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

N-substituted acrylamide derivative as DHODH inhibitor and preparation and application thereof Download PDF

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CN110357789B
CN110357789B CN201810321850.XA CN201810321850A CN110357789B CN 110357789 B CN110357789 B CN 110357789B CN 201810321850 A CN201810321850 A CN 201810321850A CN 110357789 B CN110357789 B CN 110357789B
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CN110357789A (en
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徐晓勇
李洪林
李忠
李诗良
曾凡勋
王蕊
章乐天
朱丽丽
齐甜甜
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East China University of Science and Technology
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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 derivative as DHODH inhibitor and preparation and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and particularly relates to an N-substituted acrylamide derivative serving as a DHODH inhibitor, and preparation and application thereof.
Background
Dihydroorotate dehydrogenase (DHODH) is an iron-containing flavin-dependent mitochondrial enzyme that is the intracellular rate-limiting enzyme in nucleic acid pyrimidine synthesis, catalyzing the fourth reaction in the de novo pyrimidine biosynthetic pathway. Inhibiting DHODH can block the synthesis of new pyrimidines, which leads to DNA and RNA synthesis disorders. In most organisms pyrimidine synthesis occurs in two ways: salvage pathways and de novo synthesis from small molecules. The demand for pyrimidines by organisms depends on the cell type and the differentiation stage in which the cells in rest and differentiation stages take up pyrimidines only in small part by de novo synthesis pathways, and rely primarily on salvage pathways. In contrast, rapidly differentiating human cells, such as activated T-lymphocytes, B-lymphocytes and tumor cells, require de novo pyrimidine synthesis to meet their growth requirements in order to meet the needs of the organism for nucleotide precursors and other cellular components, which makes DHODH inhibitors useful as anti-cell proliferation agents for the treatment of tumors and certain immunosuppressive reactions.
Leflunomide (leflunomide, LEF) which is marketed in 1998 is a novel isoxazole immunomodulator, and is mainly used for clinically treating autoimmune diseases such as rheumatoid arthritis and lupus erythematosus and preventing and treating acute and chronic rejection and xeno-rejection of organ transplantation. Leflunomide was later found to be a prodrug that is rapidly converted to the active metabolite a771726(MI) after oral administration via the cytosol and microsomes of the liver and intestinal wall. MI is a good inhibitor of dihydroorotate dehydrogenase in human body, and can block the de novo biosynthesis of pyrimidine, thereby influencing the synthesis of DNA and RNA. Research shows that MI may be used in preventing, treating or inhibiting various kinds of autoimmune diseases, acute and chronic rejection and heterorejection of organ transplantation, psoriasis and other dermatosis, etc.
Figure BDA0001625483630000011
Brequinar, originally studied as an anticancer drug, is one of the most potent DHODH inhibitors, but clinical phase II experiments have demonstrated its antitumor effects in general, and this compound continues to be developed as an immunosuppressant. 4SC-101 is proved to have better inhibitory action on lupus erythematosus and enteritis and is in the clinical development stage.
Because the long-term use of leflunomide can generate drug resistance and side effects such as liver enzyme abnormality, hypertension or rash, the search for a novel DHODH inhibitor with high efficiency and small side effect is still a research hotspot in the treatment of immune related diseases and tumors.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and can be used as a DHODH inhibitor, and a preparation method and application thereof.
The invention provides a compound shown in the formula I or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug or a pharmaceutically acceptable salt, a solvate or a crystal form thereof:
Figure BDA0001625483630000021
in the formula (I), the compound is shown in the specification,
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 with a group selected from the group consisting of: halogen, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-7 Cycloalkyl radical, C 5-7 Cycloalkenyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 6 -C 10 Aryl radical, C 6 -C 10 Aryloxy radical, C 6 -C 10 aryl-NH-CO-, -O- (CH) 2 )m-O-、-(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 radical, C 6 -C 10 Aryl, 5-10 membered heterocyclyl; by substituted is meant substituted with a group selected from the group consisting of: halogen, cyano (-CN), nitro (-COOH), carboxyl (-COOH), amido (-CONH) 2 ) Sulfonic acid group, sulfonamide, C 1-6 Sulfonate, hydroxy, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl halide carbonyl group, C 1-6 Aldehyde group, C 1-6 Ester group, C 1-6 Hydrazidyl, guanidino, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, C 2-6 Alkenyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 6 -C 10 Aryl radical, C 6 -C 10 Aryloxy radical, C 6 -C 10 aryl-NH-CO-, -O-CH 2 -O-、-(CH 2 ) n-; wherein n is an integer of 2-4;
R 1 selected from the group consisting of: hydrogen, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 3-7 Cycloalkyl radical, C 5-7 A cycloalkenyl group;
R 2 selected from the group consisting of: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 3-7 Cycloalkyl radical, C 5-7 (iii) a cycloalkenyl group.
In another preferred embodiment, the compound is selected from compounds represented by formula II:
Figure BDA0001625483630000022
in the formula (I), the compound is shown in the specification,
a and R 2 The definition is the same as the previous definition;
x represents a nitrogen atom or a group CY, wherein Y is selected from the group consisting of: carboxyl group, amide group, sulfonic group, sulfonamide group, C 1-6 Sulfonate, hydroxy, C 1-6 Alkylcarbonyl group, C 1-6 Haloalkylcarbonyl group, C 1-6 Aldehyde group, C 1-6 Ester group, C 1-6 Hydrazide, cyano, nitro, guanidino;
R 3 、R 4 、R 5 each independently selected from the group consisting of: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 3-7 Cycloalkyl radical, C 2-6 Alkenyl radical, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkoxy, C 6 -C 10 Aryl radical, C 6 -C 10 Aryloxy radical, 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, Y is selected from the group consisting of: carboxyl, amido, cyano.
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 group consisting of:
Figure BDA0001625483630000031
in another preferred embodiment, R 2 Selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl, cyclopropyl.
In another preferred embodiment, R 3 、R 4 、R 5 Each independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl radical, C 1-4 Halogenated alkanes, C 3-7 Cycloalkyl radical, C 1-4 Alkoxy, hydroxy.
In another preferred embodiment, R 3 、R 4 、R 5 Each independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, methyl, ethyl, methoxy, cyclopropyl, hydroxy.
In another preferred embodiment, the compound is selected from compounds represented by formula III:
Figure BDA0001625483630000032
in the formula (I), the compound is shown in the specification,
b and R 2 The definition is the same as the previous definition;
R 6 、R 7 、R 8 、R 9 、R 10 each independently selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl radical, C 1-6 A halogenated alkane,C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-7 Cycloalkyl radical, C 5-7 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 6 -C 10 Aryl radical, C 6 -C 10 Aryloxy group, 5-or 6-membered heterocyclic group, hydroxy group, C 6 -C 10 aryl-NH-CO-;
or R 6 、R 7 、R 8 、R 9 、R 10 Any two of which may be linked to form-O- (CH) 2 )m-O-、-(CH 2 ) n-, -CH ═ CH-; wherein m or n is an integer of 1 to 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 (iii) a cycloalkenyl group.
In another preferred embodiment, the 5-or 6-membered heterocyclyl is selected from the group consisting of: pyridyl, thienyl, furyl.
In another preferred embodiment, B is selected from the group consisting of:
Figure BDA0001625483630000041
in another preferred embodiment, R 8 And R 9 Can be linked to form-O- (CH) 2 )m-O-、-(CH 2 ) n-, -CH ═ CH-; wherein m or n is an integer of 1 to 4.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect, or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug or a pharmaceutically acceptable salt, solvate or crystal form thereof; and a pharmaceutically acceptable carrier or excipient.
In another preferred embodiment, the pharmaceutical composition is an injection, a sachet (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, an emulsion, a suspension, an aerosol, a suppository, an infusion, an ointment, a cream, and a tincture.
The third aspect of the present invention provides the use of a compound of the first aspect, or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug or a pharmaceutically acceptable salt, solvate, or crystal form thereof, or a pharmaceutical composition of the second aspect, for the preparation of a dihydroorotate dehydrogenase inhibitor; for the preparation of pyrimidine biosynthetic enzyme inhibitors; and/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 and/or the inhibition of pyrimidine biosynthetic enzymes.
In another preferred embodiment, said 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, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, and malaria.
