as methoxy), C _1-6 thioalkyl (such as pentafluorothiomethyl), C _1-6 thioalkoxy (such as pentafluorothio) methoxy), haloalkylcarbonyl (eg trifluoroacetyl), C _1-4 acyl, morpholinyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryloxy (eg optionally substituted phenoxy), optionally substituted benzyloxy, optionally substituted arylcarboxamido, and optionally substituted arylcarbamoyl.

Preparation

The compounds of the present invention can be prepared by the following methods:

method 1:

Method 2:

Method 3:

Method 4:

Method 5:

Method 6:

Method 7:

The raw material aldehyde compounds used can be directly purchased from the reagent company or prepared by the following methods:

1. Obtained from substituted formic acid:

2. Prepared from methyl-containing raw materials:

In the above preparation scheme, A and B are as defined above. Those skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as raw materials according to actual preparation needs.

In a preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

The raw material aldehyde compounds can be purchased directly from the reagent company or synthesized by the following methods.

1. Obtained from substituted formic acid:

The substituted aryl formic acid (10 mmol) was weighed and dissolved in 25 mL of anhydrous THF, under argon protection, and LiAlH ₄ (20 mmol) was slowly added to it in portions under ice bath conditions. After the ice bath reaction for 10 min, the reaction was carried out at room temperature for 4 h. After the reaction was completed, the ice bath was cooled, and 0.76 g of ice water, 0.76 g of 15% NaOH aqueous solution and 2.28 g of water were slowly added dropwise thereto. After stirring for a while, 20 mL of water was added, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated by spin drying under reduced pressure. An appropriate amount of water was added to the concentrated solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude substituted benzyl alcohol, yield 90-95%, which was directly used in the next reaction.

The substituted benzyl alcohol obtained in the previous step was dissolved in 100 mL of DCM, and 70 mmol of MnO ₂ was added under stirring conditions, reacted at room temperature for 4 h, filtered, and the filtrate was spin-dried and concentrated.

2. Made from arylmethyl groups:

The substituted arylmethyl compound (5 mmol) was dissolved in 10 mL of CCl ₄ , 10 mmol of NBS, 0.1 mmol of BPO were added, the reaction was refluxed for 5 h, cooled to room temperature, filtered, and the filter cake was washed with an appropriate amount of petroleum ether, spin-dried and concentrated. The obtained concentrated solution was dissolved in 10 mL of dioxane, added with 10 mL of water, 20 mmol of CaCO ₃ , refluxed for 10 h, filtered, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, spin-dried and concentrated, and purified by column to obtain substituted benzyl alcohol. rate of about 80%.

The substituted benzyl alcohol (4 mmol) obtained in the previous step was dissolved in 40 mL of DCM, 28 mmol of MnO ₂ was added under stirring conditions, reacted at room temperature for 4 h, filtered, the filtrate was spin-dried and concentrated, and purified by column to obtain substituted aromatic formaldehyde with a yield of about 90%. .

In the above formulas, A and B are as defined above;

Disperse the substituted aldehyde compound (5 mmol) into 15 mL of DCM, add 9 mmol of ethoxyformyl ethylene triphenylphosphine, react at room temperature for 12 h, spin off part of the solvent, and purify through column to obtain 2-methyl-3-substituted acrylic acid Ethyl ester intermediate, the yield is about 95%.

The 2-methyl 3-substituted ethyl acrylate (4 mmol) prepared in the previous step was dissolved in 12 mL of THF and 12 mL of MeOH, and 16 mL of 2M aqueous NaOH was added. 40 ℃ reaction 5h. Acidified with 1M HCl, a white solid was precipitated, suction filtered, washed with an appropriate amount of water, and the solid was dried to obtain 2-methyl 3-substituted acrylic acid with a yield of about 95%.

The prepared 2-methyl 3-substituted acrylic acid (1 mmol) was dispersed in 3 mL of dry DCM, oxalyl chloride (3 mmol) was added dropwise in an ice bath, a drop of DMF was added dropwise as a catalyst, a drying tube was put on, and the reaction was carried out at room temperature for 3 h under reduced pressure. Removing the solvent and concentrating to obtain the acid chloride intermediate.

The amino compound (1.2 mmol) was dissolved in 2 mL of DCM, 1.5 mmol of TEA and 0.1 mmol of DMAP were added, and cooled in an ice bath. The prepared acid chloride was dissolved in 1 mL of DCM, added dropwise to the reaction solution, and the reaction was carried out at room temperature until the end of the reaction. Acidified with 1M HCl, a solid precipitated out, filtered with suction, and recrystallized from ethanol to obtain the final product. The yield is about 70%.

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

In the above formulas, A and B are as defined above;

The preparation method of the raw material 2-methyl 3-substituted acrylic acid is similar to the above-mentioned preferred example. To a 25mL reaction flask covered with a drying tube, add 1mmol of 2-methyl 3-substituted acrylic acid, 1.1mmol of TsCl, 5mL of DCE, 0.1mmol of DMAP, 1.5mmol of TEA, react at 35°C for 1h, add 1mmol of amino compound, and react at 60°C for 10h , acidified with 1M HCl, suction filtered to obtain solid, washed with water, dried, and purified by column to obtain the target product with a yield of about 50%.

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

In the above formulas, A and B are as defined above;

Disperse 2mmol of substituted aldehyde compounds and 6mmol of malonic acid in 1.2mL of DMF, add 2mmol of pyridine, react at 90°C for 5h, cool to room temperature, add 1.2mL of water, acidify with 1M HCl to pH 2, filter with suction, and wash with water twice , and the filter cake was dried to obtain 3-substituted acrylic acid intermediate with a yield of about 80%. The subsequent steps for preparing the target compound are similar to the above-mentioned method for preparing the final product using 2-methyl-3-substituted ethyl acrylate as a raw material.

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

In the above formulas, A and B are as defined above;

Add 9mmol ethoxyformylmethylenetriphenylphosphine and 15mL DCM to the reaction flask, under argon protection, add 9mmol NCS or NBS in batches at -20℃, react at -20℃ for 1h, add 5mmol aldehyde group at room temperature The compound and 12.5mmol K ₂ CO ₃ were reacted at room temperature for 10h, the reaction solution was washed with water, the organic phase was dried with anhydrous sodium sulfate, spin-dried and concentrated, and purified by column to obtain 2-halogeno-3-substituted ethyl acrylate. The subsequent steps for preparing the target compound are similar to the above-mentioned method for preparing the final product using 2-methyl-3-substituted ethyl acrylate as a raw material.

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

In the above formulas, A and B are as defined above;

Add 4.2 mmol NaH to a 50 mL three-necked flask, under argon protection, add 24 mL of anhydrous THF, add 3.9 mmol of 2-phosphonotriethyl lipid compound, stir at room temperature for 0.5 h, and add 12 mL of carbonyl compound (3 mmol) in THF solution dropwise Add to the reaction solution, react at room temperature for 12h, acidify with 2M HCl, spin off THF, add appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, spin off the solvent and concentrate, and purify by column Obtained ethyl acrylate intermediate. The subsequent steps for preparing the target compound are similar to the above-mentioned method for preparing the final product using 2-methyl-3-substituted ethyl acrylate as a raw material.

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

Add 6mmol of aldehyde compound, 4mmol of 3,3,3-trifluoropropionic acid, 20mL of THF and 8mL of 1M _TiCl4 dichloromethane solution in sequence to the reaction flask, stir at room temperature for 0.5h, and dropwise add 16mmol of triethylamine to the reaction solution . After 40 hours of reaction at room temperature, 30 mL of water was slowly added to the reaction flask, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by silica gel column (dichloromethane: methanol=10 : 1) to obtain 2-trifluoromethacrylic acid intermediate. The steps of subsequent preparation of the target compound are similar to the above-mentioned method for preparing the final product with 2-methyl-3-substituted ethyl acrylate as a raw material

In another preferred embodiment, the compound of the present invention can be synthesized by a method comprising the following steps:

5 mmol of the aldehyde compound was dispersed in 7.5 mL of methanol, 5 mmol of methyl cyanoacetate and 0.5 mmol of piperidine were added, and the reaction was refluxed until the reaction was complete. Cool to room temperature, the solid is precipitated, suction filtration, the filter cake is washed with an appropriate amount of methanol, and the filter cake is dried to obtain the 2-cyano-3-substituted methyl acrylate intermediate. The subsequent steps for preparing the target compound are similar to the above-mentioned method for preparing the final product using 2-methyl-3-substituted ethyl acrylate as a raw material.

Active ingredient

The compound of the present invention is the compound represented by the general formula I or II or III or its stereoisomer, its cis-trans isomer, its tautomer, its prodrug or its pharmaceutically acceptable salt or solvate or crystal form.

Examples of pharmaceutically acceptable salts of the present invention include, but are not limited to, inorganic and organic acid salts, such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, etc. , malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and aspartic acid , glutamic acid and other acidic amino acids. Another preferred class of salts are the salts of the compounds of the present invention with bases, such as alkali metal salts, especially the sodium and potassium salts.

pharmaceutical composition

The compounds of the present invention have excellent DHODH inhibitory activity, and can be used in the preparation of medicaments for treating or preventing DHODH-mediated diseases.

The pharmaceutical compositions of the present invention contain a therapeutically effective amount of a compound of the present invention together with a pharmaceutically acceptable carrier or excipient.

Although the dosage of the drug required for each individual is different, one skilled in the art can determine the optimum dosage of each active ingredient in the pharmaceutical composition of the present invention. In general, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered orally to mammals daily in an amount of 0.0025 to 50 mg/kg body weight, but preferably about 0.01 to 10 mg/kg orally administered . For example, a unit oral dosage may contain about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of a compound of the present invention. A unit dose may be administered one or more times, in one or more tablets per day, each tablet containing about 0.1 to 50 mg, more preferably about 0.25 to 10 mg, of a compound of the present invention or a solvate thereof.

The pharmaceutical compositions of the present invention can be formulated into formulations suitable for various routes of administration, including but not limited to parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, In the form of nasal or topical administration, it is used to treat tumors and other diseases. The amount administered is that amount effective to ameliorate or eliminate one or more conditions. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some way alleviate symptoms associated with the disease. Such amounts can be administered as a single dose, or can be administered according to an effective therapeutic regimen. The amount given may cure the disease, but the drug is usually given to improve the symptoms of the disease. Repeated dosing is generally required to achieve the desired symptomatic improvement. The dose of the drug will be determined according to the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired effect of treatment.

The pharmaceutical formulations of the present invention can be administered to any mammal so long as they can obtain the therapeutic effects of the compounds of the present invention. The most important of these mammals are humans.

The medicament of the present invention or its pharmaceutical composition can be used to treat or prevent various diseases mediated by DHODH, including cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular disease, anti-organ transplant rejection, melanoma , psoriasis, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, malaria, etc. Such cancers include, but are not limited to, breast cancer, prostate cancer, squamous cell carcinoma of the head and neck, and multiple myeloid cancer.

)、润湿剂(如十二烷基硫酸钠)、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition are capable of admixture with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Pharmaceutically acceptable carriers include: fillers, bulking agents, disintegrating agents, binding agents, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors or fragrances, Buffer substances, etc., as well as solvents, solubilizers or agents for obtaining storage effects, and salts for changing osmotic pressure, coating agents or antioxidants, etc. Specifically, examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as Stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agent (such as sodium lauryl sulfate), pyrogen-free water, etc.

