CN108341791B - Benzothiadiazole compound, preparation method and application thereof - Google Patents

Benzothiadiazole compound, preparation method and application thereof Download PDF

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CN108341791B
CN108341791B CN201710062495.4A CN201710062495A CN108341791B CN 108341791 B CN108341791 B CN 108341791B CN 201710062495 A CN201710062495 A CN 201710062495A CN 108341791 B CN108341791 B CN 108341791B
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李佳
王文龙
陈晓禹
周宇波
李静雅
高雅
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Shanghai Institute of Materia Medica of CAS
Jiangnan University
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Jiangnan University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
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Abstract

The invention relates to a benzothiadiazole compound shown as the following general formula I, a preparation method and application thereof, wherein the compound has the function of inhibiting the biological activity of protein tyrosine phosphatase SHP2The protein tyrosine phosphatase SHP2 can be used as a tool compound to research the biological function correlation of the protein tyrosine phosphatase SHP2 in the cell signal transduction process, and a new means is provided for preventing and treating cancer, metabolism and immune diseases.

Description

Benzothiadiazole compound, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzothiadiazole compound shown in a general formula I, and a preparation method and application thereof, wherein the compound has the biological activity of inhibiting protein tyrosine phosphatase SHP2, can be used as a tool compound for researching the biological function relevance of the protein tyrosine phosphatase SHP2 in the cell signal transduction process, and provides a new means for preventing and treating cancers, metabolism and immune diseases.
Figure BDA0001217551720000011
Background
Cancer is a serious threat to human health. Among many anticancer drugs, protein tyrosine kinase (protein tyrosine kinases) inhibitors (e.g., tinib drugs such as imatinib) have the characteristics of high selectivity, small side effect and the like, and are first-line drugs for treating tumors. However, the problem of drug resistance resulting from long-term drug use has forced medical practitioners to search for new therapeutic regimens (e.g., discovery of new therapeutic targets, multi-target combinations).
Protein tyrosine phosphatases (protein tyrosine phosphatases), which are the corresponding surfaces of protein tyrosine kinases (protein tyrosine kinases), also occupy an extremely important position in the process of cell signal transduction, and are considered as potential targets for developing and treating serious diseases such as diabetes, cancer and the like. Among the large family of protein tyrosine phosphatases, SHP2 is one of the important members, expressed in systemic tissue cells, highly active in tumor cells, and is an oncogenic factor.
SHP2 is a downstream signal molecule of various growth factors, such as platelet-derived growth factor (PDGF), Epidermal Growth Factor (EGF), fibroblast factor (FGF), interleukin-3 (IL-3), Leukemia Inhibitory Factor (LIF), and alpha-interferon (INF-alpha), and participates in multiple signal pathways (such as RAS/MARK pathway, PI3K/AKT pathway, JAK/STAT pathway, JNK pathway, NF-kappa B pathway, RHO pathway, NFAT pathway, etc.), and plays a key role in the process of transmitting cell information. SHP2 is prone to mutations and can be detected in a number of diseases, for example, SHP2 mutation rates of 40-50% in noonan syndrome, 35% in juvenile myelocytic leukemia (JMML), and 6.6% in acute myeloid leukemia.
Recently, SHP2 was found to be highly expressed in various solid tumor tissues such as prostate cancer, breast cancer, pancreatic cancer, gastric cancer, and glioma. As an important node molecule, SHP2 plays an important regulatory role in the process of tumorigenesis and tumor development, and is a potential anti-tumor target.
More and more studies indicate that activation mutation and over-expression of SHP2 may be closely related to tumor development and metastasis, but the mechanism of action in tumor development, evolution and metastasis is not clear. Therefore, it is very critical to find a highly selective SHP2 inhibitor, whether as a tool compound for discovering new pathogenesis of cancer or as a lead compound for discovering anticancer drugs. However, the small amount and the lack of structural diversity of the inhibitors are obvious defects in the research field of the SHP2 selective inhibitor, and the new structural type of the benzothiadiazole compound as the SHP2 inhibitor can be used as a tool compound for researching the action mechanism of tumor occurrence and development and further used as a new means for preventing and treating cancer, metabolism and immune diseases.
Disclosure of Invention
One of the purposes of the invention is to provide a benzothiadiazole compound, and the novel small molecule active compound has the biological function of inhibiting protein tyrosine phosphatase SHP2, so that a new way for searching new ways for treating cancers, metabolism, immune diseases and the like is developed. Another object of the present invention is to provide a process for the preparation of such compounds and the use of such compounds.