The fourth aspect of the present invention provides a method for preparing the compound of the first aspect, or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug, a pharmaceutically acceptable salt, a solvate or a crystal form thereof,
the method is a method 1, and comprises the following steps:
Figure BDA0001625483630000051
(1) reacting compound 1 and compound 2 in an inert solvent to form compound 3;
(2) in an inert solvent, compound 3 undergoes a hydrolysis reaction, thereby forming compound 4;
(3) reacting compound 4, followed by oxalyl chloride and compound 5, in an inert solvent, to form compound 6;
or the method is method 2, comprising the steps of:
Figure BDA0001625483630000052
(1) reacting compound 7 with TsCl in an inert solvent, thereby forming compound 8;
(2) reacting compound 8 and compound 5 in an inert solvent to form compound 6;
or the method is method 3, comprising the steps of:
Figure BDA0001625483630000053
(1) reacting compound 1 and compound 9 in an inert solvent to form compound 10;
(2) reacting compound 10 with oxalyl chloride, followed by compound 5, in an inert solvent, to form compound 6;
or the method is method 4, comprising the steps of:
Figure BDA0001625483630000054
(1) reacting compound 1 with compound 11 and NCS or NBS in an inert solvent to form compound 12;
(2) compound 12 undergoes a hydrolysis reaction in an inert solvent, thereby forming compound 13;
(3) reacting compound 13 with oxalyl chloride, followed by compound 5, in an inert solvent, to form compound 6;
or the method is method 5, comprising the steps of:
Figure BDA0001625483630000061
(1) reacting compound 15 and compound 16 in an inert solvent to form compound 17;
(2) compound 17 undergoes a hydrolysis reaction in an inert solvent to form compound 18;
(3) reacting compound 18, followed by oxalyl chloride and compound 5, in an inert solvent, to form compound 19;
or the method is method 6, comprising the steps of:
Figure BDA0001625483630000062
(1) reacting compound 1 and compound 20 in an inert solvent to form compound 21;
(2) reacting compound 21, followed by oxalyl chloride and compound 5, in an inert solvent, to form compound 22;
or the method is method 7, comprising the steps of:
Figure BDA0001625483630000063
(1) reacting compound 1 and compound 23 in an inert solvent to form compound 24;
(2) subjecting compound 24 to a hydrolysis reaction in an inert solvent, thereby forming compound 25;
(3) reacting compound 25, followed by oxalyl chloride and compound 5, in an inert solvent, to form compound 26;
in the above formulae, other groups than the groups given have the same meanings as defined above.
The present invention provides a method of treatment or prevention comprising administering the compound of the present invention or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug or a pharmaceutically acceptable salt, solvate or crystalline form thereof or the pharmaceutical composition of the present invention to a subject in need thereof.
In another preferred embodiment, the compound is a compound of formula I, formula II, or formula III.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.
Detailed Description
The inventors of the present invention have conducted extensive and intensive studies and unexpectedly found a DHODH inhibitor having a novel structure and excellent performance for the first time. The present invention has been completed on the basis of this finding.
Term(s) for
The term "C" as used herein 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "C 2-6 The alkenyl group "means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
The term "C 2-6 Alkynyl "means a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, or the like.
The term "C 3-7 Cycloalkyl "refers to a cyclic alkyl group having 3 to 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 to 7 carbon atoms with one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl, or the like.
As used herein, the term "C 1-6 Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine.
The term "C 1-6 The haloalkane "means a straight-chain or branched alkane having 1 to 6 carbon atoms, which is substituted with the same or different one or more of the above halogen atoms, for example, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.
The term "aryl" refers to monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbon atoms and includes phenyl, naphthyl, phenanthryl, anthryl, indenyl, fluorenyl, tetralinyl, indanyl and the like. As used herein, an aryl group may be optionally substituted with one or more substituents described herein.
The term "aryloxy" refers to aryl-O-, such as phenoxy: (
Figure BDA0001625483630000071
The position marked by the curve is the substitution position, the same from top to bottom).
The term "heterocyclyl" refers to a single or fused ring structure, which may be aromatic and non-aromatic in nature, and which preferably contains from 3 to 20 ring atoms, more preferably from 5 to 14 or from 5 to 10 ring atoms, of which at least 1 and preferably up to 4 are heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heterocyclic groups herein include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, morpholinyl, carbazolyl, dibenzothienyl, 1, 2-methylenedioxyphenyl, indolyl, indazolyl, benzimidazolyl, benzo [ d ] [1,2,3] thiadiazolyl, imidazo [1,2-a ] pyridyl, cinnolinyl, phthalazinyl, 1, 8-naphthyridinyl, or benzo [ d ] [1,2,3] triazin-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, for example, pyridyl, thiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrimidinyl, tetrahydrofuryl, oxazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, or 1,3, 4-oxadiazolyl, and the like.
The term "C" as used herein 1-6 Sulfonate group "means a sulfonate group (C) having 1 to 6 carbon atoms 1-6 alkyl-S (═ O) 2 O-)。
The term "C" as used herein 1-6 Alkyl carbonylRadical "means C 1-6 alkyl-C ═ O-.
The term "C" as used herein 1-6 The "ester group" means C 1-5 alkyl-C (═ O) O-).
The term "C" as used herein 1-6 The "hydrazide group" means-C 1-6 alkyl-C ═ O-NHNH 2 Or C 1-6 alkyl-C ═ O-NHNH-.
The term "C" as used herein 1-6 Aldehyde "means-C 1-5 alkyl-CHO.
The groups described herein, whether specifically stated as "unsubstituted or optionally substituted" or "unsubstituted or optionally substituted" may be substituted with from 0 to more (typically 0, 1,2 or 3) substituents selected from the group consisting of: halogen, cyano, nitro, amino, carboxyl, mercapto, hydroxy, hydroxymethyl, C 1-4 Aldehyde group, C 1-6 Alkyl radical, C 1-6 Haloalkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-7 Cycloalkyl radical, C 5-7 Cycloalkenyl radical, C 1-6 Alkoxy (e.g. methoxy), C 1-6 Thioalkyl (e.g. pentafluorothiomethyl), C 1-6 Thioalkoxy (e.g. pentafluorothiomethoxy), haloalkylcarbonyl (e.g. trifluoroacetyl), C 1-4 An optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted aryloxy group (e.g., an optionally substituted phenoxy group), an optionally substituted benzyloxy group, an optionally substituted arylcarboxamido group, and an optionally substituted arylcarbamyl group.
Preparation method
The compound of the invention can be prepared by the following method:
the method comprises the following steps:
Figure BDA0001625483630000081
the method 2 comprises the following steps:
Figure BDA0001625483630000082
the method 3 comprises the following steps:
Figure BDA0001625483630000091
the method 4 comprises the following steps:
Figure BDA0001625483630000092
the method 5 comprises the following steps:
Figure BDA0001625483630000093
the method 6 comprises the following steps:
Figure BDA0001625483630000094
the method 7 comprises the following steps:
Figure BDA0001625483630000101
the aldehyde-based compound used as the raw material can be purchased directly from a reagent company or prepared by the following method:
1. from substituted formic acid:
Figure BDA0001625483630000102
2. prepared from methyl-containing raw materials:
Figure BDA0001625483630000103
in the above preparation schemes, A and B are as defined above. The compounds of the present invention can be prepared by those skilled in the art according to the actual preparation needs, using various starting compounds conventionally obtained in the art as starting materials.
In a preferred embodiment, the compounds of the present invention are synthesized by a method comprising the steps of:
the starting aldehyde-based compound can be purchased directly from a reagent company or synthesized by the following method.
1. From substituted formic acid:
Figure BDA0001625483630000104
substituted aromatic formic acid (10mmol) is weighed and dissolved in 25mL anhydrous THF, under the protection of argon, LiAlH is added into the solution slowly in portions under the ice bath condition 4 (20 mmol). After the reaction was carried out in ice bath for 10min, the reaction was carried out at room temperature for 4 hours, and after the reaction was completed, the reaction mixture was cooled in ice bath, and 0.76g of ice water, 0.76g of a 15% aqueous NaOH solution and 2.28g of water were slowly added dropwise thereto in this order. After stirring for a while, 20mL of water was added, the mixture was filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated by spin-drying under reduced pressure. Adding a proper amount of water into the concentrated solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain a crude product of the substituted benzyl alcohol, wherein the yield is 90-95%, and the crude product is directly used for the next reaction.
Dissolving the substituted benzyl alcohol obtained in the previous step in 100mL DCM, adding 70mmol MnO under stirring 2 Reacting for 4h at room temperature, filtering, spin-drying and concentrating the filtrate, and purifying by a column to obtain the substituted aromatic formaldehyde with the yield of 85-95%.
2. From arylmethyl groups:
Figure BDA0001625483630000111
the substituted arylmethyl compound (5mmol) was dissolved in 10mL of CCl 4 Adding 10mmol NBS and 0.1mmol BPO, refluxing for 5h, cooling to room temperature, filtering, washing the filter cake with a proper amount of petroleum ether, and concentrating by spin drying. The resulting concentrate was dissolved in 10mL of dioxane, 10mL of water, 20mmol of CaCO 3 Refluxing for 10h, filtering, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, concentrating by rotary drying, and purifying by column chromatographySubstituted benzyl alcohol was obtained in about 80% yield.