Solid dosage forms for oral administration include capsules (eg, hard or soft gelatin capsules), tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or solubilizers, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as , glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) slow solvents such as paraffin; (f) absorption acceleration agents, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, stearic acid Calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 ,3-Butanediol, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances, etc. Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like .

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, eg, in combination with existing drugs for the treatment of the aforementioned diseases. Enhancement of efficacy can be observed in the latter case.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1(E)-2-(2-methyl-3-phenylacrylamido)benzoic acid (Compound 1)

Disperse benzaldehyde (5 mmol) into 15 mL of DCM, add 9 mmol of ethoxyformyl ethylene triphenylphosphine, react at room temperature for 4 h, remove part of the solvent, and purify through column to obtain (E)-2-methyl 3-benzene Ethyl acrylate, yield 95%.

(E)-ethyl 2-methyl 3-phenylacrylate (4 mmol) prepared in the previous step was dissolved in 12 mL of THF and 12 mL of MeOH, and 16 mL of 2M aqueous NaOH was added. 40 ℃ reaction 5h. Acidified with 1M HCl, a white solid was precipitated, suction filtered, washed with an appropriate amount of water, and the solid was dried to obtain (E)-2-methyl 3-phenylacrylic acid with a yield of 95%.

The prepared (E)-2-methyl 3-phenylacrylic acid (1 mmol) was dispersed in 3 mL of dry DCM, oxalyl chloride (3 mmol) was added dropwise to an ice bath, a drop of DMF was added dropwise as a catalyst, a drying tube was put on, and room temperature The reaction was carried out for 3h, the solvent was removed under reduced pressure, and the acid chloride intermediate was obtained.

Anthranilic acid (1.2 mmol) was dissolved in 2 mL of DCM, 1.5 mmol of TEA and 0.1 mmol of DMAP were added, and cooled in an ice bath. The prepared acid chloride was dissolved in 1 mL of DCM, added dropwise to the reaction solution, and the reaction was carried out at room temperature until the end of the reaction. Acidified with 1M HCl, a solid precipitated out, filtered with suction, and recrystallized from ethanol to obtain the final product. Yield 70%.

Melting point: 179.1-181.6°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.76(s, 1H), 11.84(s, 1H), 8.70(d, J=8.0Hz, 1H), 8.04(dd, J=8.0,1.6Hz,1H),7.68-7.62(m,1H),7.53(d,J=0.8Hz,1H),7.50-7.43(m,4H),7.40-7.35(m,1H),7.22 -7.16 (m, 1H), 2.19 (d, J=1.2Hz, 3H) ppm; ¹³ CNMR (100MHz, DMSO-d6): δ 169.91, 166.89, 141.25, 135.57, 134.54, 134.26, 132.50, 131.21, 129.43, 128.51 , 128.20, 122.68, 119.73, 116.22, 13.87ppm; HRMS(EI) calc.for C ₁₇ H ₁₅ NO ₃ ⁺ 281.1052, found 281.1053.

Example 2(E)-2-(2-methyl-3-(4-trifluoromethylphenyl)acrylamido)benzoic acid (compound 2)

The preparation method is similar to that of Example 1, except that 4-trifluoromethylbenzaldehyde is used as the starting material.

Melting point: 211.6-212.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.78(s, 1H), 11.88(s, 1H), 8.69(dd, J=8.4, 0.8Hz, 1H), 8.05( dd,J＝8.0,1.6Hz,1H),7.81(d,J＝8.4Hz,2H),7.69(d,J＝8.4Hz,2H),7.67-7.63(m,1H),7.57(s,1H) ),7.23-7.18(m,1H),2.20(d,J=1.2Hz,3H)ppm; ^19F NMR(376MHz,DMSO-d6):δ-61.05(s,3F)ppm; HRMS(EI)calc .for C ₁₈ H ₁₄ F ₃ NO ₃ ⁺ 349.0926, found 349.0925.

Example 3 (E)-2-(2-methyl-3-(6-trifluoromethylpyridin-3-yl)acrylamido)benzoic acid (compound 3)

The preparation method is similar to that of Example 1, except that 6-trifluoromethylpyridine-3-carbaldehyde is used as the starting material.

Melting point: 267.6-268.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.81(s, 1H), 11.90(s, 1H), 8.87(d, J=1.6Hz, 1H), 8.69(d, J=7.6Hz, 1H), 8.19 (dd, J=8.0, 1.6Hz, 1H), 8.06 (dd, J=8.0, 1.6Hz, 1H), 7.98 (d, J=8.4Hz, 1H), 7.70- 7.63 (m, 1H), 7.60 (s, 1H), 7.24-7.18 (m, 1H), 2.23 (d, J=1.2Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.86, 165.99 , 150.47, 145.19(q, ² J _CF = 33.8Hz), 140.93, 138.40, 136.66, 135.05, 134.26, 131.22, 129.85, 124.36(q, ¹ J _CF = 264.8 Hz), 122.97, 120.47(q, ³ J _CF = 2.7 Hz), 119.86, 116.49, 13.90 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): δ-66.40 (s, 3F) ppm; HRMS (EI) calc. for C ₁₇ H ₁₃ F ₃ N ₂ O ₃ ^+350.0878 , found 350.0879.

Example 4 (E)-2-(3-(4-methoxyphenyl)-2-methacrylamido)benzoic acid (compound 4)

The preparation method is similar to that of Example 1, except that 4-methoxybenzaldehyde is used as the starting material.

Melting point: 191.4-192.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.73(s, 1H), 11.81(s, 1H), 8.70(d, J=8.4Hz, 1H), 8.04(dd, J=8.0,1.6Hz,1H),7.67-7.60(m,1H),7.49-7.42(m,3H),7.20-7.14(m,1H),7.02(d,J=8.8Hz,2H),3.80 (s, 3H), 2.19 (d, J=1.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.93, 167.14, 159.21, 141.39, 134.37, 134.24, 131.18, 130.26, 127.93, 122.53, 119.67, 116.09, 114.01, 55.19, 13.89 ppm; HRMS (EI) calc. for C ₁₈ H ₁₇ NO ₄ ⁺ 311.1158, found 311.1159.

Example 5(E)-2-(3-(4-tert-butylphenyl)-2-methacrylamido)benzoic acid (Compound 5)

The preparation method is similar to that of Example 1, except that 4-tert-butylbenzaldehyde is used as the starting material.

Melting point: 179.9-180.9°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.74(s, 1H), 11.84(s, 1H), 8.71(d, J=8.0Hz, 1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.68-7.61(m, 1H), 7.50(s, 1H), 7.47(d, J=8.4Hz, 2H), 7.42(d, J=8.4Hz, 2H), 7.21-7.16 (m, 1H), 2.20 (d, J=1.2Hz, 3H), 1.31 (s, 9H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.92, 166.96, 150.86, 141.33, 134.45, 134.24, 132.74, 131.71, 131.20, 129.32, 125.28, 122.59, 119.69, 116.12, 34.39, 30.96, 13.90ppm; HRMS(EI) calc.for C ₂₁ H ₂₃ NO ₃ ⁺ 337.1678, found 337.1680.

Example 6(E)-2-(3-(4-Chloro-3-trifluoromethylphenyl)-2-methacrylamido)benzoic acid (Compound 6)

The preparation method is similar to that of Example 1, except that 4-chloro-3-trifluoromethylbenzaldehyde is used as the starting material.

Melting point: 192.4-193.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.80(s, 1H), 11.87(s, 1H), 8.69(dd, J=8.0, 0.6Hz, 1H), 8.05( dd, J＝8.0, 1.6Hz, 1H), 7.91(s, 1H), 7.81(s, 2H), 7.69-7.62(m, 1H), 7.56(s, 1H), 7.22-7.17(m, 1H) , 2.19(d, J=1.2Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.86, 166.37, 141.03, 135.32, 134.99, 134.57, 134.26, 131.92, 131.78, 131.22, 130.08 (q, ³ J _CF = 1.5 Hz), 128.64 (q, ³ J _CF = 5.2 Hz), 126.75 (q, ² J _CF = 30.6 Hz), 124.04, 122.68 (q, ¹ J _CF = 271.5 Hz), 119.78, 116.37, 13.80 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): δ-61.33 (s, 3F) ppm; HRMS (EI) calc. for C ₁₈ H ₁₃ ³⁵ ClF ₃ NO ₃ ⁺ 383.0536, found 383.0542; calc. for C ₁₈ ^H1337ClF3NO3 _{+ 385.0507} , found _385.0515 ^.

Example 7 (E)-2-(3-(3-chloro-4-methylphenyl)-2-methacrylamido)benzoic acid (compound 7)

The preparation method is similar to the method in Example 1, except that 3-chloro-4-methylbenzaldehyde is used as the starting material.

Melting point: 225.6-226.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.76(s, 1H), 11.84(s, 1H), 8.69(dd, J=8.0, 0.4Hz, 1H), 8.04( dd,J＝8.0,1.6Hz,1H),7.68-7.61(m,1H),7.51(d,J＝1.6Hz,1H),7.46(s,1H),7.43(d,J＝8.0Hz,1H ), 7.36(dd, J=8.0, 1.2Hz, 1H), 7.22-7.16(m, 1H), 2.36(s, 3H), 2.18(d, J=1.2Hz, 3H) ppm; ¹³ C NMR (100MHz) ,DMSO-d6):δ169.89,166.68,141.17,135.46,135.17,134.24,133.36,133.24,132.98,131.26,131.20,129.47,128.06,122.72,119.72,116.86ppm; _{C18H1635ClNO3} ⁺ _329.0819 , found ^329.0823 _; calc ^. for _{C18H1637ClNO3} ⁺ _331.0789 , found _331.0791 .

Example 8 (E)-2-(3-(3,4-dichlorophenyl)-2-methacrylamido)benzoic acid (Compound 8)

The preparation method is similar to that of Example 1, except that 3,4-dichlorobenzaldehyde is used as the starting material.

Melting point: 211.8-212.5°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.78(s, 1H), 11.85(s, 1H), 8.68(d, J=8.4Hz, 1H), 8.04(dd, J=7.8,1.4Hz,1H),7.74(d,J=1.6Hz,1H),7.71(d,J=8.4Hz,1H),7.68-7.62(m,1H),7.50-7.46(m,2H) ), 7.22-7.17 (m, 1H), 2.18 (d, J=1.2Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ169.87, 166.42, 141.06, 136.37, 134.55, 134.26, 132.07, 131.24 , 131.22, 131.14, 130.63, 130.62, 129.51, 122.85, 119.76, 116.36, 13.85ppm; HRMS(EI) calc.for C ₁₇ H ₁₃ ³⁵ Cl ₂ NO ₃ ⁺ 349.0272, found 349.0274; calc.for C ₁₇ H ₁₃ ^{35 Cl37ClNO3 +} _351.0243 , found _351.0253 ; calc ^{. for C17H1337Cl2NO3+} _{353.0214 ,} ^found _353.0196 .

Example 9 (E)-2-(3-(3,5-dichlorophenyl)-2-methacrylamido)benzoic acid (Compound 9)

The preparation method is similar to that of Example 1, except that 35-dichlorobenzaldehyde is used as the starting material.