One aspect of the present invention provides a benzothiadiazole compound represented by the following general formula I:
Figure BDA0001217551720000021
wherein the content of the first and second substances,
R1is selected from-OH; -NO2；-NH2(ii) a Substituted or unsubstituted C1-C6 alkylamino wherein the substituents used to replace C1-C6 alkyl are selected from C6-C10 aryl, 5-7 membered heteroaryl, and C3-C6 cycloalkyl; a substituted or unsubstituted 5-7 membered heterocyclylamido group, wherein the substituents used to substitute the 5-7 membered heterocyclyl group are selected from C1-C6 alkyl and C1-C6 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S;
preferably, R1Is selected from-OH; -NO2；-NH2(ii) a Substituted or unsubstituted C1-C4 alkylamino wherein the substituents used to replace C1-C4 alkyl are selected from C6-C10 aryl, 5-6 membered heteroaryl, and C3-C6 cycloalkyl; a substituted or unsubstituted 5-6 membered heterocyclylamido group, wherein the substituents used to substitute the 5-6 membered heterocyclyl group are selected from C1-C4 alkyl and C1-C4 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C4 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein said heterocyclyl or heteroaryl group comprises a member selected from the group consisting of N, O, STo two heteroatoms;
preferably, R1Is selected from-OH; -NO2；-NH2(ii) a Substituted or unsubstituted C1-C3 alkylamino wherein the substituents used to replace C1-C3 alkyl are selected from phenyl, thienyl, pyridyl, furyl, cyclobutyl, cyclopentyl, and cyclohexyl; a substituted or unsubstituted 5-6 membered heterocyclylamido group, wherein the substituents used to substitute the 5-6 membered heterocyclyl group are selected from C1-C2 alkyl and C1-C2 alkoxycarbonyl, and the 5-6 membered heterocyclyl group is piperidinyl or piperazinyl; a substituted or unsubstituted aminoamido group, wherein the substituent for the substituted amino group is selected from the group consisting of phenyl, C1-C2 alkylphenyl, and benzothiadiazolyl;
preferably, R1Is selected from-OH; -NO2；-NH2(ii) a A propylamino group; a butylamino group; a benzylamino group; thiophen-2-ylmethylamino; pyridin-2-ylmethylamino; furan-2-ylmethylamino; a cyclohexylmethylamino group; 3-methylpiperidin-1-yl-amido; 4-methylpiperazin-1-ylamido; 4- (ethoxycarbonyl) piperidin-1-ylamido; 4- (ethoxycarbonyl) piperazin-1-ylamido; 3-methylphenylaminoamido; benzo [1,2,5] s]Thiadiazole-5-aminoamide group.
R2Represents 1 to 3 substituents at the 2, 4 and/or 5 position of the phenyl ring, in particular selected from hydrogen; halogen; -NO2；-NH2(ii) a C2-C6 alkenyl; a C6-C10 aryl group; substituted or unsubstituted ethynyl, wherein the substituents for substitution of ethynyl are selected from C1-C6 alkyl or haloalkyl, tri (C1-C6 alkyl) silyl, C3-C6 cycloalkyl and C6-C10 aryl; a triazolyl group; a benzyl triazolyl group;
preferably, R2Represents 1 to 2 substituents at the 2 and/or 4 position of the phenyl ring, in particular selected from hydrogen; halogen; -NO2；-NH2(ii) a C2-C4 alkenyl; a phenyl group; substituted or unsubstituted ethynyl, wherein the substituents for substitution of ethynyl are selected from C1-C4 alkyl or haloalkyl, tri (C1-C4 alkyl) silyl, C3-C5 cycloalkyl and phenyl; a triazolyl group; a benzyl triazolyl group;
preferably, R2Represents 1 to 2 substituents at the 2 and/or 4 position of the phenyl ring, in particular selected from hydrogen; fluorine; chlorine; bromine; -NO2；-NH2(ii) a A vinyl group; a phenyl group; an ethynyl group; a trimethylsilylethynyl group; a hexynyl group; a chlorohexynyl group; a tert-butyl ethynyl group; a phenylethynyl group; a cyclopropylethynyl group; a cyclohexyl ethynyl group; a triazolyl group; a benzyltriazolyl group.
Preferably, the compound of formula I is selected from the group consisting of compounds represented by the following formulae II, III and IV:
Figure BDA0001217551720000031
wherein R is1And R2As defined above.
Preferably, the compound represented by the above general formula I is selected from the following compounds:
Figure BDA0001217551720000032
Figure BDA0001217551720000041
Figure BDA0001217551720000051
the 5-7 membered heteroaryl group includes, for example, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, pyridyl, pyrazinyl, pyrimidinyl, oxazinyl and the like, but is not limited thereto.
The 5-7 membered heterocyclic group includes, for example, piperidyl, piperazinyl, morpholinyl and the like, but is not limited thereto.
The C1-C6 alkyl group includes C1-C6 straight chain or branched chain alkyl groups, including, for example, methyl, ethyl, propyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl, and the like, but is not limited thereto.
The C1-C6 alkoxy group includes C1-C6 straight chain or branched chain alkyl or alkoxy groups, for example, including methoxy, ethoxy, propoxy, butoxy, isobutoxy, n-pentyloxy, isopentyloxy, etc., but is not limited thereto.
The pharmaceutically acceptable salt may be, for example, an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, etc.; organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate, pamoate and the like.
Another aspect of the present invention provides a process for the preparation of said compounds of general formula I, said process being carried out by the following reaction scheme:
reaction scheme 1
Figure BDA0001217551720000061
Reagents and conditions a) tosyl chloride, pyridine; b) fuming nitric acid, acetic acid; c) concentrated sulfuric acid; d) thionyl chloride, toluene; e) alkynyl compounds R2H, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; f) iron powder, ammonium chloride, ethanol and water
Wherein R is2Is substituted or unsubstituted ethynyl, wherein the substituents for substituting ethynyl are selected from C1-C6 alkyl or haloalkyl, tri (C1-C6 alkyl) silyl, C3-C6 cycloalkyl and C6-C10 aryl; preferably, R2Is substituted or unsubstituted ethynyl, wherein the substituents for substituting ethynyl are selected from C1-C4 alkyl or haloalkyl, tri (C1-C4 alkyl) silyl, C3-C5 cycloalkyl and phenyl; preferably, R2Is an ethynyl group; a trimethylsilylethynyl group; a hexynyl group; 6-chloro-1-hexynyl; a tert-butyl ethynyl group; a phenylethynyl group; a cyclopropylethynyl group; a cyclohexyl ethynyl group; a triazolyl group; a benzyltriazolyl group.