The substituted benzyl alcohol (4mmol) from the previous step was dissolved in 40mL DCM and 28mmol MnO was added with stirring 2 Reacting for 4h at room temperature, filtering, spin-drying and concentrating the filtrate, and purifying by a column to obtain the substituted aromatic formaldehyde with the yield of about 90 percent.
Figure BDA0001625483630000112
In each of the above formulae, A and B are as defined above;
dispersing a substituted aldehyde compound (5mmol) into 15mL DCM, adding 9mmol of carbethoxyethylidene triphenylphosphine, reacting for 12h at room temperature, removing part of solvent by rotation, and purifying by a column to obtain a 2-methyl-3-substituted ethyl acrylate intermediate with the yield of about 95%.
The 2-methyl-3-substituted ethyl acrylate (4mmol) obtained in the previous step was dissolved in 12mL of THF and 12mL of MeOH, and 16mL of 2M aqueous NaOH solution was added. Reacting at 40 ℃ for 5 h. Acidifying with 1M HCl, separating out white solid, filtering, washing with a proper amount of water, and drying the solid to obtain the 2-methyl 3-substituted acrylic acid with the yield of about 95%.
Dispersing the prepared 2-methyl 3-substituted acrylic acid (1mmol) in 3mL dry DCM, dropwise adding oxalyl chloride (3mmol) in an ice bath, dropwise adding one drop of DMF as a catalyst, sleeving a drying tube, reacting at room temperature for 3h, and concentrating by rotary removal of a solvent under reduced pressure to obtain an acyl chloride intermediate.
The amino compound (1.2mmol) was dissolved in 2mL DCM, 1.5mmol TEA and 0.1mmol DMAP were added, and the mixture was cooled in an ice bath. The prepared acyl chloride is dissolved in 1mL DCM, and is added into the reaction liquid in a dropwise manner, and the reaction is carried out at room temperature until the reaction is finished. Acidifying with 1M HCl, separating out solid, filtering, and recrystallizing with ethanol to obtain final product. The yield thereof was found to be about 70%.
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000113
in each of the above formulae, A and B are as defined above;
the starting 2-methyl-3-substituted acrylic acid is prepared analogously to the preferred examples described above. Adding 1mmol of 2-methyl 3-substituted acrylic acid, 1.1mmol of TsCl, 5mL of DCE, 0.1mmol of DMAP and 1.5mmol of TEA into a 25mL reaction bottle with a drying tube, reacting at 35 ℃ for 1h, adding 1mmol of an amino compound, reacting at 60 ℃ for 10h, acidifying with 1M HCl, filtering to obtain a solid, washing with water, drying, and purifying by a column to obtain a target product with the yield of about 50%.
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000121
in each of the above formulae, A and B are as defined above;
dispersing 2mmol of substituted aldehyde compound and 6mmol of malonic acid in 1.2mL of DMF, adding 2mmol of pyridine, reacting at 90 ℃ for 5h, cooling to room temperature, adding 1.2mL of water, acidifying with 1M HCl until the pH value is 2, performing suction filtration, washing with water twice, and drying a filter cake to obtain a 3-substituted acrylic acid intermediate with the yield of about 80%. The subsequent steps for preparing the target compound are similar to the above method for preparing the final product by using 2-methyl-3-substituted ethyl acrylate as a raw material.
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000122
in each of the above formulae, A and B are as defined above;
adding 9mmol of carbethoxymethylenetriphenylphosphine and 15mL of DCM into a reaction bottle, adding 9mmol of NCS or NBS in batches at-20 ℃ under the protection of argon, reacting for 1h at-20 ℃, and adding 5mmol of aldehyde compound and 12.5mmol of K at room temperature 2 CO 3 Reacting at room temperature for 10h, washing the reaction solution with water, drying the organic phase with anhydrous sodium sulfate, spin-drying and concentrating, and purifying by column chromatography to obtain 2-halo-3-substituted acrylic acidAnd (4) ethyl ester. The subsequent steps for preparing the target compound are similar to the above method for preparing the final product by using 2-methyl-3-substituted ethyl acrylate as a raw material.
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000131
in each of the above formulae, A and B are as defined above;
adding 4.2mmol NaH into a 50mL three-neck flask, adding 24mL anhydrous THF under the protection of argon, adding 3.9mmol 2-phosphono triethyl ester compound, stirring at room temperature for 0.5h, dropwise adding 12mL THF solution of carbonyl compound (3mmol) into the reaction solution, reacting at room temperature for 12h, acidifying with 2M HCl, removing THF, adding appropriate amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, removing solvent by spinning, concentrating, and purifying with a column to obtain an ethyl acrylate intermediate. The subsequent procedure for the preparation of the target compound is analogous to the above procedure for the preparation of the final product starting from 2-methyl-3-substituted ethyl acrylate.
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000132
6mmol of aldehyde compound, 4mmol of 3,3, 3-trifluoropropionic acid, 20mL of THF, and 8mL of 1M TiCl were added in this order to a reaction flask 4 The dichloromethane solution was stirred at room temperature for 0.5h, and 16mmol triethylamine was added dropwise to the reaction solution. After reacting at room temperature for 40 hours, slowly adding 30mL of water into a reaction bottle, extracting with dichloromethane, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, spinning the filtrate, and separating and purifying with a silica gel column (dichloromethane: methanol ═ 10: 1) to obtain a 2-trifluoromethyl acrylic acid intermediate. The subsequent steps for preparing the target compound are similar to the above method for preparing the final product by using 2-methyl-3-substituted ethyl acrylate as a raw material
In another preferred embodiment, the compounds of the present invention can be synthesized by a method comprising the steps of:
Figure BDA0001625483630000133
5mmol of aldehyde compound is dispersed in 7.5mL of methanol, 5mmol of methyl cyanoacetate and 0.5mmol of piperidine are added, and the reaction is refluxed until the reaction is completed. Cooling to room temperature, separating out solid, filtering, washing filter cake with right amount of methanol, and drying the filter cake to obtain 2-cyano-3-substituted methyl acrylate intermediate. The subsequent steps for preparing the target compound are similar to the above method for preparing the final product by using 2-methyl-3-substituted ethyl acrylate as a raw material.
Active ingredient
The compound is a compound shown in a general formula I, II or III, or a stereoisomer, a cis-trans isomer, a tautomer, a prodrug or a pharmaceutically acceptable salt, solvate or crystal form thereof.
Examples of the pharmaceutically acceptable salts according to the present invention include, but are not limited to, inorganic and organic acid salts, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids like formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. Another preferred class of salts is that formed with bases, for example alkali metal salts, especially sodium and potassium salts, of the compounds of the invention.
Pharmaceutical composition
The compound has excellent DHODH inhibitory activity and can be used for preparing medicaments for treating or preventing DHODH-mediated diseases.
The pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
Although the dosage of the drug required will vary from person to person, one skilled in the art can determine the optimal dosage of each active ingredient in the pharmaceutical composition of the invention. Typically, the compounds of the invention, or pharmaceutically acceptable salts thereof, are administered orally to a mammal daily at a dose of from 0.0025 to 50 mg/kg body weight, but preferably from about 0.01 to 10 mg/kg. For example, a unit oral dosage may include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the present invention. The unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, more preferably from about 0.25 to 10 mg, of a compound of the invention or a solvate thereof.
The pharmaceutical compositions of the present invention may be formulated for administration by a variety of routes of administration, including, but not limited to parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes for the treatment of tumors and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more symptoms. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some way reduce the symptoms associated with the disease. Such amounts may be administered as a single dose or may be administered according to an effective treatment regimen. The amount administered may be sufficient to cure the disease, but is generally administered to ameliorate the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms. The dosage of the drug will depend on the age, health and weight of the patient, the kind of concurrent treatment, the frequency of the treatment, and the desired therapeutic effect.
The pharmaceutical preparation of the present invention can be administered to any mammals as long as they can obtain the therapeutic effects of the compound of the present invention. Of these mammals, the most important is human.
The medicament or the pharmaceutical composition thereof can be used for treating or preventing various DHODH-mediated diseases, including cancer, rheumatoid arthritis, colitis, lupus erythematosus, glomerular diseases, organ transplant rejection resistance, melanoma, psoriasis, arthritis, fibrosis, rhinitis, psoriasis, multiple sclerosis, uveitis, asthma, leukemia, malaria and the like. Such cancers include, but are not limited to, breast cancer, prostate cancer, head and neck squamous cell carcinoma and multiple myelomas.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Pharmaceutically acceptable carriers include: fillers, bulking agents, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors or fragrances, buffer substances and the like, as well as solvents, solubilizers or agents for achieving a depot effect, and salts for varying the osmotic pressure, coating agents or antioxidants and the like. Specifically, examples of the pharmaceutically acceptable carrier moiety are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0001625483630000151
) Wetting agents (e.g., sodium lauryl sulfate), pyrogen-free water, and the like.