Melting point: 222.5-223.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.79(s, 1H), 11.85(s, 1H), 8.67(d, J=8.0Hz, 1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.68-7.63(m, 1H), 7.62(t, J=2.0Hz, 1H), 7.53(d, J=1.6Hz, 2H), 7.46(s, 1H), 7.23-7.17 (m, 1H), 2.18 (d, J=1.2Hz, 3H) ppm; ¹³ CNMR (100MHz, DMSO-d6): δ 169.84, 166.27, 140.99, 139.25, 135.34, 134.27, 134.16, 131.80, 131.23, 127.79, 127.50, 122.91, 119.78, 116.41, 13.86ppm; HRMS(EI) calc.for C ₁₇ H ₁₃ ³⁵ Cl ₂ NO ₃ ⁺ 349.0272, found 349.0278; calc.for C ₁₇ H ₁₃ ³⁵ Cl ³⁷ ClNO ₃ ⁺ 351.0243, found35 _.0251 ; calc ^{. for C17H1337Cl2NO3+} _{353.0214 , found} ^353.0206 .

Example 10 (E)-2-(3-(3,4-dimethylphenyl)-2-methacrylamido)benzoic acid (Compound 10)

The preparation method is similar to that of Example 1, except that 3,4-dimethylbenzaldehyde is used as the starting material.

Melting point: 221.4-222.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.75(s, 1H), 11.84(s, 1H), 8.71(d, J=8.0Hz, 1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.67-7.61(m, 1H), 7.46(s, 1H), 7.25(s, 1H), 7.21(s, 2H), 7.20-7.15(m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.19 (d, J=1.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.94, 167.03, 141.36, 136.62, 136.34, 134.64, 134.23 , 133.08, 131.45, 131.20, 130.61, 129.58, 126.91, 122.54, 119.66, 116.08, 19.33, 19.18, 13.92ppm; HRMS(EI) calc.for C ₁₉ H ₁₉ NO ₃ ⁺ 309.1365, found 309.1368.

Example 11 (E)-2-(3-(3,4-dimethoxyphenyl)-2-methacrylamido)benzoic acid (Compound 11)

The preparation method is similar to that of Example 1, except that 3,4-dimethoxybenzaldehyde is used as the starting material.

Melting point: 170.0-170.9°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.74(s, 1H), 11.81(s, 1H), 8.71(d, J=8.4Hz, 1H), 8.04(dd , J=8.0, 1.6Hz, 1H), 7.67-7.60(m, 1H), 7.48(s, 1H), 7.18(t, J=7.4Hz, 1H), 7.09-7.02(m, 3H), 3.80( s, 3H), 3.80 (s, 3H), 2.22 (d, J=1.2Hz, 1H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.91, 167.16, 148.94, 148.46, 141.40, 134.74, 134.23, 131.20, 130.42, 128.17, 122.61, 122.52, 119.68, 116.09, 113.21, 111.58, 55.49, 13.96ppm; HRMS(EI) calc.for C ₁₉ H ₁₉ NO ₅ ⁺ 341.1263, found 341.1262.

Example 12 (E)-2-(3-(1,3-benzodioxin-5-yl)-2-methacrylamido)benzoic acid (Compound 12)

The preparation method is similar to the method in Example 1, except that 1,3-benzodioxin-5-carbaldehyde is used as the starting material.

HRMS (EI) calc. for C ₁₈ H ₁₅ NO ₅ ⁺ 325.0950, found 325.0952.

Example 13 (E)-2-(3-(2,3-dihydro-1H-inden-5-yl)-2-methacrylamido)benzoic acid (Compound 13)

The preparation method is similar to that of Example 1, except that 2,3-dihydro-1H-indene-5-carbaldehyde is used as the starting material.

Melting point: 185.4-186.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.75(s, 1H), 11.84(s, 1H), 8.71(d, J=7.6Hz, 1H), 8.04(dd, J=8.0, 1.6Hz, 1H), 7.67-7.59(m, 1H), 7.50(s, 1H), 7.33(s, 1H), 7.30(d, J=7.6Hz, 1H), 7.23(d, J =7.6Hz,1H),7.20-7.15(m,1H),2.89(q,J=6.8Hz,4H),2.19(d,J=1.2Hz,3H),2.08-1.99(m,2H)ppm; ¹³ C NMR(100MHz,DMSO-d6):δ169.94,167.05,144.17,144.09,141.36,135.07,134.24,133.51,131.37,131.20,127.69,125.25,124.28,122.55,119.64,116.08,32.19,24.97,13.94ppm； HRMS (EI) calc. for C ₂₀ H ₁₉ NO ₃ ⁺ 321.1365, found 321.1366.

Example 14 (E)-2-(2-methyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamido)benzoic acid (Compound 14)

5,6,7,8-Tetrahydronaphthalene-2-carboxylic acid (10 mmol) was dissolved in 25 mL of anhydrous THF, under argon protection, to which was slowly added LiAlH ₄ (20 mmol) in portions under ice bath conditions. After the ice bath reaction for 10 min, the reaction was carried out at room temperature for 4 h. After the reaction was completed, the ice bath was cooled, and 0.76 g of ice water, 0.76 g of 15% NaOH aqueous solution and 2.28 g of water were slowly added dropwise thereto. After stirring for a while, 20 mL of water was added, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated by spin drying under reduced pressure. An appropriate amount of water was added to the concentrated solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude substituted benzyl alcohol with a yield of 98%.

The prepared substituted benzyl alcohol was dissolved in 100 mL of DCM, 70 mmol of MnO ₂ was added under stirring, the reaction was carried out at room temperature for 4 h, filtered, the filtrate was spin-dried and concentrated, and purified by column to obtain 5,6,7,8-tetrahydronaphthalene-2 -Formaldehyde, 90% yield. The subsequent steps for preparing the target compound are similar to those in Example 1. Melting point: 232.3-233.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.75(s, 1H), 11.84(s, 1H), 8.70(d, J=8.4Hz, 1H), 8.04(dd, J=7.8, 1.4Hz, 1H), 7.67-7.61(m, 1H), 7.44(s, 1H), 7.22-7.10(m, 4H), 2.75(d, J=3.6Hz, 4H), 2.18(d , J=0.8Hz, 3H), 1.79-1.72 (m, 4H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ169.94, 167.05, 141.35, 141.09, 137.11, 136.77, 134.67, 134.24, 132.71, 131.48, 131.21, 130.11, 129.04, 126.59, 122.56, 119.64, 116.11, 28.71, 28.62, 22.58, 13.93ppm; HRMS(EI) calc.for C ₂₁ H ₂₁ NO ₃ ⁺ 335.1521, found 335.1522.

Example 15 (E)-2-(3-(6-methoxynaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 15)

The preparation method is similar to the method in Example 1, except that 6-methoxy-2-naphthaldehyde is used as the starting material.

Melting point: 206.8-207.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.78(s, 1H), 11.90(s, 1H), 8.74(d, J=7.6Hz, 1H), 8.06(dd, J=7.8, 1.4Hz, 1H), 7.98(s, 1H), 7.89(t, J=8.8Hz, 2H), 7.69-7.63(m, 2H), 7.58(dd, J=8.4, 1.6Hz, 1H) ), 7.36(d, J=2.4Hz, 1H), 7.23-7.16(m, 2H), 3.90(s, 3H), 2.29(d, J=1.2Hz, 3H) ppm; ¹³ C NMR(100MHz, DMSO -d6):δ169.96,167.03,157.96,141.36,134.77,134.27,133.85,131.82,131.23,130.75,129.81,128.86,128.15,127.63,126.82,122.61,119.70,119.09,116.15,105.83,55.25,14.07ppm；HRMS (EI) calc. for C ₂₂ H ₁₉ NO ₄ ⁺ 361.1314, found 361.1312.

Example 16 (E)-2-(3-(6-bromonaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 16)

The preparation method is similar to that of Example 1, except that 6-bromo-2-naphthaldehyde is used as the starting material.

Melting point: 213.8-214.4°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.80(s, 1H), 11.93(s, 1H), 8.74(d, J=8.4Hz, 1H), 8.24(s, 1H), 8.07(s, 2H), 7.97(dd, J=8.4, 5.8Hz, 2H), 7.70-7.63(m, 4H), 7.20(t, J=7.6Hz, 1H), 2.28(s, 3H )ppm； ¹³ C NMR(100MHz,DMSO-d6):δ169.94,166.76,141.24,134.25,134.19,133.76,133.44,133.28,131.25,131.22,130.38,129.46,129.44,128.73,128.27,127.16,122.70,119.89, 119.74, 116.24, 14.05ppm; HRMS(EI) calc. for C ₂₁ H ₁₆ ⁷⁹ BrNO ₃ ⁺ 409.0314, found 409.0313; calc. for C ₂₁ H ₁₆ ⁸¹ BrNO ₃ ⁺ 411.0293, found 411.0291.

Example 17 (E)-2-(3-(5-chloronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 17)

The preparation method is similar to that of Example 1, except that benzaldehyde is replaced with 5-chloro-2-naphthaldehyde.

Melting point: 232.8-233.6°C; ¹ H NMR (400MHz, DMSO-d6): δ13.79(s, 1H), 11.92(s, 1H), 8.72(d, J=7.6Hz, 1H), 8.23(d, J＝8.8Hz,1H),8.15(s,1H),8.06(dd,J＝8.0,1.6Hz,1H),8.02(d,J＝8.4Hz,1H),7.79(dd,J＝8.8,1.6 Hz, 1H), 7.74(dd, J＝7.2, 0.8Hz, 1H), 7.69(s, 1H), 7.68-7.64(m, 1H), 7.56(t, J＝8.0Hz, 1H), 7.23-7.18 (m, 1H), 2.29 (d, J=0.8Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.93, 166.73, 141.20, 134.28, 134.25, 134.06, 133.85, 133.77, 131.23, 130.44, 129.24,129.18,128.73,127.97,126.93,126.82,123.82,122.78,119.79,116.33,14.05ppm; HRMS(EI) calc.for C ₂₁ H ₁₆ ³⁵ ClNO ₃ ⁺ _365.0819 ,found C _365.0815 ; ³⁷ ClNO ₃ ⁺ 367.0789, found 367.0783.

Wherein, described 5-chloro-2-naphthalene carboxaldehyde can be obtained by the following method of main steps:

5-Bromo-2-naphthoic acid (0.75 g, 3 mmol) was dispersed in 10 mL of methanol, cooled in an ice bath, 1 mL of concentrated sulfuric acid was slowly added dropwise to the reaction solution, refluxed for 2 h, added with 20 mL of water, and extracted with DCM. The organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain methyl 5-bromo-2-naphthoate with a yield of 97%.

The obtained methyl 5-bromo-2-naphthoate, CuCl (0.45 g, 4.5 mmol) and 12 mL of N,N-dimethylformamide (DMF) were dispersed in a 50 mL eggplant-shaped flask, protected by argon, and refluxed for reaction overnight. Cool to room temperature, add 25 mL of water, filter with suction, and dry the filter cake. The obtained filter cake was dispersed in 10 mL of DCM, filtered to remove insoluble impurities, washed with an appropriate amount of DCM, and the filtrate was concentrated to obtain methyl 5-chloro-2-naphthoate with a yield of 97%.