Or scheme 2
Figure BDA0001217551720000062
Reagents and conditions: a) trimethyl acetylene silicon, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; b) tetrabutylammonium fluoride, tetrahydrofuran; c) iron powder, ammonium chloride, ethanol and water; d) palladium on carbon, hydrogen
Or scheme 3
Figure BDA0001217551720000063
Reagents and conditions: a) benzyl azide, cuprous iodide, glycerol; b) iron powder, ammonium chloride, ethanol and water
Or scheme 4
Figure BDA0001217551720000064
Reagents and conditions: a) tetrakis (triphenylphosphine) palladium, cesium carbonate, toluene, water; b) iron powder, ammonium chloride, ethanol and water
Or scheme 5
Figure BDA0001217551720000071
Reagents and conditions a) thionyl chloride, toluene; b) iron powder, ammonium chloride, ethanol and water; c) aldehyde compound R3CHO, sodium borohydride, methanol
Wherein R is1Is selected from substituted or unsubstituted C1-C6 alkylamino, wherein the substituent used for substituting C1-C6 alkyl is selected from C6-C10 aryl, 5-7 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R1Is selected from substituted or unsubstituted C1-C4 alkylamino, wherein the substituent used for substituting C1-C4 alkyl is selected from C6-C10 aryl, 5-6 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R1Selected from substituted or unsubstituted C1-C3 alkylamino wherein the substituents used to substitute C1-C3 alkyl are selected from phenyl, thienyl, pyridyl, furyl, cyclobutyl, cyclopentyl and cyclohexyl; preferably, R1Selected from propylamino; a butylamino group; a benzylamino group; thiophen-2-ylmethylamino; pyridin-2-ylmethylamino; furan-2-ylmethylamino; a cyclohexylmethylamino group.
R3Is selected from substituted or unsubstituted C1-C5 alkyl, wherein, the substituent used for substituting C1-C5 alkyl is selected from C6-C10 aryl, 5-7 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R3Is selected from substituted or unsubstituted C1-C3 alkyl, wherein, the substituent used for substituting C1-C3 alkyl is selected from C6-C10 aryl, 5-6 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R3Is selected from substituted or unsubstituted C1-C2 alkyl, wherein, the substituent used for substituting C1-C2 alkyl is selected from phenyl, thienyl, pyridyl, furyl, cyclobutyl, cyclopentyl and cyclohexyl; preferably, R3Is selected from propyl; a butyl group; a benzyl group; thiophen-2-ylmethyl; pyridin-2-ylmethyl; furan-2-ylmethyl; a cyclohexylmethyl group.
Or scheme 6
Figure BDA0001217551720000072
Reagents and conditions a) triphosgene, dichloroethane, amino compounds
Wherein R is1Selected from substituted or unsubstituted 5-7 membered heterocyclylamido, wherein the substituents for the 5-7 membered heterocyclyl are selected from C1-C6 alkyl and C1-C6 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R1Selected from substituted or unsubstituted 5-6 membered heterocyclylamido, wherein the substituents for the 5-6 membered heterocyclyl are selected from C1-C4 alkyl and C1-C4 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C4 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R1Selected from substituted or unsubstitutedA substituted 5-6 membered heterocyclylamido, wherein the substituents used to substitute the 5-6 membered heterocyclyl are selected from C1-C2 alkyl and C1-C2 alkoxycarbonyl, and the 5-6 membered heterocyclyl is piperidinyl or piperazinyl; substituted or unsubstituted aminoamido, wherein the substituent for the substituted amino is selected from phenyl, C1-C2 alkylphenyl and benzothiadiazolylaminoamido; preferably, R1Selected from 3-methylpiperidin-1-yl-amido; 4-methylpiperazin-1-ylamido; 4- (ethoxycarbonyl) piperidin-1-ylamido; 4- (ethoxycarbonyl) piperazin-1-ylamido; 3-methylphenylaminoamido; benzo [1,2,5] s]Thiadiazole-5-aminoamide group.
Wherein the amino compound is, for example, a substituted or unsubstituted piperidine, a substituted or unsubstituted piperazine, a substituted or unsubstituted aniline, or a benzo [1,2,5] thiadiazol-5-amine, wherein the substituents used for substitution are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxycarbonyl.
Or scheme 7
Figure BDA0001217551720000081
Reagents and conditions a) Bromoic Water, acetic acid
Or scheme 8
Figure BDA0001217551720000082
Reagents and conditions a) sodium hydroxide, water
Or scheme 9
Figure BDA0001217551720000083
Reagents and conditions a) acetic anhydride; b) potassium nitrate, sulfuric acid; c) iron powder, ammonium chloride, ethanol and water
The above reaction can be carried out in the following solvents: n, N-Dimethylformamide (DMF), ethanol, dichloromethane, dichloroethane, Tetrahydrofuran (THF), water, or a mixed solvent of the above solvents. Sometimes, the reaction also needs to add an activating agent such as pyridine, triethylamine, thionyl chloride and the like. Depending on the reaction of the particular compound, the reaction temperature is generally from-20 ℃ to room temperature or the heating temperature is from 45 ℃ to 100 ℃. The reaction time depends on the particular reactants. Usually, TLC is used to track and determine the completion degree of the reaction, and the post-treatment methods generally adopted after the reaction include suction filtration, solvent removal from concentrated reaction solution, extraction, column chromatography separation and the like. The final product was confirmed by NMR and LC-MS detection.
Still another aspect of the present invention provides a use of the benzothiadiazole-based compound or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing and/or treating cancer, metabolic and immune diseases, cardiovascular diseases, and neurological diseases.