Solid dosage forms for oral administration include: capsules (e.g., 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 the following ingredients: (a) fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents such as paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells 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 delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. 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 compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, and in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils, or mixtures of such materials and the like. In addition to 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 as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration 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 which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds, for example, in combination with existing drugs for the treatment of the aforementioned diseases. In the latter case an increase in the efficacy is observed.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Example 1(E) -2- (2-methyl-3-phenylacrylamide yl) benzoic acid (Compound 1)
Figure BDA0001625483630000161
Benzaldehyde (5mmol) is dispersed into 15mL DCM, 9mmol of carbethoxyethylidene triphenylphosphine is added, the mixture reacts for 4h at room temperature, partial solvent is removed by rotation, and the ethyl (E) -2-methyl-3-phenylacrylate is obtained by column purification with the yield of 95%.
Ethyl (E) -2-methyl-3-phenylacrylate (4mmol) prepared in the previous step was dissolved in 12mL THF and 12mL MeOH, and 16mL 2M aqueous NaOH was added. Reacting for 5h at 40 ℃. Acidifying with 1M HCl, separating out white solid, filtering, washing with a proper amount of water, and drying the solid to obtain the (E) -2-methyl 3-phenyl acrylic acid with the yield of 95%.
Dispersing the prepared (E) -2-methyl 3-phenylacrylic acid (1mmol) in 3mL of dry DCM, dropwise adding oxalyl chloride (3mmol) in an ice bath, dropwise adding one drop of DMF as a catalyst, sleeving a drying tube, reacting at room temperature for 3h, and concentrating by rotary removal of a solvent under reduced pressure to obtain an acyl chloride intermediate.
Anthranilic acid (1.2mmol) was dissolved in 2mL DCM, 1.5mmol TEA and 0.1mmol DMAP were added, and the mixture was cooled in an ice bath. The prepared acyl chloride is dissolved in 1mL DCM, and is dripped into the reaction liquid to react at room temperature until the reaction is finished. Acidifying with 1M HCl, separating out solid, filtering, and recrystallizing with ethanol to obtain final product. The yield thereof was found to be 70%.
Melting point: 179.1-181.6 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.76(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 C NMR(100MHz,DMSO-d6):δ169.91,166.89,141.25,135.57,134.54,134.26,132.50,131.21,129.43,128.51,128.20,122.68,119.73,116.22,13.87ppm；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 was carried out in analogy to the procedure of example 1, but with the difference that 4-trifluoromethylbenzaldehyde was used as starting material.
Figure BDA0001625483630000171
Melting point: 211.6-212.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.78(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； 19 F 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 process is similar to that of example 1, except that 6-trifluoromethylpyridine-3-carbaldehyde is used as a starting material.
Figure BDA0001625483630000172
Melting point: 267.6-268.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.81(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):δ169.86,165.99,150.47,145.19(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 ＝264.8Hz),122.97,120.47(q, 3 J CF ＝2.7Hz),119.86,116.49,13.90ppm； 19 F NMR(376MHz,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 process is similar to that of example 1, except that 4-methoxybenzaldehyde is used as the starting material.
Figure BDA0001625483630000173
Melting point: 191.4 to 192.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.73(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＝1.2Hz,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ169.93,167.14,159.21,141.39,134.37,134.24,131.18,130.26,127.93,122.53,119.67,116.09,114.01,55.19,13.89ppm；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 process is similar to that of example 1, except that 4-tert-butylbenzaldehyde is used as starting material.
Figure BDA0001625483630000181
Melting point: 179.9 to 180.9 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.74(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):δ169.92,166.96,150.86,141.33,134.45,134.24,132.74,131.71,131.20,129.32,125.28,122.59,119.69,116.12,34.39,30.96,13.90ppm；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 process is similar to that of example 1, except that 4-chloro-3-trifluoromethylbenzaldehyde is used as a starting material.
Figure BDA0001625483630000182
Melting point: 192.4-193.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.80(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):δ169.86,166.37,141.03,135.32,134.99,134.57,134.26,131.92,131.78,131.22,130.08(q, 3 J CF ＝1.5Hz),128.64(q, 3 J CF ＝5.2Hz),126.75(q, 2 J CF ＝30.6Hz),124.04,122.68(q, 1 J CF ＝271.5Hz),119.78,116.37,13.80ppm； 19 F NMR(376MHz,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 H 13 37 ClF 3 NO 3 + 385.0507,found 385.0515。
example 7(E) -2- (3- (3-chloro-4-methylphenyl) -2-methacrylamido) benzoic acid (Compound 7)
The preparation was carried out in analogy to the procedure of example 1, but with the difference that 3-chloro-4-methylbenzaldehyde was used as starting material.
Figure BDA0001625483630000191
Melting point: 225.6-226.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.76(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):δ169.89,166.68,141.17,135.46,135.17,134.24,133.36,133.24,132.98,131.26,131.20,129.47,128.06,122.72,119.72,116.26,19.39,13.86ppm；HRMS(EI)calc.for C 18 H 16 35 ClNO 3 + 329.0819,found 329.0823；calc.for C 18 H 16 37 ClNO 3 + 331.0789,found 331.0791。
example 8(E) -2- (3- (3, 4-dichlorophenyl) -2-methacrylamido) benzoic acid (Compound 8)
The preparation process is similar to that of example 1, except that 3, 4-dichlorobenzaldehyde is used as the starting material.
Figure BDA0001625483630000192
Melting point: 211.8-212.5 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.78(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 Cl 37 ClNO 3 + 351.0243,found 351.0253；calc.for C 17 H 13 37 Cl 2 NO 3 + 353.0214,found 353.0196。
example 9(E) -2- (3- (3, 5-dichlorophenyl) -2-methacrylamido) benzoic acid (Compound 9)
The preparation is analogous to that of example 1, except that 35-dichlorobenzaldehyde is used as starting material.
Figure BDA0001625483630000193
Melting point: 222.5-223.3 deg.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 C NMR(100MHz,DMSO-d6):δ169.84,166.27,140.99,139.25,135.34,134.27,134.16,131.80,131.23,127.79,127.50,122.91,119.78,116.41,13.86ppm；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,found 351.0251；calc.for C 17 H 13 37 Cl 2 NO 3 + 353.0214,found 353.0206。
example 10(E) -2- (3- (3, 4-dimethylphenyl) -2-methacrylamido) benzoic acid (Compound 10)
The preparation process is similar to that of example 1, except that 3, 4-dimethylbenzaldehyde is used as a starting material.
Figure BDA0001625483630000201
Melting point: 221.4-222.3 ℃; 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＝1.2Hz,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ169.94,167.03,141.36,136.62,136.34,134.64,134.23,133.08,131.45,131.20,130.61,129.58,126.91,122.54,119.66,116.08,19.33,19.18,13.92ppm；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 process is similar to that of example 1, except that 3, 4-dimethoxybenzaldehyde is used as the starting material.
Figure BDA0001625483630000202
Melting point: 170.0-170.9 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.74(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(100MHz,DMSO-d6):δ169.91,167.16,148.94,148.46,141.40,134.74,134.23,131.20,130.42,128.17,122.61,122.52,119.68,116.09,113.21,111.58,55.49,13.96ppm；HRMS(EI)calc.for C 19 H 19 NO 5 + 341.1263,found 341.1262。
example 12(E) -2- (3- (1, 3-benzodioxol-5-yl) -2-methacrylamido) benzoic acid (Compound 12)
The preparation is analogous to that of example 1, but differs from this in that 1, 3-benzodioxole-5-carbaldehyde is used as starting material.
Figure BDA0001625483630000203
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 process is similar to that of example 1, except that 2, 3-dihydro-1H-indene-5-carbaldehyde is used as the starting material.
Figure BDA0001625483630000211
Melting point: 185.4 to 186.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.75(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)
Figure BDA0001625483630000212
Dissolving 5,6,7, 8-tetrahydronaphthalene-2-carboxylic acid (10mmol) in 25mL of anhydrous THF, under the protection of argon, slowly adding LiAlH in portions under ice bath condition 4 (20 mmol). After the reaction was carried out in ice bath for 10min, the reaction was carried out at room temperature for 4 hours, and after the reaction was completed, the reaction mixture was cooled in ice bath, and 0.76g of ice water, 0.76g of a 15% aqueous NaOH solution and 2.28g of water were slowly added dropwise thereto in this order. Stirring for a while, adding 20mL of water, filtering, and adding a small amount of ethyl acetateWashing, and concentrating the filtrate under reduced pressure. Adding a proper amount of water into the concentrated solution, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain a crude product of the substituted benzyl alcohol with the yield of 98%.