Methyl 5-chloro-2-naphthoate (0.44 g, 2 mmol) was dissolved in 10 mL of anhydrous THF, and under argon protection, LiAlH ₄ (0.1 g, 2.6 mmol) was slowly added thereto in portions under ice bath conditions. After ice bath reaction for 10 min, it was kept at room temperature for 12 h, cooled in ice bath, and 0.1 g of ice water, 0.1 g of 15% NaOH aqueous solution and 0.3 g of water were slowly added dropwise thereto. After stirring for a while, 10 mL of water was added, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated by spin drying under reduced pressure. An appropriate amount of water was added to the concentrated solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain crude (5-chloronaphthalen-2-yl)methanol with a yield of 90%.

The (5-chloronaphthalen-2-yl)methanol prepared above was dissolved in 20 mL of DCM, 14 mmol of MnO ₂ was added under stirring, reacted at room temperature for 4 h, filtered, the filtrate was spin-dried and concentrated, and purified by column to obtain 5- Chloro-2-naphthalenecarboxaldehyde, yield 90%.

Example 18 (E)-2-(2-methyl-3-(4-phenoxyphenyl)acrylamido)benzoic acid (Compound 18)

Phenol (705 mg, 7.5 mmol), p-fluorobenzaldehyde (625 mg, 5.0 mmol) and K ₂ CO ₃ (1.38 g, 10.0 mmol) were dispersed in 5 mL of DMSO under argon protection and reacted at 110° C. overnight. Cool to room temperature, add an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated brine three times, dry over anhydrous sodium sulfate, spin dry and concentrate, and purify by column to obtain 4-phenoxybenzaldehyde. The method for subsequent preparation of the final product is the same as that in Example 1. Melting point: 184.4-185.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.75(s, 1H), 11.84(s, 1H), 8.71(d, J=8.4Hz, 1H), 8.05(dd, J=7.6, 1.2Hz, 1H), 7.67-7.61(m, 1H), 7.53(s, 1H), 7.51(s, 2H), 7.44(t, J=8.0Hz, 2H), 7.19(q, J =7.2Hz,2H),7.09(d,J=8.0Hz,2H),7.06(d,J=8.8Hz,2H), 2.21(s,3H)ppm; ^13C NMR (100MHz, DMSO-d6): δ169.93,166.95,156.80,155.96,141.32,134.24,133.90,131.53,131.44,131.20,130.53,130.13,123.94,122.60,119.69,119.17,118.10,116.14,13.88ppm；HRMS(EI)calc.forC ₂₃ H ₁₉ NO ₄ ⁺ 373.1314, found 373.1316.

Example 19 (E)-2-(2-methyl-3-(3-phenoxyphenyl)acrylamido)benzoic acid (Compound 19)

Disperse m-bromobenzaldehyde (5 mmol) into 15 mL of DCM, add 9 mmol of ethoxyformyl ethylene triphenylphosphine, react at room temperature for 4 h, spin off part of the solvent, and purify through column to obtain (E)-3-(3- bromophenyl)-ethyl 2-methacrylate, 94% yield.

Phenol (6 mmol), (E)-3-(3-bromophenyl)-2-methacrylate ethyl ester (5 mmol), K ₂ CO ₃ (10 mmol), CuCl (0.25 mmol), N -Butylimidazole (2.5mmol) and 5mL of o-xylene, under argon protection, react at 140°C for 16h. Filter, wash the filtrate with dilute hydrochloric acid and saturated brine successively, dry over anhydrous sodium sulfate, spin dry and concentrate, and purify by column to obtain (E)-ethyl 2-methyl-3-(3-phenoxyphenyl)acrylate. The method for subsequent preparation of the final product is the same as that in Example 1. Melting point: 158.6-159.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.75(s, 1H), 11.82(s, 1H), 8.68(d, J=8.0Hz, 1H), 8.04(dd, J=8.0, 1.6Hz, 1H), 7.66-7.61(m, 1H), 7.50-7.45(m, 2H), 7.45-7.39(m, 2H), 7.25(d, J=7.6Hz, 1H), 7.21 -7.15(m,2H),7.09-7.07(m,2H),7.07-7.05(m,1H),7.01(dd,J=8.0,2.0Hz,1H),2.15(d,J=1.2Hz,3H) )ppm； ¹³ C NMR(100MHz,DMSO-d6):δ169.86,166.72,156.78,156.37,141.16,137.51,134.22,133.76,133.30,131.19,130.16,130.09,124.49,123.66,122.71,119.75,119.20,118.80, 118.22, 116.29, 13.89 ppm; HRMS (EI) calc. for C ₂₃ H ₁₉ NO ₄ ⁺ 373.1314, found 373.1313.

Example 20 (E)-2-(2-methyl-3-(4-phenylcarbamoylphenyl)acrylamido)benzoic acid (Compound 20)

4-Aldobenzoic acid (10 mmol), EDCI (11 mmol) and HOBT (1.1 mmol) were added to 30 mL of DCM and the reaction was stirred at room temperature. The reaction was followed by TLC. When the reaction of 4-aldehyde benzoic acid was completed, (10 mmol) aniline was added, and the reaction was continued at room temperature. After the reaction, part of the solvent was removed, and 4-formyl-N-phenylbenzamide was obtained by column purification. The method for subsequent preparation of the final product is the same as that in Example 1. HRMS(EI) calc. for C ₂₄ H ₂₀ N ₂ O ₄ ⁺ 400.1423, found 400.1418.

Example 21 (E)-2-(3-([1,1'-biphenyl]-4-yl)-2-methacrylamido)benzoic acid (Compound 21)

The preparation method is similar to that of Example 14, except that [1,1'-biphenyl]-4-carboxylic acid is used as the starting material.

Melting point: 241.3-242.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.76(s, 1H), 11.87(s, 1H), 8.71(d, J=8.4Hz, 1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.77(d, J=8.0Hz, 2H), 7.73(d, J=6.8Hz, 2H), 7.68-7.63(m, 1H), 7.60(s, 1H), 7.58(s, 1H), 7.57(s, 1H), 7.50(t, J=7.6Hz, 2H), 7.40(t, J=7.2Hz, 1H), 7.19(t, J=7.6Hz, 1H), 2.25 (d, J=1.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.92, 166.91, 141.27, 139.81, 139.38, 134.70, 134.26, 134.13, 132.56, 131.22, 130.17, 129.73, 137.00, 127.73 126.71, 126.63, 122.68, 119.74, 116.26, 14.02 ppm; HRMS (EI) calc. for C ₂₃ H ₁₉ NO ₃ ⁺ 357.1365, found 357.1363.

Example 22 (E)-2-(3-(1H-indol-6-yl)-2-methacrylamido)benzoic acid (Compound 22)

The preparation method is similar to that of Example 1, except that 1H-indole-6-carbaldehyde is used as the starting material.

HRMS(EI) calc. for C ₁₉ H ₁₆ N ₂ O ₃ ⁺ 320.1161, found 320.1165.

Example 23 (E)-2-(2-methyl-3-(1-methyl-1H-indol-6-yl)acrylamido)benzoic acid (Compound 23)

The preparation method is similar to that of Example 1, except that 1-methyl-1H-indole-6-carbaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₀ H ₁₈ N ₂ O ₃ ⁺ 334.1317, found 334.1312.

Example 24 (E)-2-(2-methyl-3-(1-methyl-1H-indol-2-yl)acrylamido)benzoic acid (Compound 24)

The synthetic method of raw material (E)-2-methyl-3-(1-methyl-1H-indol-2-yl) acrylic acid is the same as that in Example 14, except that 1-methyl-1H-indol -2-carboxylic acid instead of 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid.

(E)-2-methyl-3-(1-methyl-1H-indol-2-yl)acrylic acid (215 mg, 1.0 mmol) and p-toluenesulfonyl chloride were successively added to a 25 mL reaction flask covered with a drying tube. (209 mg, 1.1 mmol), 1,2-dichloroethane (5 mL), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and triethylamine (152 mg, 1.5 mmol), react at 35°C for 1 hour, add o- Aminobenzoic acid (137 mg, 1.0 mmol) was reacted at 60°C for 10 hours, acidified with 1M HCl, suction filtered to obtain a solid, washed with water, dried, and recrystallized from ethanol, yield: 50%. Melting point: 243.3-244.1°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.82(s, 1H), 11.98(s, 1H), 8.73(d, J=8.4Hz, 1H), 8.06(dd, J=8.0, 1.2Hz, 1H), 7.69-7.62(m, 3H), 7.53(d, J=8.4Hz, 1H), 7.25-7.17(m, 2H), 7.08(t, J=7.4Hz, 1H) ), 6.87(s, 1H), 3.84(s, 3H), 2.33(s, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ170.03, 166.61, 141.50, 141.35, 137.40, 134.47, 134.30, 132.73 , 131.27, 127.23, 122.87, 122.66, 120.73, 119.75, 119.62, 116.21, 110.00, 104.77, 29.74, 14.68ppm; HRMS(EI) calc.for C ₂₀ H ₁₈ N ₂ O ₃ ⁺ 334.1317, found 334.13.

Example 25 (E)-2-(2-methyl-3-(quinolin-3-yl)acrylamido)benzoic acid (Compound 25)

The preparation method is similar to that of Example 1, except that 3-quinolinecarboxaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₀ H ₁₆ N ₂ O ₃ ⁺ 332.1161, found 332.1159.

Example 26 (E)-2-(3-(isoquinolin-3-yl)-2-methacrylamido)benzoic acid (compound 26)

The preparation method is similar to that of Example 1, except that 3-isoquinolinecarboxaldehyde is used as the starting material.

Melting point: 252.6-253.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.86(s, 1H), 11.96(s, 1H), 9.41(s, 1H), 8.75(d, J=8.4Hz, 1H), 8.16(d, J＝8.0Hz, 1H), 8.08-8.04(m, 2H), 8.02(d, J＝8.4Hz, 1H), 7.82(t, J＝7.6Hz, 1H), 7.73( t, J=7.4Hz, 1H), 7.69-7.62 (m, 2H), 7.20 (t, J=7.6Hz, 1H), 2.61 (s, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ169.94,167.14,152.15,148.44,141.26,135.43,134.45,134.23,133.35,131.22,130.99,128.19,127.61,127.13,126.95,123.11,122.72,119.78,116.33,13.93ppm；HRMS(EI)calc.for C ₂₀ H ₁₆ N ₂ O ₃ ⁺ 332.1161, found 332.1160.

Example 27 (E)-2-(2-methyl-3-(quinolin-7-yl)acrylamido)benzoic acid (Compound 27)

The preparation method is similar to that of Example 1, except that 7-quinolinecarboxaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₀ H ₁₆ N ₂ O ₃ ⁺ 332.1161, found 332.1158.

Example 28 (E)-2-(3-(isoquinolin-6-yl)-2-methacrylamido)benzoic acid (Compound 28)

The preparation method is similar to that of Example 1, except that 6-isoquinolinecarboxaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₀ H ₁₆ N ₂ O ₃ ⁺ 332.1161, found 332.1163.

Example 29 (E)-2-(3-(benzothiophen-2-yl)-2-methacrylamido)benzoic acid (compound 29)

The preparation method is similar to that of Example 1, except that benzothiophene-2-carbaldehyde is used as the starting material.

HRMS(EI) calc. for _C19H15NO3S ⁺ _337.0773 , found _337.0771 .

Example 30 (E)-2-(3-(benzothiophen-6-yl)-2-methacrylamido)benzoic acid (Compound 30)

The preparation method is similar to that of Example 1, except that benzothiophene-6-carbaldehyde is used as the starting material.

HRMS(EI) calc. for _C19H15NO3S ⁺ _337.0773 , found _337.0774 .