In still another aspect of the invention, the benzothiadiazole compound or a pharmaceutically acceptable salt thereof is used for preparing the protein tyrosine phosphatase SHP2 inhibitor.
In still another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the benzothiadiazole-type compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can be used for preventing and/or treating cancer, metabolic and immune diseases, cardiovascular diseases and neurological diseases.
Detailed Description
The invention will now be further illustrated, but is not limited, by the following specific examples.
Reaction operation 1:
Figure BDA0001217551720000091
reagents and conditions a) tosyl chloride, pyridine; b) fuming nitric acid, acetic acid; c) concentrated sulfuric acid; d) thionyl chloride, toluene; e) alkynyl compounds R2H, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; f) iron powder, ammonium chloride, ethanol and water
P-toluenesulfonyl chloride (2.0eq) in pyridine was added to 4-bromo o-phenylenediamine (1.0eq) in pyridine, stirred under reflux, and after completion of the reaction monitored by TLC plate, poured into ice preparation water: generating solid in the mixed solution of hydrochloric acid (4: 1), filtering, washing with water, and drying to obtain the compound1. Under the ice-bath condition, fuming nitric acid (2.5eq) is diluted by acetic acid, is dropwise added into an acetic acid solution of the compound 1(1.0eq), is heated to 55 ℃ and is stirred for 2 hours, and after the reaction is monitored, the mixture is cooled, filtered, recrystallized and dried to obtain a compound 2. Compound 2(1eq) was added to 90% H2SO4And (3) heating to 85 ℃ for reaction, tracking and determining the completion degree of the reaction by TLC, cooling after the reaction is completed, pouring into ice water, adjusting alkali by ammonia water, cooling, performing suction filtration, and washing by water to obtain a compound 3. Under the ice bath condition, dropwise adding thionyl chloride (4eq) into a toluene solution of a compound 3(1eq), heating to 65 ℃ for reaction, tracking and determining the completion degree of the reaction by TLC, concentrating a filtrate after the reaction is completed, and performing column chromatography separation to obtain a compound 4. Will contain compound 4(1eq), PdCl2(PPh3)2(0.05eq), CuI (0.05eq) and Et3The mixed solution of N (1mL) is put into an oil bath at 50 ℃ for reaction, and the corresponding alkynyl compound R is added dropwise2H (2eq), after monitoring the reaction is complete, extracting, drying, concentrating and carrying out column chromatography separation to obtain a compound 5. Adding compound 5(1eq) and NH4And placing the solution of Cl (4eq) and water (2:1) in an oil bath kettle at 90 ℃ for reflux reaction for 30min, adding iron powder (4eq), continuing heating reaction, tracking and determining the completion degree of the reaction by TLC, monitoring the completion of the reaction, cooling, performing hot suction filtration, adjusting the alkali of the filtrate, extracting, drying, concentrating, and performing column chromatography separation to obtain the compound 6.
Wherein R is2Is substituted or unsubstituted ethynyl, wherein the substituents for substituting ethynyl are selected from C1-C6 alkyl or haloalkyl, tri (C1-C6 alkyl) silyl, C3-C6 cycloalkyl and C6-C10 aryl; preferably, R2Is substituted or unsubstituted ethynyl, wherein the substituents for substituting ethynyl are selected from C1-C4 alkyl or haloalkyl, tri (C1-C4 alkyl) silyl, C3-C5 cycloalkyl and phenyl; preferably, R2Is an ethynyl group; a trimethylsilylethynyl group; a hexynyl group; 6-chloro-1-hexynyl; a tert-butyl ethynyl group; a phenylethynyl group; a cyclopropylethynyl group; a cyclohexyl ethynyl group; a triazolyl group; a benzyltriazolyl group.
Reaction operation 2:
Figure BDA0001217551720000101
reagents and conditions: a) trimethyl acetylene silicon, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; b) tetrabutylammonium fluoride, tetrahydrofuran; c) iron powder, ammonium chloride, ethanol and water; d) palladium on carbon, hydrogen
Will contain compound 4(1eq), PdCl2(PPh3)2(0.05eq), CuI (0.05eq) and Et3And (3) placing the mixed solution of N (1mL) in an oil bath at 50 ℃ for reaction, dropwise adding trimethylethynylsilicon (2eq), monitoring the completion of the reaction, extracting, drying, concentrating, and carrying out column chromatography separation to obtain a compound 7. Under the ice bath condition, tetrabutylammonium fluoride (6eq) is dropwise added into a THF solution of a compound 7(1eq), after the addition is finished, the reaction is carried out at room temperature, TLC is used for tracking and determining the completion degree of the reaction, and after the reaction is completed, extraction, drying, concentration and column chromatography separation are carried out to obtain a compound 8. Will contain compound 8(1eq) and NH4And placing the solution of Cl (4eq) and water (2:1) in an oil bath kettle at 90 ℃ for reflux reaction for 30min, adding iron powder (4eq), continuing heating reaction, tracking and determining the completion degree of the reaction by TLC, monitoring the completion of the reaction, cooling, performing hot suction filtration, adjusting the alkali of the filtrate, extracting, drying, concentrating, and performing column chromatography separation to obtain a compound 9. The compound 9(1eq) was dissolved in methanol, Pd/C (0.1eq) was added and H was bubbled through2The reaction was carried out overnight at room temperature. And after the reaction is monitored to be complete, filtering, washing with solid methanol, concentrating, and performing column chromatography to obtain the compound 10.