The resulting substituted benzyl alcohol was dissolved in 100mL DCM and 70mmol MnO was added with stirring 2 Reacting for 4 hours at room temperature, filtering, spin-drying and concentrating the filtrate, and purifying by a column to obtain 5,6,7, 8-tetrahydronaphthalene-2-formaldehyde with the yield of 90 percent. The subsequent procedure for the preparation of the target compound is analogous to example 1. Melting point: 232.3-233.3 ℃; 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 that of example 1, except that 6-methoxy-2-naphthaldehyde is used as a starting material.
Figure BDA0001625483630000221
Melting point: 206.8-207.3 ℃; 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 a starting material.
Figure BDA0001625483630000222
Melting point: 213.8-214.4 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.80(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 process was similar to that of example 1, except that 5-chloro-2-naphthaldehyde was used in place of benzaldehyde.
Figure BDA0001625483630000223
Melting point: 232.8-233.6 ℃; 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＝8.8,1.6Hz,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):δ169.93,166.73,141.20,134.28,134.25,134.06,133.85,133.77,131.23,130.44,129.24,129.18,128.73,127.97,126.93,126.82,123.82,122.78,119.79,116.33,14.05ppm；HRMS(EI)calc.for C 21 H 16 35 ClNO 3 + 365.0819,found 365.0815；calc.for C 21 H 16 37 ClNO 3 + 367.0789,found 367.0783。
wherein, the 5-chloro-2-naphthaldehyde can be prepared by the method mainly comprising the following steps:
Figure BDA0001625483630000231
5-bromo-2-naphthoic acid (0.75g, 3mmol) was dispersed in 10mL of methanol, cooled in an ice bath, and 1mL of concentrated sulfuric acid was slowly added dropwise to the reaction solution, reacted under reflux for 2h, added with 20mL of water, and extracted with DCM. The organic phase was washed with a saturated sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl 5-bromo-2-naphthoate in a yield of 97%.
The obtained methyl 5-bromo-2-naphthoate, CuCl (0.45g,4.5mmol), and 12mL of N, N-Dimethylformamide (DMF) were dispersed in a 50mL eggplant-shaped bottle, and the mixture was refluxed overnight under protection of argon. Cooled to room temperature, 25mL of water are added, suction filtered and the filter cake dried. The resulting filter cake was dispersed in 10mL DCM, filtered to remove insoluble impurities, washed with the appropriate amount of DCM, and the filtrate was concentrated to give methyl 5-chloro-2-naphthoate in 97% yield.
Methyl 5-chloro-2-naphthoate (0.44g,2mmol) was dissolved in 10mL anhydrous THF under argon protection to which LiAlH was slowly added in portions under ice bath conditions 4 (0.1g,2.6 mmol). After the reaction was carried out in ice bath for 10min, the reaction mixture was kept at room temperature for 12 hours, cooled in ice bath, and then 0.1g of ice water, 0.1g of a 15% aqueous NaOH solution and 0.3g of water were slowly added dropwise thereto. After stirring for a while, 10mL of water was added, the mixture was filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated by spin-drying under reduced pressure. Adding appropriate amount of water into the concentrated solution, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain (5-chloronaphthalene-2-yl) methanol crude product with yield of 90%.
(5-Chloronaphthalen-2-yl) methanol prepared above was dissolved in 20mL of DCM and stirredAdding 14mmol of MnO 2 Reacting for 4 hours at room temperature, filtering, spin-drying and concentrating the filtrate, and purifying by a column to obtain the 5-chloro-2-naphthaldehyde with the yield of 90 percent.
Example 18(E) -2- (2-methyl-3- (4-phenoxyphenyl) acrylamido) benzoic acid (Compound 18)
Figure BDA0001625483630000241
Phenol (705mg, 7.5mmol), p-fluorobenzaldehyde (625mg, 5.0mmol) and K 2 CO 3 (1.38g, 10.0mmol) was dispersed in 5mL DMSO under argon and reacted at 110 ℃ overnight. Cooling to room temperature, adding a proper amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated salt water for three times, drying with anhydrous sodium sulfate, spin-drying, concentrating, and purifying by column chromatography to obtain the 4-phenoxybenzaldehyde. The subsequent preparation of the final product was carried out as in example 1. Melting point: 184.4-185.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.75(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； 13 C 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.for C 23 H 19 NO 4 + 373.1314,found 373.1316。
example 19(E) -2- (2-methyl-3- (3-phenoxyphenyl) acrylamido) benzoic acid (Compound 19)
Figure BDA0001625483630000251
The m-bromobenzaldehyde (5mmol) is dispersed into 15mL DCM, 9mmol of carbethoxyethylidene triphenylphosphine is added, the reaction is carried out for 4h at room temperature, partial solvent is removed by rotation, and the (E) -3- (3-bromophenyl) -2-ethyl methacrylate is obtained by column purification with the yield of 94%.
Phenol (6 mmol) was added to the reaction flask) Ethyl (E) -3- (3-bromophenyl) -2-methacrylate (5mmol), K 2 CO 3 (10mmol), CuCl (0.25mmol), N-butylimidazole (2.5mmol) and 5mL o-xylene, under the protection of argon, and reacting at 140 ℃ for 16 h. Filtering, washing the filtrate with dilute hydrochloric acid and saturated salt water, drying with anhydrous sodium sulfate, concentrating by rotary drying, and purifying by column chromatography to obtain (E) -2-methyl-3- (3-phenoxyphenyl) ethyl acrylate. The subsequent preparation of the final product was carried out as in example 1. Melting point: 158.6-159.3 ℃; 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):δ169.86,166.72,156.78,156.37,141.16,137.51,134.22,133.76,133.30,131.19,130.16,130.09,124.49,123.66,122.71,119.75,119.20,118.80,118.22,116.29,13.89ppm；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)
Figure BDA0001625483630000261
4-Aldenebenzoic acid (10mmol), EDCI (11mmol) and HOBT (1.1mmol) were added to 30mL of DCM and the reaction was stirred at RT. TLC was used to follow the reaction, and when 4-aldehyde benzoic acid was completely reacted, aniline (10mmol) was added and the reaction was continued at room temperature. After the reaction is finished, partial solvent is removed by spinning, and the 4-formyl-N-phenyl benzamide is obtained by column purification. The subsequent preparation of the final product was carried out as in example 1. For C of HRMS (EI) 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 process is similar to that of example 14, except that [1,1' -biphenyl ] -4-carboxylic acid is used as the starting material.
Figure BDA0001625483630000262
Melting point: 241.3 to 242.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.76(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＝1.2Hz,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ169.92,166.91,141.27,139.81,139.38,134.70,134.26,134.13,132.56,131.22,130.17,129.00,127.73,126.71,126.63,122.68,119.74,116.26,14.02ppm；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 process is similar to that of example 1, except that 1H-indole-6-carbaldehyde is used as the starting material.
Figure BDA0001625483630000263
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 process is similar to that of example 1, except that 1-methyl-1H-indole-6-carbaldehyde is used as the starting material.
Figure BDA0001625483630000271
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)
Figure BDA0001625483630000272
The procedure for synthesizing (E) -2-methyl-3- (1-methyl-1H-indol-2-yl) acrylic acid as a starting material was conducted in the same manner as in example 14 except that 1-methyl-1H-indol-2-carboxylic acid was used in place of 5,6,7, 8-tetrahydronaphthalene-2-carboxylic acid.
To a 25mL reaction flask equipped with a drying tube were added (E) -2-methyl-3- (1-methyl-1H-indol-2-yl) acrylic acid (215mg, 1.0mmol), p-toluenesulfonyl chloride (209mg, 1.1mmol), 1, 2-dichloroethane (5mL), 4-dimethylaminopyridine (12mg, 0.1mmol) and triethylamine (152mg, 1.5mmol) in this order, reacted at 35 ℃ for 1 hour, anthranilic acid (137mg, 1.0mmol) was added, reacted at 60 ℃ for 10 hours, acidified with 1M HCl, filtered to give a solid, washed with water, dried, recrystallized from ethanol, yield: 50 percent. Melting point: 243.3-244.1 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.82(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 334.1312。
example 25(E) -2- (2-methyl-3- (quinolin-3-yl) acrylamido) benzoic acid (compound 25)
The preparation process is similar to that of example 1, except that 3-quinolinecarboxaldehyde is used as the starting material.
Figure BDA0001625483630000273
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-isoquinoline-formaldehyde is used as a starting material.
Figure BDA0001625483630000281
Melting point: 252.6-253.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.86(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 process is similar to that of example 1, except that 7-quinolinecarboxaldehyde is used as the starting material.
Figure BDA0001625483630000282
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 process is similar to that of example 1, except that 6-isoquinoline carboxaldehyde is used as the starting material.