Example 31 (E)-2-(3-(benzofuran-2-yl)-2-methacrylamido)benzoic acid (compound 31)

The preparation method is similar to that of Example 1, except that benzofuran-2-carbaldehyde is used as the starting material.

HRMS (EI) calc. for C ₁₉ H ₁₅ NO ₄ ⁺ 321.1001, found 321.1003.

Example 32 (E)-2-(3-(benzofuran-6-yl)-2-methacrylamido)benzoic acid (compound 32)

The preparation method is similar to that of Example 1, except that benzofuran-6-carbaldehyde is used as the starting material.

HRMS (EI) calc. for C ₁₉ H ₁₅ NO ₄ ⁺ 321.1001, found 321.1006.

Example 33 (E)-2-(3-(naphthalen-2-yl)acrylamido)benzoic acid (compound 33)

Disperse 2 mmol 2-naphthaldehyde and 6 mmol malonic acid in 1.2 mL DMF, add 2 mmol pyridine, react at 90°C for 5 h, cool to room temperature, add 1.2 mL water, acidify with 1 M HCl, filter with suction, wash twice with water, and dry the filter cake That is, (E)-3-(naphthalene-2-yl)acrylic acid is obtained with a yield of 80%, and the method for subsequent preparation of the final product is the same as that in Example 1. Melting point: 241.9-242.7°C; ¹ H NMR (400MHz, DMSO-d6): δ13.65(s, 1H), 11.41(s, 1H), 8.66(d, J=8.4Hz, 1H), 8.23(s, 1H),8.04(dd,J=8.0,1.6Hz,1H),7.99-7.92(m,4H),7.80(d,J=15.6Hz,1H),7.68-7.61(m,1H),7.60-7.54 (m, 2H), 7.23-7.18 (m, 1H), 7.04 (d, J=15.6Hz, 1H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.44, 163.79, 141.34, 140.85, 134.00, 133.60 , 132.94, 132.01, 131.13, 129.48, 128.47, _128.40 , _127.66 , ^127.15 , 126.71, 124.09, 122.88, _122.73 , 120.41, 116.82ppm;

Example 34 (E)-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 34)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material.

Melting point: 231.5-232.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.80(s, 1H), 11.92(s, 1H), 8.74(d, J=8.0Hz, 1H), 8.07(dd, J=8.0,1.6Hz,1H),8.05(s,1H),8.00-7.94(m,3H),7.70-7.64(m,2H),7.62(dd,J=8.8,1.6Hz,1H),7.60 -7.54 (m, 2H), 2.30 (d, J=1.2Hz, 3H) ppm; ¹³ CNMR (100MHz, DMSO-d6): δ 169.95, 166.90, 141.29, 134.54, 134.28, 133.14, 132.87, 132.74, 132.37, 131.23 , 128.81, 128.19, 127.92, 127.52, 127.09, 126.71, 126.50, 122.69, 119.74, 116.22, 14.05ppm; HRMS(EI) calc.for C ₂₁ H ₁₇ NO ₃ ⁺ 331.1208, found 331.1204.

Example 35 (E)-2-(3-(naphthalen-2-yl)-2-butenamido)benzoic acid (compound 35)

In a 50mL three-necked flask, add 4.2mmol NaH, under argon protection, add 24mL anhydrous THF, add 3.9mmol triethyl 2-phosphoryl acetate, stir at room temperature for 0.5h, add 12mL 1-(naphthalene-2-yl)-1 -The THF solution of ethyl ketone (3mmol) was added dropwise to the reaction solution, reacted at room temperature for 12h, acidified with 2M HCl, spin off THF, add an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate , filtered, the solvent was removed by rotation, concentrated, and purified by column to obtain ethyl 2-(naphthalene-2-ylmethylene) crotonate with a yield of 50%. The method for subsequent preparation of the final product is the same as that in Example 1. HRMS(EI) calc.for C21H17NO3+331.1208, found 331.1206.

Example 36 (E)-2-(2-methyl-3-(naphthalen-2-yl)-2-butenamido)benzoic acid (Compound 36)

The preparation method was similar to that of Example 35, except that triethyl 2-phosphonopropionate was used instead of triethyl phosphonoacetate.

HRMS (EI) calc. for C ₂₂ H ₁₉ NO ₃ ⁺ 345.1365, found 345.1361.

Example 37 (Z)-2-(2-Chloro-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 37)

Add 9mmol ethoxyformylmethylenetriphenylphosphine and 15mL DCM to the reaction flask, under argon protection, add 9mmol NCS in batches at -20℃, react at -20℃ for 1h, add 5mmol 2-naphthaldehyde at room temperature and 12.5mmol K ₂ CO ₃ , reacted at room temperature for 10h, the reaction solution was washed with water, the organic phase was dried with anhydrous sodium sulfate, spin-dried and concentrated, and purified by column to obtain (Z)-2-chloro-3-(naphthalene-2-yl ) ethyl acrylate. The method for subsequent preparation of the final product is the same as that in Example 1. Melting point: 236.1-237.0°C; ¹ H NMR (400MHz, DMSO-d6): δ13.92(s, 1H), 12.53(s, 1H), 8.74(d, J=8.0Hz, 1H), 8.49(s, 1H), 8.24(s, 1H), 8.09(dd, J=7.8, 1.2Hz, 1H), 8.03(s, 3H), 7.97(d, J=7.2Hz, 1H), 7.70(t, J=7.4 Hz, 1H), 7.66-7.56 (m, 2H), 7.27 (t, J=7.4Hz, 1H) ppm. ¹³ C NMR (100MHz, DMSO-d6): δ169.61, 160.22, 140.24, 134.39, 134.29, 133.26, 132.53, 131.29, 130.97, 130.23, ^128.66 , _128.11 , _127.66 , _127.56 , 126.77, 126.71, 123.65, 123.60, ^119.86 , 116.90ppm; .for C ₂₀ H ₁₄ ³⁷ ClNO ₃ ⁺ 353.0633, found 353.0643.

Example 38 (Z)-2-(2-bromo-3-(naphthalen-2-yl)acrylamido)benzoic acid (compound 38)

Add 9mmol ethoxyformylmethylenetriphenylphosphine and 15mL DCM to the reaction flask, under argon protection, add 9mmol NBS in batches at -20℃, react at -20℃ for 1h, add 5mmol 2-naphthaldehyde at room temperature and 12.5mmol K ₂ CO ₃ , reacted at room temperature for 10h, the reaction solution was washed with water, the organic phase was dried with anhydrous sodium sulfate, spin-dried and concentrated, and purified by column to obtain (Z)-2-bromo-3-(naphthalene-2-yl ) ethyl acrylate. The method for subsequent preparation of the final product is the same as that in Example 1. Melting point: 233.9-234.7°C; ¹ H NMR (400MHz, DMSO-d6): δ13.89(s, 1H), 12.36(s, 1H), 8.69(d, J=8.0Hz, 1H), 8.48(s, 1H), 8.45(s, 1H), 8.08(dd, J=8.0, 1.6Hz, 1H), 8.04-7.99(m, 3H), 7.97(d, J=7.6Hz, 1H), 7.75-7.66(m , 1H), 7.66-7.55 (m, 2H), 7.27 (t, J=7.6Hz, 1H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ169.49, 160.86, 140.26, 138.03, 134.20, 133.21, 132.43 , 131.27, 131.25, 130.35, 128.55, 127.95, 127.61, 127.56, 126.77, ^126.39 , _123.62 , 119.97, _117.08 , ^115.82ppm ; HRMS(EI) _calc.forC ; _{C20H1481BrNO3 + 397.0137} ^, found ^397.0132 .

Example 39 (E)-2-(2-(naphthalen-2-ylmethylene)butenamido)benzoic acid (compound 39)

The preparation method is similar to that of Example 35, except that 1-(naphthalen-2-yl)-1-ethanone is replaced by 2-naphthaldehyde, and triethyl 2-phosphonobutyrate is replaced by triethyl phosphonoacetate. ethyl ester.

Melting point: 184.6-185.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.78(s, 1H), 11.91(s, 1H), 8.74(d, J=8.4Hz, 1H), 8.06(dd, J=7.8,1.4Hz,1H),8.02-7.93(m,4H),7.70-7.63(m,1H),7.62-7.55(m,4H),7.21(t,J=7.4Hz,1H),2.71 (q, J=7.2Hz, 2H), 1.23 (t, J=7.4Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.96, 166.76, 141.22, 139.76, 134.28, 133.60, 133.05, 132.79 , 132.40, 131.23, 128.24, 128.21, ^128.11 , 127.51, 126.70, 126.56, 126.55, 122.72, _119.77 , _116.26 , 20.47, _13.53ppm ; HRMS(EI) calc.

Example 40 (Z)-2-(3-(naphthalen-2-yl)-2-trifluoromethacrylamido)benzoic acid (compound 40)

Add 6mmol 2-naphthalenecarboxaldehyde, 4mmol 3,3,3-trifluoropropionic acid, 20mL THF and 8mL 1M _TiCl in the reaction flask successively in dichloromethane solution, stir at room temperature for 0.5h, add 16mmol triethyl ether dropwise to the reaction solution amine. After 40 hours of reaction at room temperature, 30 mL of water was slowly added to the reaction flask, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by silica gel column (dichloromethane: methanol=10 : 1) to obtain (Z)-3-(naphthalene-2-yl)-2-(trifluoromethyl)acrylic acid. The method for subsequent preparation of the final product is the same as that in Example 1. HRMS (EI) calc. for C ₂₁ H ₁₄ F ₃ NO ₃ ⁺ 385.0926, found 385.0922.

Example 41 (E)-2-(2-cyano-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 41)

5 mmol of 2-naphthaldehyde was dispersed in 7.5 mL of methanol, 5 mmol of methyl cyanoacetate and 0.5 mmol of piperidine were added, and the reaction was refluxed until the reaction was complete. Cool to room temperature, the solid is precipitated, suction filtration, the filter cake is washed with an appropriate amount of methanol, and the filter cake is dried to obtain (E)-2-cyano-3-(naphthalene-2-yl) methyl acrylate intermediate. Yield 90%. The method for subsequent preparation of the final product is the same as that in Example 1. HRMS(EI) calc. for C ₂₁ H ₁₄ N ₂ O ₃ ⁺ 342.1004, found 342.1007.

Example 42 (E)-5-Fluoro-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 42)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

Melting point: 237.4-238.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 14.11(s, 1H), 11.71(s, 1H), 8.73(dd, J=9.2, 5.2Hz, 1H), 8.03( s,1H),8.01-7.92(m,3H),7.76(dd,J=9.2,3.2Hz,1H),7.68(s,1H),7.61(dd,J=8.6,1.2Hz,1H),7.59 -7.52 (m, 3H), 2.28 (s, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 168.74, 166.79, 156.70 (d, ¹ J _CF = 239.4 Hz), 137.71 (d, ⁴ J _CF = 2.3Hz), 134.61, 133.10, 132.69(d, ³ J _CF =8.3Hz), 132.36, 128.82, 128.18, 127.91, 127.51, 127.07, 126.71, 126.50, 121.99(d, ³ J _CF =7.4Hz), 121. (d, ² J _CF = 21.9 Hz), 118.33, 118.26, 116.94 (d, ² J _CF = 23.7 Hz), 14.01 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): δ-118.88--118.96 (m, 1F) ppm; HRMS (EI) calc. for _C21H16FNO3 ⁺ _349.1114 , found _349.1113 .