Reaction operation 3:
Figure BDA0001217551720000102
reagents and conditions: a) benzyl azide, cuprous iodide, glycerol; b) iron powder, ammonium chloride, ethanol and water
A mixture of compound 8(1eq), benzyl azide (1eq), CuI (0.05eq) and glycerol was placed in an oil bath at 40 ℃ and reacted overnight. After the reaction is completely monitored by thin layer chromatography, extraction, drying, concentration and column chromatography separation are carried out (a compound 11 is obtained, and the compound 11(1eq) and NH are contained4Cl (4eq) in ethanol and water (2:1) solution was placed in a 90 ℃ oil bathAnd (3) carrying out reflux reaction for 30min, adding iron powder (4eq), continuously heating for reaction, tracking and measuring the completion degree of the reaction by TLC (thin layer chromatography), monitoring the completion of the reaction, cooling, carrying out hot suction filtration, adjusting the alkali of the filtrate, extracting, drying, concentrating, and carrying out column chromatography separation to obtain the compound 12.
Reaction operation 4:
Figure BDA0001217551720000111
reagents and conditions: a) tetrakis (triphenylphosphine) palladium, cesium carbonate, toluene, water; b) iron powder, ammonium chloride, ethanol and water
Pd (PPh)3)4(0.05eq) was added to Compound 4(1eq), Cs2CO3(2eq), phenylboronic acid (1eq), and a mixed solution of toluene and water (1:1), N2After protection, the temperature is raised to 80 ℃ for reaction, after the reaction is monitored by thin-layer chromatography, the compound 12 is obtained by cooling, extraction, drying, concentration and column chromatography separation. Adding a mixture containing 13(1eq) and NH4And placing the solution of Cl (4eq) and water (2:1) in an oil bath kettle at 90 ℃ for reflux reaction for 30min, adding iron powder (4eq), continuing heating reaction, tracking and determining the completion degree of the reaction by TLC, monitoring the completion of the reaction, cooling, performing hot suction filtration, adjusting the alkali of the filtrate, extracting, drying, concentrating, and performing column chromatography separation to obtain the compound 14.
Reaction operation 5:
Figure BDA0001217551720000112
reagents and conditions a) thionyl chloride, toluene; b) iron powder, ammonium chloride, ethanol and water; c) aldehyde compound R3CHO, sodium borohydride, methanol
Under the ice bath condition, thionyl chloride (4eq) is added into a toluene solution of a compound 15(1eq) dropwise, the temperature is increased to 65 ℃ for reaction, TLC is used for tracking and measuring the completion degree of the reaction, and after the reaction is completed, filtrate is concentrated to obtain a compound 16. Will contain compound 16(1eq) and NH4Refluxing Cl (4eq) solution of ethanol and water (2:1) in 90 deg.C oil bath for 30min, adding iron powder (4eq), heating for reaction, and tracking and determining by TLCAnd (3) monitoring the degree of reaction, cooling, carrying out hot suction filtration, adjusting the alkali of the filtrate, extracting, drying and concentrating to obtain a compound 17. Dissolving compound 17(1eq), aldehyde compound (1eq) and trace acetic acid in methanol, reacting at room temperature, tracking and determining the completion degree of the reaction by TLC, monitoring the reaction, and adding NABH in batches4(1.12eq), monitoring the reaction completion by thin layer chromatography, adding acetone for quenching, extracting, drying, concentrating, and separating by column chromatography to obtain compound 18.
Wherein R is1Is selected from substituted or unsubstituted C1-C6 alkylamino, wherein the substituent used for substituting C1-C6 alkyl is selected from C6-C10 aryl, 5-7 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R1Is selected from substituted or unsubstituted C1-C4 alkylamino, wherein the substituent used for substituting C1-C4 alkyl is selected from C6-C10 aryl, 5-6 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R1Selected from substituted or unsubstituted C1-C3 alkylamino wherein the substituents used to substitute C1-C3 alkyl are selected from phenyl, thienyl, pyridyl, furyl, cyclobutyl, cyclopentyl and cyclohexyl; preferably, R1Selected from propylamino; a butylamino group; a benzylamino group; thiophen-2-ylmethylamino; pyridin-2-ylmethylamino; furan-2-ylmethylamino; a cyclohexylmethylamino group.
R3Is selected from substituted or unsubstituted C1-C5 alkyl, wherein, the substituent used for substituting C1-C5 alkyl is selected from C6-C10 aryl, 5-7 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R3Is selected from substituted or unsubstituted C1-C3 alkyl, wherein, the substituent used for substituting C1-C3 alkyl is selected from C6-C10 aryl, 5-6 membered heteroaryl and C3-C6 cycloalkyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R3Is selected from substituted or unsubstituted C1-C2 alkyl, wherein, the substituent used for substituting C1-C2 alkyl is selected from phenyl, thienyl, pyridyl, furyl, cyclobutyl, cyclopentylAnd a cyclohexyl group; preferably, R3Is selected from propyl; a butyl group; a benzyl group; thiophen-2-ylmethyl; pyridin-2-ylmethyl; furan-2-ylmethyl; a cyclohexylmethyl group.
Reaction operation 6:
Figure BDA0001217551720000121
reagents and conditions a) triphosgene, dichloroethane, amino compounds
Under the ice-bath condition, slowly adding a 1, 2-dichloroethane solution of the compound 17(1eq) into a 1, 2-dichloroethane solution of triphosgene (0.5eq), stirring at room temperature for 30min, heating to 75 ℃ for reaction, monitoring by thin-layer chromatography, cooling and standing at room temperature. Adding 1, 2-dichloroethane solution of the corresponding amino compound (1eq), stirring at room temperature for 15min, monitoring the reaction by thin layer chromatography, concentrating, dissolving in water, adjusting alkali, extracting, drying, concentrating, and separating by column chromatography to obtain compound 19.