Figure BDA0001625483630000283
HRMS(EI)calc.for C 20 H 16 N 2 O 3 + 332.1161,found 332.1163。
Example 29(E) -2- (3- (benzothien-2-yl) -2-methacrylamido) benzoic acid (Compound 29)
The preparation process is similar to that of example 1, except that benzothiophene-2-carbaldehyde is used as the starting material.
Figure BDA0001625483630000284
HRMS(EI)calc.for C 19 H 15 NO 3 S + 337.0773,found 337.0771。
Example 30(E) -2- (3- (benzothien-6-yl) -2-methacrylamido) benzoic acid (Compound 30)
The preparation process is similar to that of example 1, except that benzothiophene-6-carbaldehyde is used as the starting material.
Figure BDA0001625483630000285
HRMS(EI)calc.for C 19 H 15 NO 3 S + 337.0773,found 337.0774。
Example 31(E) -2- (3- (benzofuran-2-yl) -2-methacrylamido) benzoic acid (compound 31)
The preparation process is similar to that of example 1, except that benzofuran-2-carbaldehyde is used as the starting material.
Figure BDA0001625483630000291
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 process is similar to that of example 1, except that benzofuran-6-carbaldehyde is used as the starting material.
Figure BDA0001625483630000292
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)
Figure BDA0001625483630000293
Dispersing 2mmol of 2-naphthaldehyde and 6mmol of malonic acid in 1.2mL of DMF, adding 2mmol of pyridine, reacting at 90 ℃ for 5h, cooling to room temperature, adding 1.2mL of water, acidifying with 1M HCl, filtering, washing with water twice, drying the filter cake to obtain (E) -3- (naphthalene-2-yl) acrylic acid with yield of 80%, and preparing the final product by the same method as in example 1. Melting point: 241.9-242.7 ℃; 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):δ169.44,163.79,141.34,140.85,134.00,133.60,132.94,132.01,131.13,129.48,128.47,128.40,127.66,127.15,126.71,124.09,122.88,122.73,120.41,116.82ppm；HRMS(EI)calc.for C 20 H 15 NO 3 + 317.1052,found 317.1055。
example 34(E) -2- (2-methyl-3- (naphthalen-2-yl) acrylamido) benzoic acid (Compound 34)
The preparation process is similar to that of example 1, except that 2-naphthaldehyde is used as a starting material.
Figure BDA0001625483630000301
Melting point: 231.5-232.3 ℃; 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 C NMR(100MHz,DMSO-d6):δ169.95,166.90,141.29,134.54,134.28,133.14,132.87,132.74,132.37,131.23,128.81,128.19,127.92,127.52,127.09,126.71,126.50,122.69,119.74,116.22,14.05ppm；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)
Figure BDA0001625483630000302
Adding 4.2mmol NaH into a 50mL three-neck flask, adding 24mL anhydrous THF, adding 3.9mmol 2-phosphoryl triethyl acetate, stirring at room temperature for 0.5h, dropwise adding 12mL THF solution of 1- (naphthalene-2-yl) -1-ethanone (3mmol) into the reaction solution, reacting at room temperature for 12h, acidifying with 2M HCl, removing THF, adding an appropriate amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating by removing a solvent, and purifying by column to obtain ethyl 2- (naphthalene-2-yl methylene) crotonate with the yield of 50%. The subsequent preparation of the final product was carried out as 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 process was similar to that of example 35, except that triethyl phosphonoacetate was replaced with triethyl 2-phosphonopropionate.
Figure BDA0001625483630000303
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)
Figure BDA0001625483630000311
9mmol of carbethoxymethylenetriphenylphosphine and 15mL of DCM are added into a reaction flask under the protection of argon, 9mmol of NCS are added in portions at-20 ℃, reaction is carried out for 1h at-20 ℃, and 5mmol of 2-naphthaldehyde and 12.5mmol of K are added at room temperature 2 CO 3 Reacting at room temperature for 10h, washing the reaction solution, drying the organic phase by anhydrous sodium sulfate, concentrating by rotary drying, and purifying by a column to obtain the (Z) -2-chloro-3- (naphthalene-2-yl) ethyl acrylate. The subsequent preparation of the final product was carried out as in example 1. Melting point: 236.1-237.0 ℃; 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＝7.4Hz,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；HRMS(EI)calc.for C 20 H 14 35 ClNO 3 + 351.0662,found 351.0664；calc.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)
Figure BDA0001625483630000321
Adding 9mmol of carbethoxymethylenetriphenylphosphine and 15mL of DCM into a reaction bottle, adding 9mmol of NBS in batches at-20 ℃ under the protection of argon, reacting for 1h at-20 ℃, and adding 5mmol of 2-naphthaldehyde and 12.5mmol of K at room temperature 2 CO 3 Reacting at room temperature for 10h, washing the reaction solution with water, drying the organic phase with anhydrous sodium sulfate,spin-drying, concentrating, and purifying with column to obtain (Z) -2-bromo-3- (naphthalene-2-yl) ethyl acrylate. The subsequent preparation of the final product was carried out as in example 1. Melting point: 233.9-234.7 ℃; 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.for C 20 H 14 79 BrNO 3 + 395.0157,found 395.0158；calc.for C 20 H 14 81 BrNO 3 + 397.0137,found 397.0132。
example 39(E) -2- (2- (naphthalen-2-ylmethylene) butenamido) benzoic acid (Compound 39)
The preparation was carried out in a similar manner to that of example 35 except that 1- (naphthalen-2-yl) -1-ethanone was replaced by 2-naphthaldehyde and triethyl phosphonoacetate was replaced by triethyl 2-phosphonobutyrate.
Figure BDA0001625483630000322
Melting point: 184.6-185.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.78(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):δ169.96,166.76,141.22,139.76,134.28,133.60,133.05,132.79,132.40,131.23,128.24,128.21,128.11,127.51,126.70,126.56,126.55,122.72,119.77,116.26,20.47,13.53ppm；HRMS(EI)calc.for C 22 H 19 NO 3 + 345.1365,found 345.1363。
example 40(Z) -2- (3- (naphthalen-2-yl) -2-trifluoromethylacrylamido) benzoic acid (Compound 40)
Figure BDA0001625483630000331
6mmol of 2-naphthaldehyde, 4mmol of 3,3, 3-trifluoropropionic acid, 20mL of THF, and 8mL of 1M TiCl were added in succession to the reaction flask 4 The dichloromethane solution was stirred at room temperature for 0.5h, and 16mmol triethylamine was added dropwise to the reaction solution. After 40 hours of reaction at room temperature, 30mL of water was slowly added to the reaction flask, and the mixture was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning and purified by a silica gel column (dichloromethane: methanol ═ 10: 1) to obtain (Z) -3- (naphthalen-2-yl) -2- (trifluoromethyl) acrylic acid. The subsequent preparation of the final product was carried out as in example 1. For C of HRMS (EI) 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)
Figure BDA0001625483630000332
5mmol of 2-naphthaldehyde is dispersed in 7.5mL of methanol, 5mmol of methyl cyanoacetate and 0.5mmol of piperidine are added, and the reaction is refluxed until the reaction is completed. Cooling to room temperature, separating out solid, filtering, washing a filter cake with a proper amount of methanol, and drying the filter cake to obtain the (E) -2-cyano-3- (naphthalene-2-yl) methyl acrylate intermediate. The yield thereof was found to be 90%. The subsequent preparation of the final product was carried out as in example 1. For C of HRMS (EI) 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 process was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000341
Melting point: 237.4-238.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ14.11(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(100MHz,DMSO-d6):δ168.74,166.79,156.70(d, 1 J CF ＝239.4Hz),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),121.08(d, 2 J CF ＝21.9Hz),118.33,118.26,116.94(d, 2 J CF ＝23.7Hz),14.01ppm； 19 F NMR(376MHz,DMSO-d6):δ-118.88--118.96(m,1F)ppm；HRMS(EI)calc.for C 21 H 16 FNO 3 + 349.1114,found 349.1113。
example 43(E) -4-fluoro-2- (2-methyl-3- (naphthalen-2-yl) acrylamido) benzoic acid (Compound 43)
The preparation process was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4-fluorobenzoic acid.
Figure BDA0001625483630000342
Melting point: 238.6 to 239.2 ℃; 1 HNMR(400MHz,DMSO-d6):δ13.96(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(100MHz,DMSO-d6):δ169.27,167.18,165.00(d, 1 J CF ＝247.8Hz),143.43(d, 3 J CF ＝13.0Hz),135.11,133.96(d, 3 J CF ＝11.2Hz),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 ＝2.4Hz),109.65(d, 2 J CF ＝22.1Hz),106.15(d, 2 J CF ＝28.1Hz),13.92ppm； 19 F NMR(376MHz,DMSO-d6):δ-102.67--102.97(m,1F)ppm；HRMS(EI)calc.for C 21 H 16 FNO 3 + 349.1114,found 349.1115。
example 44(E) -5-chloro-2- (2-methyl-3- (naphthalen-2-yl) acrylamido) benzoic acid (Compound 44)
The preparation method was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-chlorobenzoic acid.