Example 43 (E)-4-Fluoro-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 43)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-4-fluorobenzoic acid.

Melting point: 238.6-239.2°C; ¹ HNMR (400MHz, DMSO-d6): δ 13.96(s, 1H), 12.17(s, 1H), 8.58(dd, J=12.4, 2.4Hz, 1H), 8.13(dd ,J=8.6,7.0Hz,1H),8.04(s,1H),8.00-7.93(m,3H),7.70(s,1H),7.61(dd,J=8.6,1.0Hz,1H),7.59- 7.55 (m, 2H), 7.03 (td, J=8.6, 2.4Hz, 1H), 2.29 (s, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.27, 167.18, 165.00 (d, ¹ J _CF = 247.8Hz), 143.43 (d, ³ J _CF = 13.0 Hz), 135.11, 133.96 (d, ³ J _CF = 11.2 Hz), 132.98, 132.72, 132.43, 132.42, 128.92, 128.20, 127.94, 127.51, 127.04 126.77, 126.52, 112.73 (d, ⁴ J _CF = 2.4 Hz), 109.65 (d, ² J _CF = 22.1 Hz), 106.15 (d, ² J _CF = 28.1 Hz), 13.92 ppm; ¹⁹ F NMR (376 MHz, DMSO -d6): δ-102.67--102.97 (m, 1F) ppm; HRMS (EI) calc. for C ₂₁ H ₁₆ FNO ₃ ⁺ 349.1114, found349.1115.

Example 44 (E)-5-Chloro-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 44)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-chlorobenzoic acid.

Melting point: 251.5-252.2°C; ¹ H NMR (400MHz, DMSO-d6): δ14.18(s, 1H), 11.83(s, 1H), 8.74(d, J=9.2Hz, 1H), 8.03(s, 1H),8.00-7.92(m,4H),7.72(dd,J=9.0,2.6Hz,1H),7.69(s,1H),7.61(dd,J=8.6,1.6Hz,1H),7.59-7.53 (m, 2H), 2.28 (d, J=1.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 168.69, 166.90, 140.05, 134.86, 133.83, 133.04, 132.72, 132.56, 132.39, 130.32, 128.87, 128.19, 127.92, 127.51, 127.05, 126.74, 126.51, 126.24, 121.58, 118.12, 13.99ppm; HRMS(EI) calc.for C ₂₁ H ₁₆ ³⁵ ClNO ₃ ^{+ 365.0819} , _{foundC 365.0816} ; ClNO ₃ ⁺ 367.0789, found 367.0789.

Example 45 (E)-5-Bromo-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 45)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-bromobenzoic acid.

Melting point: 256.9-257.6°C; ¹ H NMR (400MHz, DMSO-d6): δ 14.18(s, 1H), 11.83(s, 1H), 8.69(d, J=8.8Hz, 1H), 8.11(d, J=2.8Hz, 1H), 8.02(s, 1H), 8.00-7.92(m, 3H), 7.82(dd, J=8.8, 2.4Hz, 1H), 7.68(s, 1H), 7.60(dd, J =8.6, 1.4Hz, 1H), 7.58-7.53 (m, 2H), 2.28 (d, J=0.8Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 168.62, 166.88, 140.44, 136.67, _{134.88,133.21,133.04,132.71,132.55,132.38,128.87,128.19,127.91,127.50,127.03,126.73,126.49,121.81,118.34,114.01,13.98NOppm _} ^_ _{_} ^_ 409.0314, found 409.0312; calc. for C ₂₁ H ₁₆ ⁸¹ BrNO ₃ ⁺ 411.0293, found 411.0308.

Example 46 (E)-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)-5-trifluoromethylbenzoic acid (Compound 46)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-trifluoromethylbenzoic acid.

Melting point: 228.7-229.4°C; ¹ H NMR (400MHz, DMSO-d6): δ12.20(s, 1H), 8.92(d, J=8.8Hz, 1H), 8.28(d, J=2.0Hz, 1H) ,8.04(s,1H),8.02-7.93(m,4H),7.72(s,1H),7.62(dd,J=8.6,1.4Hz,1H),7.59-7.54(m,2H),2.30(d , J=1.2Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 168.77, 167.27, 144.37, 135.28, 132.95, 132.71, 132.48, 132.43, 130.66 (q, ³ J _CF =3.4Hz), 128.96 , 128.21, 127.94, 127.91 (q, ³ J _CF = 3.5Hz), 127.51, 127.02, 126.79, 126.52, 123.83 (q, ¹ J _CF = 270 Hz), 122.49 (q, ² J _CF = 32.6 Hz), 120.16, 116.86, 13.99 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): delta-60.79 (s, 3F) ppm; HRMS (EI) calc. for C ₂₂ H ₁₆ F ₃ NO ₃ ⁺ 399.1082, found 399.1088.

Example 47 (E)-5-methyl-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (Compound 47)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-methylbenzoic acid.

Melting point: 194.6-195.3°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.73(s, 1H), 11.81(s, 1H), 8.63(d, J=8.4Hz, 1H), 8.03(s, 1H), 8.00-7.92(m, 3H), 7.87(s, 1H), 7.67(s, 1H), 7.61(d, J=8.4Hz, 1H), 7.58-7.53(m, 2H), 7.47(dd , J=8.4, 1.2Hz, 1H), 2.33(s, 3H), 2.28(s, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ169.96, 166.66, 138.93, 134.80, 134.34, 133.19, 132.88 , 132.74, 132.34, 131.76, 131.23, 128.77, 128.17, 127.89, 127.51, _127.09 , _126.68 , _126.48 , ^119.78 , 116.12, 20.20, 14.03ppm; 1367.

Example 48 (E)-5-methoxy-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoic acid (compound 48)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-methoxybenzoic acid.

Melting point: 218.6-219.3°C; ¹ H NMR (400MHz, DMSO-d6): δ13.70(s, 1H), 11.60(s, 1H), 8.65(d, J=9.2Hz, 1H), 8.02(s, 1H), 7.99(t, J=2.8Hz, 1H), 7.97-7.92(m, 2H), 7.67(s, 1H), 7.61(dd, J=8.4, 1.6Hz, 1H), 7.57(d, J ＝3.2Hz, 1H), 7.55(d, J＝3.6Hz, 1H), 7.53(d, J＝2.8Hz, 1H), 7.28(dd, J＝9.2, 3.2Hz, 1H), 3.81(s, 3H) ), 2.28 (d, J=1.2 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ169.49, 166.44, 154.16, 134.67, 134.15, 133.25, 132.87, 132.75, 132.32, 128.72, 128.15, 127.88, 127.49, 127.08, 126.64, 126.46, 121.63, 120.23, 117.74, 114.89, 55.37, 14.02ppm; HRMS(ES+) calcd for C ₂₂ H ₁₉ NO ₄ Na(M+Na) ⁺ , 384.1212; found, 384.1213.

Example 49 (E)-2-(3-(1-Fluoronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 49)

The preparation method is similar to that of Example 1, except that 1-fluoro-2-naphthaldehyde is used as the raw material.

Melting point: 247.3-248.2°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.83(s, 1H), 11.98(s, 1H), 8.74(d, J=8.0Hz, 1H), 8.14-8.09( m,1H),8.07(dd,J=8.0,1.4Hz,1H),8.05-8.01(m,1H),7.85(d,J=8.8Hz,1H),7.71-7.65(m,4H),7.62 (t, J=8.0 Hz, 1H), 7.24-7.18 (m, 1H), 2.19 (s, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 169.99, 166.14, 154.97 (d, ¹ J _CF = 252.1Hz), 141.14, 135.12, 134.30, 134.08 (d, ³ J _CF = 5.8 Hz), 131.23, 127.68, 127.40 (d, ³ J _CF = 3.0 Hz), 127.23 (d, ⁴ J _CF = 1.4 Hz) , 126.71 (d, ³ J _CF = 3.2Hz), 123.71 (d, ³ J _CF = 4.1 Hz), 122.83, 122.58 (d, ² J _CF = 16.6 Hz), 120.23, 120.17, 119.77, 117.85 (d, ² J _CF = 12.7 Hz), 116.30, 14.25 ppm; ¹⁹ FNMR (376 MHz, DMSO-d6): δ-122.81 (d, J=7.2 Hz, 1 F) ppm; HRMS (EI) calc. for C ₂₁ H ₁₆ FNO ₃ ^+349.1114 , found 349.1120.

Wherein, described 1-fluoro-2-naphthalene carboxaldehyde can be prepared by the following method:

2-methyl-1-naphthylamine (1.57g, 10mmol) was added to a 100mL eggplant-shaped flask, fluoroboric acid (15mL) was added dropwise to the reaction flask, cooled in an ice bath, and 10mL _NaNO was slowly added dropwise to the reaction solution. The solution (2.76 g, 40 mmol) was reacted in an ice bath for 0.5 h, filtered with suction, and the filter cake was dried to obtain the diazonium salt. The obtained diazonium salt was added to 50 mL of toluene, reacted at 90° C. for 1 h, and reacted under reflux for 2 h. The reaction solution was washed successively with saturated NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column to obtain 1-fluoro-2-methylnaphthalene in a yield of 67%.

The prepared 1-fluoro-2-methylnaphthalene (5 mmol) was dissolved in 10 mL of CCl ₄ , 10 mmol of NBS, 0.1 mmol of dibenzoyl peroxide (BPO) were added, refluxed for 5 h, cooled to room temperature, filtered, and washed with an appropriate amount of The filter cake was washed with petroleum ether and concentrated. The obtained concentrated solution was dissolved in 10 mL of dioxane, added 10 mL of water, 20 mmol of CaCO ₃ , refluxed for 10 h, filtered, extracted with ethyl acetate, combined with the organic phases, dried over anhydrous sodium sulfate, spin-dried and concentrated, and purified by column to obtain ( 1-Fluoronaphthalen-2-yl)methanol, 80% yield.

The prepared (1-fluoronaphthalen-2-yl)methanol (4 mmol) was dissolved in 40 mL of DCM, 28 mmol of MnO ₂ was added under stirring, the reaction was carried out at room temperature for 4 h, filtered, the filtrate was spin-dried and concentrated, and purified by column. 1-Fluoro-2-naphthalenecarboxaldehyde (starting material), 90% yield.

Example 50 (Z)-2-(2-Chloro-3-(1-fluoronaphthalen-2-yl)acrylamido)-5-fluorobenzoic acid (Compound 50)

The preparation method is similar to that of Example 37, except that 1-fluoro-2-naphthalenecarboxaldehyde is used as the raw material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.21 (s, 1H), 12.53 (s, 1H), 8.73 (dd, J=9.2, 5.2 Hz, 1H), 8.06 (dd, J=8.0, 1.4Hz, 1H), 8.05-8.01(m, 1H), 7.81(d, J=8.8Hz, 1H), 7.71-7.63(m, 4H), 7.62(t, J=8.0Hz, 1H), 7.25- 7.20(m, 1H), ppm; HRMS(EI) calc.for C ₂₀ H ₁₂ ClF ₂ NO ₃ ⁺ 387.0474, found 387.0471; HRMS(EI) calc. for C ₂₀ H ₁₂ ³⁷ ClF ₂ NO ₃ ⁺ 389.0445, found389 .0447.