Wherein R is1Selected from substituted or unsubstituted 5-7 membered heterocyclylamido, wherein the substituents for the 5-7 membered heterocyclyl are selected from C1-C6 alkyl and C1-C6 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C6 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein the heterocyclyl or heteroaryl group contains one to three heteroatoms selected from N, O, S; preferably, R1Selected from substituted or unsubstituted 5-6 membered heterocyclylamido, wherein the substituents for the 5-6 membered heterocyclyl are selected from C1-C4 alkyl and C1-C4 alkoxycarbonyl; substituted or unsubstituted aminoamido, wherein the substituents for the substituted amino are selected from the group consisting of C6-C10 aryl, C1-C4 alkyl C6-C10 aryl, and benzothiadiazolyl; wherein the heterocyclic or heteroaryl group contains one to two heteroatoms selected from N, O, S; preferably, R1Is selected from substituted or unsubstituted 5-6 membered heterocyclylamido, wherein the substituents for the 5-6 membered heterocyclyl are selected from C1-C2 alkyl and C1-C2 alkoxycarbonyl, and the 5-6 membered heterocyclyl is piperidinyl or piperazinyl; substituted or unsubstituted aminoacylAmino, wherein the substituent for substituting the amino is selected from phenyl, C1-C2 alkylphenyl and benzothiadiazolylamido; preferably, R1Selected from 3-methylpiperidin-1-yl-amido; 4-methylpiperazin-1-ylamido; 4- (ethoxycarbonyl) piperidin-1-ylamido; 4- (ethoxycarbonyl) piperazin-1-ylamido; 3-methylphenylaminoamido; benzo [1,2,5] s]Thiadiazole-5-aminoamide group.
Wherein the amino compound is, for example, a substituted or unsubstituted piperidine, a substituted or unsubstituted piperazine, a substituted or unsubstituted aniline, or a benzo [1,2,5] thiadiazol-5-amine, wherein the substituents used for substitution are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxycarbonyl.
Reaction operation 7:
Figure BDA0001217551720000131
reagents and conditions a) Bromoic Water, acetic acid
Br was added under ice-bath conditions2(1eq) is added into acetic acid solution of the compound 17(1eq) dropwise, after the addition is finished, the reaction is carried out at room temperature, after the completion of the reaction is monitored by thin layer chromatography, alkali is adjusted, extraction, drying, concentration and column chromatography separation are carried out, and the compound 20 and the compound 21 are obtained.
Reaction operation 8:
Figure BDA0001217551720000132
reagents and conditions a) sodium hydroxide, water
Adding NaOH aqueous solution (1N) into ethanol solution of the compound 17(1.0eq), heating to 90 ℃ for reaction, tracking and determining the completion degree of the reaction by TLC, extracting after the reaction is finished, washing, drying, spin-drying, and separating by column chromatography to obtain the compound 22.
Reaction operation 9:
Figure BDA0001217551720000133
reagents and conditions a) acetic anhydride; b) potassium nitrate, sulfuric acid; c) iron powder, ammonium chloride, ethanol and water.
Under the ice-bath condition, slowly reducing acetic anhydride (2eq) to a 1, 4-dioxane solution of a compound 17(1eq), reacting at room temperature after dropwise addition, adding water for dilution, performing suction filtration, washing with water, and drying to obtain a compound 23 after the reaction is completely monitored by thin-layer chromatography. Under the ice-bath condition, KNO is added3(1.2eq) of H2SO4The solution was slowly added with compound 23(1eq) of H2SO4And (3) after the addition is finished, heating to 40 ℃ for reaction, monitoring the reaction by thin layer chromatography, cooling, diluting with ice water, performing suction filtration, washing solid with water, and drying to obtain a compound 24. Will contain compound 24(1eq) and NH4And placing a Cl (4eq) solution in ethanol and water (2:1) in a 90 ℃ oil bath kettle for reflux reaction for 30min, adding iron powder (4eq), continuing heating reaction, tracking and determining the completion degree of the reaction by TLC, monitoring the completion degree of the reaction, cooling, performing hot suction filtration, adjusting the alkali of the filtrate, extracting, drying, concentrating, and performing column chromatography separation to obtain a compound 25.
In the following preparations, NMR was measured with a Bruker AV III 400M instrument manufactured by Bruker, and NMR was calibrated: H/C7.26/77.0ppm (CDCl)3) (ii) a The reagent is mainly provided by Shanghai chemical reagent company, the product purification is mainly performed by column chromatography, silica gel (200-300 meshes), the type of the silica gel used by the column chromatography is crude silica gel (ZLX-II), and the product is produced by Qingdao oceanic factories and factories.
The methods and apparatuses employed in the present invention are well known in the art, unless otherwise specified.
Example 1 (synthesized as compound 6):
Figure BDA0001217551720000141
reagents and conditions a) tosyl chloride, pyridine; b) fuming nitric acid, acetic acid; c) concentrated sulfuric acid; d) thionyl chloride, toluene; e) tert-butyl acetylene, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; f) iron powder, ammonium chloride, ethanol and water.
Adding a pyridine solution (20mL) of p-toluenesulfonyl chloride (10.19g, 53.4mmol) into a pyridine solution (20mL) of 4-bromo-o-phenylenediamine (5g,26.7mmol), placing the mixture in an oil bath kettle at 85 ℃ for refluxing and stirring after the addition is finished, reacting for 18h, after the reaction is completely monitored by thin layer chromatography, placing the reaction system at room temperature for cooling, and slowly pouring into ice preparation water: in a mixed solution (250mL) of hydrochloric acid (4: 1), a solid precipitated, which was filtered, and the filter cake was washed with distilled water to give a brown solid product, which was dried for 5 hours to give Compound 1(13.1g, 99.0%).