Figure BDA0001625483630000343
Melting point: 251.5-252.2 ℃; 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＝1.2Hz,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ168.69,166.90,140.05,134.86,133.83,133.04,132.72,132.56,132.39,130.32,128.87,128.19,127.92,127.51,127.05,126.74,126.51,126.24,121.58,118.12,13.99ppm；HRMS(EI)calc.for C 21 H 16 35 ClNO 3 + 365.0819,found 365.0816；calc.for C 21 H 16 37 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 was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-bromobenzoic acid.
Figure BDA0001625483630000351
Melting point: 256.9-257.6 ℃; 1 H NMR(400MHz,DMSO-d6):δ14.18(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):δ168.62,166.88,140.44,136.67,134.88,133.21,133.04,132.71,132.55,132.38,128.87,128.19,127.91,127.50,127.03,126.73,126.49,121.81,118.34,114.01,13.98ppm；HRMS(EI)calc.for C 21 H 16 79 BrNO 3 + 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 was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-trifluoromethylbenzoic acid.
Figure BDA0001625483630000352
Melting point: 228.7-229.4 ℃; 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):δ168.77,167.27,144.37,135.28,132.95,132.71,132.48,132.43,130.66(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 ＝270Hz),122.49(q, 2 J CF ＝32.6Hz),120.16,116.86,13.99ppm； 19 F NMR(376MHz,DMSO-d6):δ-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 process was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-methylbenzoic acid.
Figure BDA0001625483630000361
Melting point: 194.6-195.3 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.73(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；HRMS(EI)calc.for C 22 H 19 NO 3 + 345.1365,found 345.1367。
example 48(E) -5-methoxy-2- (2-methyl-3- (naphthalen-2-yl) acrylamido) benzoic acid (Compound 48)
The preparation method was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-methoxybenzoic acid.
Figure BDA0001625483630000362
Melting point: 218.6 to 219.3 ℃; 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＝1.2Hz,3H)ppm； 13 C NMR(100MHz,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 a raw material.
Figure BDA0001625483630000363
Melting point: 247.3-248.2 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.83(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＝8.0Hz,1H),7.24-7.18(m,1H),2.19(s,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ169.99,166.14,154.97(d, 1 J CF ＝252.1Hz),141.14,135.12,134.30,134.08(d, 3 J CF ＝5.8Hz),131.23,127.68,127.40(d, 3 J CF ＝3.0Hz),127.23(d, 4 J CF ＝1.4Hz),126.71(d, 3 J CF ＝3.2Hz),123.71(d, 3 J CF ＝4.1Hz),122.83,122.58(d, 2 J CF ＝16.6Hz),120.23,120.17,119.77,117.85(d, 2 J CF ＝12.7Hz),116.30,14.25ppm； 19 F NMR(376MHz,DMSO-d6):δ-122.81(d,J＝7.2Hz,1F)ppm；HRMS(EI)calc.for C 21 H 16 FNO 3 + 349.1114,found 349.1120。
wherein, the 1-fluoro-2-naphthaldehyde can be prepared by the following method:
Figure BDA0001625483630000371
adding 2-methyl-1-naphthylamine (1.57g, 10mmol) into 100mL eggplant-shaped bottle, dropwise adding fluoroboric acid (15mL) into the reaction bottle, cooling in ice bath, and slowly dropwise adding 10mL NaNO into the reaction solution 2 The solution (2.76g, 40mmol) reacts for 0.5h in an ice bath, and the diazo salt is obtained after suction filtration and filter cake drying. The obtained diazonium salt is added into 50mL toluene, and the mixture reacts for 1h at the temperature of 90 ℃ and for 2h under reflux. Sequentially with saturated NaHCO 3 The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentratedThe reaction solution was condensed and purified by column chromatography to obtain 1-fluoro-2-methylnaphthalene with a yield of 67%.
The obtained 1-fluoro-2-methylnaphthalene (5mmol) was dissolved in 10mL of CCl 4 Adding 10mmol of NBS and 0.1mmol of dibenzoyl peroxide (BPO), refluxing for 5h, cooling to room temperature, filtering, washing the filter cake with a proper amount of petroleum ether, and concentrating. The resulting concentrate was dissolved in 10mL dioxane, 10mL water, 20mmol CaCO 3 Refluxing for 10h, filtering, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate, concentrating by rotary drying, and purifying with column to obtain (1-fluoronaphthalene-2-yl) methanol with yield of 80%.
The resulting (1-fluoronaphthalen-2-yl) methanol (4mmol) was dissolved in 40mL DCM and 28mmol MnO was added with stirring 2 Reacting for 4h at room temperature, filtering, spin-drying and concentrating the filtrate, and purifying by a column to obtain the 1-fluoro-2-naphthaldehyde (the initial raw material) with the yield of 90 percent.
Example 50(Z) -2- (2-chloro-3- (1-fluoronaphthalen-2-yl) acrylamido) -5-fluorobenzoic acid (Compound 50)
The preparation process was similar to that in example 37, except that 1-fluoro-2-naphthaldehyde was used as a starting material and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000381
1 H NMR(400MHz,DMSO-d 6 ):δ14.21(s,1H),12.53(s,1H),8.73(dd,J＝9.2,5.2Hz,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,found 389.0447.
Example 51(E) -5-fluoro-2- (3- (1-fluoronaphthalen-2-yl) -2-methacrylamido) benzoic acid (Compound 51)
The preparation method was similar to that of example 1, except that 1-fluoro-2-naphthaldehyde was used as a raw material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000382
Melting point: 250.8-251.7 ℃; 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＝8.0Hz,1H),7.59-7.53(m,1H),2.17(s,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ168.76,166.07,156.80(d, 1 J CF ＝239.8Hz),154.97(d, 1 J CF ＝252.3Hz),137.54(d, 4 J CF ＝2.3Hz),134.94,134.08(d, 3 J CF ＝5.0Hz),127.69,127.67,127.47(d, 4 J CF ＝3.2Hz),127.23(d, 4 J CF ＝1.3Hz),126.69(d, 3 J CF ＝3.4Hz),123.71(d, 3 J CF ＝4.2Hz),122.59(d, 2 J CF ＝16.5Hz),122.07(d, 3 J CF ＝7.4Hz),121.09(d, 2 J CF ＝22.1Hz),120.20(d, 3 J CF ＝5.6Hz),118.46(d, 3 J CF ＝6.7Hz),117.82(d, 2 J CF ＝12.6Hz),116.97(d, 2 J CF ＝23.5Hz),14.22ppm； 19 F NMR(376MHz,DMSO-d6):δ-118.53--119.11(m,1F),-122.80(d,J＝6.6Hz,1F)ppm；HRMS(EI)calc.for C 21 H 15 F 2 NO 3 + 367.1020,found 367.1018。
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 a starting material.
Figure BDA0001625483630000383
Melting point: 240.3-241.2 ℃; 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 process was similar to that of example 1, except that 1-chloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000391
Melting point: 255.8-256.7 ℃; 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 ＝22.3Hz),118.35(d, 3 J CF ＝5.4Hz),116.99(d, 2 J 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 process was similar to that of example 37, except that 1-chloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000392
1 H NMR(400MHz,DMSO-d 6 ):δ14.23(s,1H),12.32(s,1H),8.72(dd,J＝9.2,5.2Hz,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 a starting material.
Figure BDA0001625483630000393
Melting point: 235.6 to 236.2 ℃; 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):δ169.95,166.04,141.11,134.85,134.32,134.28,134.22,133.45,131.41,131.27,128.45,128.27,127.80,127.46,127.33,126.40,123.41,122.86,119.77,116.25,13.92ppm；HRMS(EI)calc.for C 21 H 16 79 BrNO 3 + 409.0314,found 409.0316；calc.for C 21 H 16 81 BrNO 3 + 411.0293,found 411.0302。
example 56(Z) -2- (3- (1-bromonaphthalen-2-yl) -2-chloropropenamido) -5-fluorobenzoic acid (compound 56)
The preparation process was similar to that of example 37, except that 1-bromo-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000401
1 H NMR(400MHz,DMSO-d 6 ):δ14.24(s,1H),12.22(s,1H),8.71(dd,J＝9.2,5.2Hz,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,found 446.9678。
Example 57(E) -2- (3- (1-bromonaphthalen-2-yl) -2-methacrylamido) -5-fluorobenzoic acid (compound 57)
The preparation method was similar to that of example 1, except that 1-bromo-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000402
Melting point: 261.9-262.7 deg.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＝1.6Hz,3H)ppm； 13 C NMR(100MHz,DMSO-d6):δ168.72,165.94,156.79(d, 1 J CF ＝239.9Hz),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 ＝7.2Hz),121.12(d, 2 J CF ＝21.6Hz),118.31(d, 3 J CF ＝6.8Hz),116.99(d, 2 J CF ＝23.6Hz),13.88ppm； 19 F NMR(376MHz,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-naphthaldehyde is used as a starting material.