Example 51 (E)-5-Fluoro-2-(3-(1-fluoronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 51)

The preparation method is similar to the method in Example 1, except that 1-fluoro-2-naphthalenecarboxaldehyde is used as a raw material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

Melting point: 250.8-251.7°C; ¹ H NMR (400MHz, DMSO-d6): δ14.13(s, 1H), 11.76(s, 1H), 8.72(dd, J=9.2, 5.2Hz, 1H), 8.14- 8.09(m,1H),8.06-8.01(m,1H),7.85(d,J=8.4Hz,1H),7.77(dd,J=9.2,3.2Hz,1H),7.70-7.64(m,3H) , 7.61 (d, J=8.0 Hz, 1H), 7.59-7.53 (m, 1H), 2.17 (s, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 168.76, 166.07, 156.80 (d, ¹ J _CF = 239.8 Hz), 154.97 (d, ¹ J _CF = 252.3 Hz), 137.54 (d, ⁴ J _CF = 2.3 Hz), 134.94, 134.08 (d, ³ J _CF = 5.0 Hz), 127.69, 127.67, 127.47 (d, ⁴ J _CF = 3.2 Hz), 127.23 (d, ⁴ J _CF = 1.3 Hz), 126.69 (d, ³ J _CF = 3.4 Hz), 123.71 (d, ³ J _CF = 4.2 Hz), 122.59 (d , ² J _CF = 16.5 Hz), 122.07 (d, ³ J _CF = 7.4 Hz), 121.09 (d, ² J _CF = 22.1 Hz), 120.20 (d, ³ J _CF = 5.6 Hz), 118.46 (d, ³ J _CF = 6.7 Hz), 117.82 (d, ² J _CF = 12.6 Hz), 116.97 (d, ² J _CF = 23.5 Hz), 14.22 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): δ-118.53-- 119.11 (m, 1F), -122.80 (d, J=6.6Hz, 1F) ppm; HRMS (EI) calc ^{. for C21H15F2NO3+} _{367.1020 , found367.1018 .}

Example 52 (E)-2-(3-(1-chloronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 52)

The preparation method is similar to that of Example 1, except that 1-chloro-2-naphthaldehyde is used as the starting material.

Melting point: 240.3-241.2°C; ¹ H NMR (400MHz, DMSO-d6): δ13.82(s, 1H), 11.99(s, 1H), 8.75(d, J=8.0Hz, 1H), 8.28(d, J=8.4Hz, 1H), 8.08-8.05(m, 2H), 8.02(d, J=8.4Hz, 1H), 7.78(s, 1H), 7.77-7.71(m, 1H), 7.71-7.65(m , 2H), 7.62 (d, J=8.4Hz, 1H), 7.22 (t, J=7.2Hz, 1H), 2.13 (d, J=0.8Hz, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6 ):δ169.96,166.11,141.11,134.80,134.31,133.50,132.21,131.74,131.26,130.17,130.07,128.40,128.04,127.38,127.22,127.07,123.76,122.87,119.78,116.29,14.02ppm；HRMS(EI)calc .for C ₂₁ H ₁₆ ³⁵ ClNO ₃ ⁺ 365.0819, found 365.0824; calc. for C ₂₁ H ₁₆ ³⁷ ClNO ₃ ⁺ 367.0789, found 367.0827.

Example 53 (E)-2-(3-(1-chloronaphthalen-2-yl)-2-methacrylamido)-5-fluorobenzoic acid (Compound 53)

The preparation method is similar to the method in Example 1, except that 1-chloro-2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

Melting point: 255.8-256.7°C; ¹ H NMR (400MHz, DMSO-d6): δ14.15(s, 1H), 11.79(s, 1H), 8.75(dd, J=9.2, 5.2Hz, 1H), 8.27( d, J=5.6Hz, 1H), 8.08-7.98 (m, 2H), 7.80-7.65 (m, 4H), 7.63-7.52 (m, 2H), 2.12 (s, 3H) ppm; ¹³ C NMR (100MHz) , DMSO-d6): δ168.76, 165.99, 156.79 (d, ¹ J _CF = 239.6Hz), 137.52 (d, ⁴ J _CF = 2.4Hz), 134.60, 133.49, 132.28, 131.69, 130.18, 130.06, 128.38, 128.02, 127.36, 127.18, 127.05, 123.75, 122.00 (d, ³ J _CF = 6.6Hz), 121.11 (d, ² J _CF = 22.3 Hz), 118.35 (d, ³ J _CF = 5.4 Hz), 116.99 (d, ² J CF = 22.3 Hz) _CF = 24.0Hz), 13.98ppm; ¹⁹ F NMR (376MHz, DMSO-d6): δ-118.64--118.74 (m, 1F) ppm; HRMS (EI) calc. for C ₂₁ H ₁₅ ³⁵ ClFNO ₃ ⁺ 383.0724, found 383.0724.

Example 54 (Z)-2-(2-Chloro-3-(1-chloronaphthalen-2-yl)acrylamido)-5-fluorobenzoic acid (Compound 54)

The preparation method is similar to that of Example 37, except that 1-chloro-2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 14.23 (s, 1H), 12.32 (s, 1H), 8.72 (dd, J=9.2, 5.2 Hz, 1H), 8.05-7.96 (m, 3H) ,7.71(dd,J=9.2,3.2Hz,1H),7.63(s,1H),7.61(dd,J=8.6,1.2Hz,1H),7.58-7.49(m,3H)ppm; HRMS(EI) calc. for C ₂₀ H ₁₂ ³⁵ Cl ₂ FNO ₃ ⁺ 403.0178, found 403.0176.

Example 55 (E)-2-(3-(1-bromonaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 55)

The preparation method is similar to that of Example 1, except that 1-bromo-2-naphthaldehyde is used as the starting material.

Melting point: 235.6-236.2°C; ¹ H NMR (400MHz, DMSO-d6): δ13.83(s, 1H), 11.99(s, 1H), 8.76(d, J=8.4Hz, 1H), 8.27(d, J=8.4Hz, 1H), 8.09-8.01(m, 3H), 7.76-7.71(m, 2H), 7.70-7.63(m, 2H), 7.61-7.55(m, 1H), 7.22(t, J= 7.6Hz, 1H), 2.10(s, 3H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 169.95, 166.04, 141.11, 134.85, 134.32, 134.28, 134.22, 133.45, 131.41, 131.27, 128.45, 128.27, 128.80 , ^{127.46,127.33,126.40,123.41,122.86,119.77,116.25,13.92ppm} ; HRMS(EI) _calc.for C ₂₁ H ₁₆ ⁷⁹ BrNO ₃ ⁺ _409.0314 ,found ^409.0316 _; found 411.0302.

Example 56 (Z)-2-(3-(1-bromonaphthalen-2-yl)-2-chloroacrylamido)-5-fluorobenzoic acid (Compound 56)

The preparation method is similar to that of Example 37, except that 1-bromo-2-naphthaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 14.24 (s, 1H), 12.22 (s, 1H), 8.71 (dd, J=9.2, 5.2 Hz, 1H), 8.01-7.93 (m, 3H) ,7.74(dd,J=9.2,3.2Hz,1H),7.63(s,1H),7.61(dd,J=8.6,1.2Hz,1H),7.59-7.49(m,3H)ppm; HRMS(EI) calc. for C ₂₀ H ₁₂ ⁷⁹ Br ³⁵ ClFNO ₃ ⁺ 446.9673, found446.9678.

Example 57 (E)-2-(3-(1-bromonaphthalen-2-yl)-2-methacrylamido)-5-fluorobenzoic acid (Compound 57)

The preparation method is similar to that of Example 1, except that 1-bromo-2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

Melting point: 261.9-262.7°C; ¹ H NMR (400MHz, DMSO-d6): δ14.17(s, 1H), 11.79(s, 1H), 8.76(dd, J=9.2, 5.2Hz, 1H), 8.27( d,J=8.4Hz,1H),8.07-8.03(m,2H),7.77(dd,J=9.2,3.2Hz,1H),7.75-7.71(m,2H),7.69-7.65(m,1H) , 7.60-7.54 (m, 2H), 2.09 (d, J=1.6 Hz, 3H) ppm; ¹³ C NMR (100 MHz, DMSO-d6): δ 168.72, 165.94, 156.79 (d, ¹ J _CF =239.9 Hz), 137.55 (d, ⁴ J _CF = 2.2Hz), 134.91, 134.24, 134.04, 133.45, 131.41, 128.44, 128.26, 127.79, 127.42, 127.32, 126.40, 123.40, 122.00 (d, ³ J _CF = 7.2 Hz) d, ² J _CF = 21.6 Hz), 118.31 (d, ³ J _CF = 6.8 Hz), 116.99 (d, ² J _CF = 23.6 Hz), 13.88 ppm; ¹⁹ F NMR (376 MHz, DMSO-d6): δ- 118.64--118.72(m, 1F)ppm; HRMS(EI) calc.for C ₂₁ H ₁₅ ⁷⁹ BrFNO ₃ ⁺ 427.0219, found 427.0216; calc. for C ₂₁ H ₁₅ ⁸¹ BrFNO ₃ ⁺ 429.0199, found 429.0189.

Example 58 (E)-2-(3-(1-Fluoro-6-methoxynaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 58)

The preparation method is similar to that of Example 1, except that 1-fluoro-6-methoxy-2-naphthalenecarboxaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₂ H ₁₈ FNO ₄ ⁺ 379.1220, found 379.1226.

Example 59 (E)-2-(3-(6-Bromo-1-fluoronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 59)

The preparation method is similar to that of Example 1, except that 6-bromo-1-fluoro-2-naphthalenecarboxaldehyde is used as the starting material.

HRMS(EI) calc. for C ₂₁ H ₁₅ ⁷⁹ BrFNO ₃ ⁺ 427.0219, found 427.0217; calc. for C ₂₁ H ₁₅ ⁸¹ BrFNO ₃ ⁺ 429.0199, found 429.0192.

Example 60 (E)-2-(3-(1,6-dichloronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 60)

The preparation method is similar to that of Example 1, except that 1,6-dichloro-2-naphthalenecarboxaldehyde is used as the starting material.

HRMS(EI) calc.for C ₂₁ H ₁₅ ³⁵ Cl ₂ NO ₃ ⁺ 399.0429, found 399.0427; calc. for C ₂₁ H ₁₅ ³⁵ Cl ³⁷ ClNO ₃ ⁺ 401.0399, found 401.0392; calc. for C ₂₁ H ₁₅ ³⁷ Cl ₂ NO ₃ ⁺ 403.0396, found403.0394.

Example 61 (E)-2-(3-(1,6-dichloronaphthalen-2-yl)-2-methacrylamido)-5-fluorobenzoic acid (Compound 61)

The preparation method is similar to the method in Example 1, except that 1,6-dichloro-2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-5-fluorobenzoic acid.

HRMS(EI) calc.for C ₂₁ H ₁₅ ³⁵ Cl ₂ FNO ₃ ⁺ 417.0335, found 417.0336; calc. for C ₂₁ H ₁₅ ³⁵ Cl ³⁷ ClFNO ₃ ⁺ 419.0305, found 419.0302; calc. for C ₂₁ H ₁₅ ³⁷ Cl ₂ FNO ₃ ⁺ 421.0275, found421.0277.

Example 62 (E)-2-(3-(5-Chloro-1-fluoronaphthalen-2-yl)-2-methacrylamido)benzoic acid (Compound 62)

The preparation method is similar to that of Example 1, except that 5-chloro-1-fluoro-2-naphthalenecarboxaldehyde is used as the starting material.