Compound 1(2g, 4.04mmol) was dissolved in acetic acid (8mL), placed in an oil bath at 50 ℃ and heated under reflux with stirring, a solution of fuming nitric acid (0.45mL, 10.12mmol) in acetic acid (1mL) was added dropwise, stirring was maintained at 50-55 ℃ for 2h, after completion of the monitoring reaction, cooling, filtration, recrystallization from ethanol, and drying gave Compound 2(0.92g, 41.0%).
Compound 2(0.92g, 1.71mmol) was placed in a round bottom flask (10mL) and 90% H was added dropwise2SO4(2mL), the reaction mixture was stirred under reflux in an oil bath at 85 ℃ for 2 hours, and after completion of the reaction was monitored, the reaction mixture was taken out and cooled, the reaction mixture was poured into water (50mL), and the pH was adjusted to 9 with ammonia water to precipitate a red solid, which was then cooled and filtered, and the solid was washed with water 2 times to obtain compound 3(0.34g, 86.8%).
A toluene solution (8mL) of Compound 3(0.34g, 1.47mmol) was placed in a three-necked flask (25mL), and DMF (0.1mL) and SOCl were added sequentially under ice-bath conditions2(0.36mL, 5mmol), after the dropwise addition, the reaction solution was transferred to a 65 ℃ oil bath and reacted for 3h with stirring under reflux. After completion of the reaction was monitored, the filtrate was concentrated and separated by column chromatography (30:1 petroleum ether/ethyl acetate) to give pure compound 4(164mg, 43.1%).
Will contain compound 4(100mg, 0.385mmol), PdCl2(PPh3)2(13.5mg, 0.01925mmol), CuI (3.65mg, 0.01925mmol) and Et3The mixture of N (1mL) was placed in a 50 ℃ oil bath and tert-butylacetylene (75mg, 0.77mmol) was added dropwise, the reaction was allowed to proceed for about 2h, after completion of the reaction was monitored, the ethyl acetate and water were diluted, extracted, the organic phases combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (30:1 petroleum ether/ethyl acetate) to give compound 5(75mg, 74.6%).
The mixture containing compound 5(65mg, 0.249mmol) and NH4Cl (53.3mg, 0.996mmol) in ethanol andplacing water (2:1, 1.5mL) solution in 90 deg.C oil bath, reflux reacting for 30min, adding iron powder (55.8mg, 0.996mmol), stirring under reflux for 3 hr, monitoring reaction, hot filtering, washing filter residue with ethanol, filtering, and adding saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (15:1 petroleum ether/ethyl acetate) to obtain compound 6(15mg, yield 25.8%).
The following compounds were prepared according to the preparation method in example 1, except for appropriately substituting the corresponding reaction compounds.
Figure BDA0001217551720000151
Figure BDA0001217551720000161
Example 2:
Figure BDA0001217551720000171
reagents and conditions: a) trimethyl acetylene silicon, bis (triphenylphosphine) palladium dichloride, cuprous iodide and triethylamine; b) tetrabutylammonium fluoride, tetrahydrofuran; c) iron powder, ammonium chloride, ethanol and water; d) palladium on carbon, hydrogen.
Will contain compound 4(400mg, 1.54mmol), PdCl2(PPh3)2(54mg, 0.07mmol), CuI (14.6mg, 0.07mmol) and Et3The mixture of N (4mL) was put in a 50 ℃ oil bath, trimethylethynylsilicon (300mg, 3.08mmol) was added dropwise, the reaction was carried out for about 2h, after completion of the reaction was monitored, ethyl acetate and water were diluted, the organic phases were extracted, combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (30:1 petroleum ether/ethyl acetate) to give compound 7(300mg, 70.8%).
Tetrabutylammonium fluoride (1.6mL, 5.84mmol) was added dropwise to a solution of compound 7(250mg, 0.903mmol) in THF (3mL) under ice-bath conditions, and the reaction was carried out at room temperature for 0.5 h. After the reaction is monitored to be complete, water is added for quenching, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying and concentration,column chromatography (30:1 petroleum ether/ethyl acetate) gave compound 8(86mg, yield 46.5%).1H NMR(400MHz,CDCl3):8.66(s,1H),8.38(s,1H),3.60(s,1H)；13C NMR(100MHz,CDCl3):154.67,152.46,150.64,128.65,118.33,117.23,86.32.
Will contain compound 8(40mg, 0.195mmol) and NH4Placing Cl (41.37mg, 0.78mmol) solution of ethanol and water (2:1, 1mL) in 90 deg.C oil bath, reflux reacting for 30min, adding iron powder (43mg, 0.78mmol), stirring under reflux for 3 hr, monitoring reaction, vacuum filtering, washing filter residue with ethanol, and filtering with saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (5:1 petroleum ether/ethyl acetate) to obtain compound 9(31mg, yield 91.2%).1H NMR(400MHz,CDCl3):8.06(s,1H),7.05(s,1H),4.64(s,2H),3.59(s,1H)；13C NMR(100MHz,CDCl3):156.24,149.39,147.21,125.68,116.60,98.26,85.66,79.19.