Figure BDA0001625483630000411
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-naphthaldehyde is used as a starting material.
Figure BDA0001625483630000412
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 process is similar to that of example 1, except that 1, 6-dichloro-2-naphthaldehyde is used as the starting material.
Figure BDA0001625483630000413
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,found 403.0394。
Example 61(E) -2- (3- (1, 6-Dichloronaphthalen-2-yl) -2-methacrylamido) -5-fluorobenzoic acid (compound 61)
The preparation process was similar to that of example 1, except that 1, 6-dichloro-2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-5-fluorobenzoic acid.
Figure BDA0001625483630000414
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,found 421.0277。
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-naphthaldehyde is used as a starting material.
Figure BDA0001625483630000421
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 was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-3-thiophenecarboxylic acid.
Figure BDA0001625483630000422
Melting point: 219.0-219.9 ℃; 1 H NMR(400MHz,DMSO-d6):δ13.36(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):δ166.75,164.77,147.92,136.27,132.76,132.70,132.51,130.01,129.14,128.26,127.98,127.54,127.06,126.89,126.56,124.30,116.68,114.14,13.69ppm；HRMS(ES+)calcd for C 19 H 15 NO 3 SNa(M+Na) + ,360.0670；found,360.0672。
the 2-amino-3-thiophenecarboxylic acid can be prepared by the following method mainly comprising the following steps:
Figure BDA0001625483630000423
dispersing 2-amino-3-thiophenecarboxylic acid methyl ester (314mg, 2.0mmol) in a mixed solvent of 10mL of water and 10mL of methanol, adding sodium hydroxide (1.6g, 40.0mmol), refluxing under argon for 2 hours, cooling, removing methanol by rotation, acidifying with 1M HCl, extracting with ethyl acetate, washing twice with saturated saline, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate, and separating and purifying with silica gel column (dichloromethane: methanol ═ 10: 1) to obtain 2-amino-3-thiophenecarboxylic acid with a yield of 46%.
Example 64(E) -4-methyl-2- (2-methyl-3- (naphthalen-2-yl) acrylamido) thiophene-3-carboxylic acid (Compound 64)
The preparation method was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4-methylthiophene-3-carboxylic acid.
Figure BDA0001625483630000424
HRMS(EI)calc.for C 20 H 17 NO 3 S + 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 was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-amino-4, 5-dimethylthiophene-3-carboxylic acid.
Figure BDA0001625483630000431
HRMS(EI)calc.for C 21 H 19 NO 3 S + 365.1086,found 365.1081。
Example 66(E) -4- (2-methyl-3- (naphthalen-2-yl) acrylamido) nicotinic acid (Compound 66)
Figure BDA0001625483630000432
The preparation method of the raw material (E) -2-methyl-3- (naphthalen-2-yl) acrylic acid is similar to the synthesis method of (E) -2-methyl-3-phenylacrylic acid in example 1, except that 2-naphthaldehyde is used as a starting material.
(E) -2-methyl-3- (naphthalen-2-yl) acrylic acid (212mg,1.0mmol) was dispersed in dry dichloromethane (3mL), cooled in ice bath, oxalyl chloride (381mg, 3.0mmol) was added dropwise thereto, one drop of dimethylformamide was added dropwise, a drying tube was fitted, reacted at room temperature for 3h, the solvent was removed under reduced pressure to obtain an acid chloride intermediate, which was dissolved in 1mL pyridine.
4-Aminonicotinic acid (138mg, 1.0mmol) was dispersed in 2mL of pyridine, cooled in an ice bath, and the above acid chloride pyridine solution was added dropwise thereto and reacted at room temperature overnight. Adding 5mL of water dropwise into the reaction solution, filtering, washing the filter cake with a proper amount of water, drying, separating and purifying with a silica gel column (dichloromethane: methanol: 3: 1) to obtain a compound 66 with yield30 percent. Melting point: 303.3 to 304.2 ℃; 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 for C 20 H 17 N 2 O 3 (M+H) + ,333.1239；found,333.1241。
example 67(E) -N- (2-cyanophenyl) -2-methyl-3- (naphthalen-2-yl) acrylamide (Compound 67)
The preparation method was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with o-cyanobenzoic acid.
Figure BDA0001625483630000433
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 was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 2-aminobenzamide.
Figure BDA0001625483630000441
Melting point: 169.8-170.6 ℃; 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):δ171.07,166.67,140.14,134.17,133.24,133.05,132.75,132.42,132.33,128.73,128.66,128.17,127.89,127.51,127.09,126.66,126.48,122.42,120.06,119.25,14.05ppm；HRMS(EI)calc.for C 21 H 18 N 2 O 2 + 330.1368,found 330.1371。
example 69 methyl (E) -2- (2-methyl-3- (naphthalen-2-yl) acrylamido) benzoate (Compound 69)
Figure BDA0001625483630000442
Compound 34(1.0mmol) and 5mL of dichloromethane were sequentially added to a reaction flask fitted with a drying tube, cooled in an ice bath, and 3mmol of oxalyl chloride, one drop of DMF, and 1.5mmol of methanol were added dropwise to the reaction solution. The reaction is carried out for 12h at room temperature, the reaction liquid is dried and concentrated, and is separated and purified by a silica gel column (petroleum ether: ethyl acetate: 3: 1), so as to obtain the compound 64 with the yield of 40%. Melting point: 113.4-114.2 ℃; 1 H NMR(400MHz,CDCl 3 ):δ11.71(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(100MHz,CDCl 3 ):δ168.93,167.99,141.92,135.71,134.76,133.76,133.16,132.99,132.81,130.94,128.99,128.23,127.92,127.68,127.19,126.52,126.39,122.52,120.62,115.24,52.42,14.31ppm；HRMS(EI)calc.for C 22 H 19 NO 3 + 345.1365,found 345.1366。
example 70(E) -2-methyl-3- (naphthalen-2-yl) -N- (pyridin-2-yl) acrylamide (Compound 70)
The preparation process was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material and anthranilic acid was replaced with 2-aminopyridine.
Figure BDA0001625483630000443
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 process was similar to that of example 1, except that 2-naphthaldehyde was used as a starting material, and anthranilic acid was replaced with 1-amino-2-cyano-1-cyclopentene.
Figure BDA0001625483630000451
HRMS(EI)calc.for C 20 H 18 N 2 O + 302.1419,found 302.1415。
Example 72 DHODH inhibitory Activity of Compounds of the invention
DHODH catalyzes the oxidation of its natural substrate DHO (dihydroorotate) to Orotate under certain conditions. Under the catalysis of DHODH, two H of substrate DHO are firstly added + And e - Transfer to coenzyme FMN followed by FMNH in reduced state 2 Electrons are transferred to free coenzyme Q. The free coenzyme Q finally transfers electrons to a chromogenic substrate DCIP, and the DCIP is reduced. DCIP has maximum light absorption at 600nm, 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 degree of reduction of the absorbance. The degree of oxidation of the substrate DHO in unit time is the initial speed of the enzymatic reaction, and the initial speed of the enzymatic reaction is reduced after the inhibitor is added. The measurement adopts a 96-well plate, and the absorbance at 600nm is read by a BioTek microplate reader. mu.L of viability assay buffer (50mM HEPES (pH8.0), 0.15M KCl, 0.1% Triton X-100, 100. mu.M coenzyme Q, 100. mu.M DCIP) was added to each well. Adding 0.4 μ L of compound, incubating at room temperature for 5min, adding 1 μ L substrate DHO (final concentration of 500 μ M) into each well, mixing, immediately measuring light absorption at 600nm with microplate reader, reading data every 30s, and reading for 6 min. At least 3 replicates were set for each experiment. Finally, the inhibition rates of the compounds with different concentrations are calculated, and the half effective inhibition concentration IC is calculated through origin8.0 50 The value is obtained. With particular reference to Sci. Rep.,2015.5: 14836.
Table 1 activity list of representative compounds 1-71
Figure BDA0001625483630000452
Figure BDA0001625483630000461
Figure BDA0001625483630000471
Figure BDA0001625483630000481
Figure BDA0001625483630000491
Figure BDA0001625483630000501
Figure BDA0001625483630000511
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (11)

1. A compound of formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0003649146540000011
in the formula (I), the compound is shown in the specification,
a is
Figure FDA0003649146540000012
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:
Figure FDA0003649146540000013
in the formula (I), the compound is shown in the specification,
a is
Figure FDA0003649146540000014
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:
Figure FDA0003649146540000015
7. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003649146540000021
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.
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