HRMS (EI) calc. for C ₂₁ H ₁₅ ³⁵ ClFNO ₃ ⁺ 383.0724, found 383.0722; calc. for C ₂₁ H ₁₅ ³⁷ ClFNO ₃ ⁺ 385.0694, found 385.0692.

Example 63 (E)-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)thiophene-3-carboxylic acid (Compound 63)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-3-thiophenecarboxylic acid.

Melting point: 219.0-219.9°C; ¹ H NMR (400MHz, DMSO-d6): δ 13.36(s, 1H), 11.93(s, 1H), 8.07(s, 1H), 8.04-7.93(m, 3H), 7.76(s, 1H), 7.64(d, J=8.4Hz, 1H), 7.57(s, 2H), 7.23(d, J=5.6Hz, 1H), 7.04(d, J=5.6Hz, 1H), 2.31(s,3H)ppm; ¹³ C NMR (100MHz, DMSO-d6): δ166.75,164.77,147.92,136.27,132.76,132.70,132.51,130.01,129.14,128.26,127.98,127.54,126.06,123 , 116.68, 114.14, 13.69 ppm; HRMS (ES+) calcd for C ₁₉ H ₁₅ NO ₃ SNa (M+Na) ⁺ , 360.0670; found, 360.0672.

Said 2-amino-3-thiophenecarboxylic acid can be prepared by the following main steps:

2-Amino-3-thiophene methyl ester (314 mg, 2.0 mmol) was dispersed in 10 mL of water and 10 mL of methanol mixed solvent, sodium hydroxide (1.6 g, 40.0 mmol) was added, under argon protection, refluxed for 2 hours, cooled, Spin off methanol, acidify with 1M HCl, extract with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify on silica gel column (dichloromethane:methanol=10:1) to obtain 2- Amino-3-thiophenecarboxylic acid, yield 46%.

Example 64 (E)-4-methyl-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)thiophene-3-carboxylic acid (Compound 64)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-4-methylthiophene-3-carboxylic acid.

HRMS(EI) calc. for _C20H17NO3S ⁺ _351.0929 , found _351.0926 .

Example 65 (E)-4,5-dimethyl-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)thiophene-3-carboxylic acid (Compound 65)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-amino-4,5-dimethylthiophene-3-carboxylic acid.

HRMS(EI) calc. for _C21H19NO3S ⁺ _365.1086 , found _365.1081 .

Example 66 (E)-4-(2-methyl-3-(naphthalen-2-yl)acrylamido)nicotinic acid (Compound 66)

The preparation method of raw material (E)-2-methyl-3-(naphthalene-2-yl) acrylic acid is similar to the synthesis method of (E)-2-methyl-3-phenyl acrylic acid in Example 1, the difference lies in , using 2-naphthaldehyde as the starting material.

(E)-2-methyl-3-(naphthalen-2-yl)acrylic acid (212 mg, 1.0 mmol) was dispersed in dry dichloromethane (3 mL), cooled in an ice bath, and oxalyl chloride (381 mg) was added dropwise thereto. , 3.0 mmol), dropwise add a drop of dimethylformamide, put on a drying tube, react at room temperature for 3 h, and remove the solvent under reduced pressure to obtain an acid chloride intermediate, which is dissolved in 1 mL of pyridine.

4-Aminonicotinic acid (138 mg, 1.0 mmol) was dispersed in 2 mL of pyridine, cooled in an ice bath, the above acid chloride pyridine solution was added dropwise thereto, and the reaction was carried out at room temperature overnight. 5 mL of water was added dropwise to the reaction solution, filtered with suction, the filter cake was washed with an appropriate amount of water, dried, and separated and purified on a silica gel column (dichloromethane:methanol=3:1) to obtain compound 66 in a yield of 30%. Melting point: 303.3-304.2°C; ¹ H NMR (400MHz, DMSO-d6): δ14.55(s, 1H), 9.11(s, 1H), 8.51(d, J=5.6Hz, 1H), 8.46(d, J=5.6Hz, 1H), 8.02(s, 1H), 7.97(d, J=8.4Hz, 2H), 7.94(d, J=5.2Hz, 1H), 7.69(s, 1H), 7.61(d, J=8.4Hz, 1H), 7.58-7.52 (m, 2H), 2.27 (s, 3H) ppm. ¹³ C NMR (100MHz, DMSO-d6): δ169.28, 167.65, 152.54, 151.23, 147.21, 134.69, 133.23, 133.02,132.73,132.35,128.82,128.17,127.88,127.51,127.08,126.70,126.49,118.00,112.44,14.09ppm.HRMS(ES+)calcd forC ₂₀ H ₁₇ N ₂ O ₃ (M+H) ⁺ ,333 , 333.1241.

Example 67 (E)-N-(2-cyanophenyl)-2-methyl-3-(naphthalen-2-yl)acrylamide (Compound 67)

The preparation method is similar to the method in Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with o-cyanobenzoic acid.

HRMS(EI) calc. for C ₂₁ H ₁₆ N ₂ O ⁺ 312.1263, found 312.1266.

Example 68 (E)-2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzamide (Compound 68)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-aminobenzamide.

Melting point: 169.8-170.6°C; ¹ H NMR (400MHz, DMSO-d6): δ12.57(s, 1H), 8.69(d, J=8.0Hz, 1H), 8.39(s, 1H), 8.03(s, 1H),8.00-7.93(m,3H),7.89(dd,J=7.6,1.2Hz,1H),7.83(s,1H),7.64(s,1H),7.61(dd,J=8.4,1.2Hz , 1H), 7.59-7.54 (m, 3H), 7.20-7.14 (m, 1H), 2.27 (d, J=0.8Hz, 1H) ppm; ¹³ C NMR (100MHz, DMSO-d6): δ 171.07, 166.67, 140.14,134.17,133.24,133.05,132.75,132.42,132.33,128.73,128.66,128.17,127.89,127.51,127.09,126.66,126.48,122.42,120.06,119.25,14.05ppm；HRMS(EI)calc.for C ₂₁ H ₁₈ N ₂ O ₂ ⁺ 330.1368, found 330.1371.

Example 69 (E)-Methyl 2-(2-methyl-3-(naphthalen-2-yl)acrylamido)benzoate (Compound 69)

Compound 34 (1.0 mmol) and 5 mL of dichloromethane were sequentially added to a reaction flask covered with a drying tube, cooled in an ice bath, and 3 mmol of oxalyl chloride, one drop of DMF and 1.5 mmol of methanol were added dropwise to the reaction solution. The reaction was carried out at room temperature for 12 h, the reaction solution was spin-dried and concentrated, and the silica gel column was separated and purified (petroleum ether:ethyl acetate=3:1) to obtain compound 64 with a yield of 40%. Melting point: 113.4-114.2°C; ¹ H NMR (400MHz, CDCl ₃ ): δ 11.71 (s, 1H), 8.90 (d, J=8.4Hz, 1H), 8.08 (dd, J=8.0, 1.6Hz, 1H) ),7.89-7.83(m,4H),7.78(s,1H),7.63-7.58(m,1H),7.54(dd,J=8.6,1.4Hz,1H),7.52-7.48(m,2H), 7.14-7.09 (m, 1H), 3.95 (s, 3H), 2.37 (d, J=1.2Hz, 3H) ppm; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 168.93, 167.99, 141.92, 135.71, 134.76, 133.76 , 133.16, 132.99, 132.81, 130.94, 128.99, 128.23, ^127.92 , 127.68, 127.19, _126.52 , _126.39 , 122.52, 120.62, 115.24, 52.42, _14.31ppm ; HRMS(EI) calc. found 345.1366.

Example 70 (E)-2-methyl-3-(naphthalen-2-yl)-N-(pyridin-2-yl)acrylamide (Compound 70)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 2-aminopyridine.

HRMS(EI) calc. for C ₁₉ H ₁₆ N ₂ O ⁺ 288.1263, found 288.1261.

Example 71 (E)-N-(2-cyano-1-cyclopenten-1-yl)-2-methyl-3-(naphthalen-2-yl)acrylamide (Compound 71)

The preparation method is similar to that of Example 1, except that 2-naphthalenecarboxaldehyde is used as the starting material, and anthranilic acid is replaced with 1-amino-2-cyano-1-cyclopentene.

HRMS(EI) calc. for C ₂₀ H ₁₈ N ₂ O ⁺ 302.1419, found 302.1415.

Example 72 DHODH inhibitory activity test of the compounds of the present invention

DHODH can catalyze the oxidation of its natural substrate DHO (dihydroorotic acid) to Orotate under certain conditions. Under the catalysis of DHODH, the two H ⁺ and e ^- of the substrate DHO are firstly transferred to the coenzyme FMN, and then the reduced FMNH ₂ transfers electrons to the free coenzyme Q. The free coenzyme Q finally transfers electrons to the chromogenic substrate DCIP, which is reduced. DCIP has a maximum light absorption at 600 nm, while DCIP in the reduced state has no light absorption at 600 nm. The degree of oxidation of the substrate DHO can be judged according to the decrease in absorbance. The degree of oxidation of the substrate DHO per unit time is the initial rate of the enzymatic reaction. After adding the inhibitor, the initial rate of the enzymatic reaction decreases. A 96-well plate was used for the determination, and the absorbance at 600 nm was read by a BioTek microplate reader. 199 μL of assay buffer (50 mM HEPES (pH 8.0), 0.15 M KCl, 0.1% Triton X-100, 100 μM Coenzyme Q, 100 μM DCIP) was added to each well. Add 0.4 μL of compound, incubate at room temperature for 5 min, then add 1 μL of substrate DHO (final concentration 500 μM) to each well and mix well, then immediately measure the absorbance at 600 nm with a microplate reader, and read the data every 30 s for a total of 6 min . At least 3 parallels were set up for each experiment. Finally, the inhibition rates of different concentrations of compounds were calculated, and the IC ₅₀ value of the half effective inhibitory concentration was calculated by Origin8.0. Specific reference is Sci.Rep., 2015.5:14836.

Table 1 Activity list of representative compounds 1-71

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (11)

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

in the formula (I), the compound is shown in the specification,

a is

B is unsubstituted or substituted phenyl; said substituted means substituted with a group selected from the group consisting of: halogen, carboxyl (-COOH), C _1-6 An ester group;

R ₁ is hydrogen;

R ₂ selected from the group consisting of: hydrogen, halogen, C _1-6 An alkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from compounds of formula II:

in the formula (I), the compound is shown in the specification,

a is

X is CY, wherein Y is selected from the group consisting of: carboxy, C _1-6 An ester group;

R ₃ 、R ₄ is hydrogen;

R ₅ is hydrogen or halogen.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is carboxy.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is ₂ Selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl.

5. The compound of claim 2 or pharmaceutically acceptable thereofA salt, characterized in that R ₅ Hydrogen, fluorine or chlorine.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

7. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.

9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8,

for the preparation of inhibitors of dihydroorotate dehydrogenase; or

For the preparation of a medicament for the prevention or treatment of a pathological condition or disease ameliorated by the inhibition of dihydroorotate dehydrogenase.

10. Use according to claim 9, wherein the pathological condition or disease is selected from the group consisting of: cancer, colitis, lupus erythematosus, anti-organ transplant rejection, melanoma, psoriasis, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, and malaria.

11. Use according to claim 9, wherein the pathological condition or disease is rheumatoid arthritis.