Compound 9(20mg, 0.114mmol) was dissolved in methanol (0.5mL), Pd/C (1mg,0.0114mmol) was added, and the system was replaced with H2After that, the reaction was carried out at ordinary temperature overnight. After completion of the reaction was monitored, the reaction mixture was filtered, washed with solid methanol, the filtrate was concentrated, and column chromatography (8:1 petroleum ether/ethyl acetate) was performed to give compound 10(8mg, yield 39.6%).1H NMR(400MHz,CDCl3):8.06(s,1H),7.05(s,1H),4.64(s,2H),3.59(s,1H)；13C NMR(100MHz,CDCl3):156.24,149.39,147.21,125.68,116.60,98.26,85.66,79.19.
Example 3:
Figure BDA0001217551720000172
reagents and conditions: a) benzyl azide, cuprous iodide, glycerol; b) iron powder, ammonium chloride, ethanol and water.
A mixture of Compound 8(20mg, 0.098mmol), benzyl azide (14mg, 0.098mmol), CuI (0.92mg, 0.0048mmol), and glycerol (0.5mL) was placed in a 40 ℃ oil bath and reacted overnight. After the reaction is completely monitored by thin layer chromatography, water is added for quenching, ethyl acetate is used for extraction, and anhydrous sulfur is addedSodium sulfate was dried, concentrated, and separated by column chromatography (6:1 petroleum ether/ethyl acetate) to give compound 11(20mg, yield 62.5%).1H NMR(400MHz,CDCl3):8.57(s,1H),8.46(s,1H),7.70(s,1H),7.45-7.32(m,5H),5.63(s,2H).
Will contain compound 11(20mg, 0.059mmol) and NH4Placing Cl (12.5mg, 0.237mmol) solution of ethanol and water (2:1, 1mL) in an oil bath kettle at 90 deg.C for reflux reaction for 30min, adding iron powder (13.27mg, 0.237mmol), stirring under reflux for 1h, monitoring reaction completion, hot filtering, washing filter residue with ethanol, filtering, and adding saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (2:1 petroleum ether/ethyl acetate) to obtain compound 12(3mg, yield 16.5%).1H NMR(400MHz,CDCl3):7.92(s,1H),7.85(s,1H),7.44-7.36(m,5H),7.08(s,2H),5.64(s,2H),5.35(t,J＝9.6Hz,2H).
Example 4:
Figure BDA0001217551720000181
reagents and conditions: a) tetrakis (triphenylphosphine) palladium, cesium carbonate, toluene, water; b) iron powder, ammonium chloride, ethanol and water.
Pd (PPh)3)4(11mg, 0.096mmol) was added to Compound 4(50mg, 0.192mmol), Cs2CO3(124mg, 0.384mmol), phenylboronic acid (23.46mg, 0.192mmol), toluene, and water (1:1, 1mL) in a mixture of N2After protection, the mixture is put in an oil bath at 80 ℃ for reaction for 3h, after the completion of the reaction is monitored by thin layer chromatography, the mixture is taken out for cooling, water and ethyl acetate are added for extraction, anhydrous sodium sulfate is dried, concentration and column chromatography separation (30:1 petroleum ether/ethyl acetate) are carried out, and the compound 13(35mg, the yield is 71.4%) is obtained.1HNMR(400MHz,CDCl3):8.51(s,1H),8.09(s,1H),7.50-7.40(m,5H)；13C NMR(100MHz,CDCl3):154.97,152.29,151.47,136.85,136.34,128.99,128.93,127.80,123.73,117.35.
Will contain compound 13(30mg, 0.117mmol) and NH4A solution of Cl (24.75mg, 0.467mmol) in ethanol and water (2:1, 1mL) was placed in a 90 deg.C oil bath and reacted under refluxAdding iron powder (26.15mg, 0.467mmol) after 30min, continuing refluxing and stirring for reaction for 1h, monitoring reaction completion, hot filtering, washing filter residue with ethanol, and filtering with saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (8:1 petroleum ether/ethyl acetate) to obtain compound 14(21mg, yield 79.2%).1H NMR(400MHz,CDCl3):7.70(s,1H),7.52-7.43(m,5H),7.07(s,1H),4.18(s,1H)；13C NMR(100MHz,CDCl3):155.95,150.56,146.29,137.49,136.90,129.12,129.02,128.58,121.53,98.84.
Example 5 (with compound 18 as an example):
Figure BDA0001217551720000191
reagents and conditions a) thionyl chloride, toluene; b) iron powder, ammonium chloride, ethanol and water; c) benzaldehyde, sodium borohydride and methanol.
A toluene solution (20mL) of Compound 15(2g, 13.07mmol) was placed in a three-necked flask (100mL), and DMF (0.1mL) and SOCl were added sequentially under ice-bath conditions2(3.76mL,52.28mmol), after the addition, the reaction solution was transferred to a 65 ℃ oil bath and the reaction was stirred under reflux for 3 h. After completion of the reaction was monitored, the filtrate was concentrated to give pure compound 16(2.2g, yield 93.2%).
The mixture containing compound 16(2g, 11.04mmol) and NH4Placing Cl (2.34g, 44.20mmol) solution of ethanol and water (2:1, 3mL) in an oil bath kettle at 90 deg.C for reflux reaction for 30min, adding iron powder (2.47g, 44.20mmol), stirring under reflux for reaction for 3h, monitoring reaction completion, hot filtering, washing filter residue with ethanol, filtering, and adding saturated NaHCO3Adjusted to alkali, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound 17(1.5g, yield 90.3%).
Benzaldehyde (70mg, 0.662mmol) and acetic acid (0.1mL) were added to a solution of compound 17(100mg, 0.662mmol) in methanol (1mL) and allowed to react at ambient temperature for 4h, and after completion of the reaction was monitored, NABH was added in portions4(28mg, 0.74mmol), continuing the reaction for 3h at normal temperature, monitoring the reaction completion by thin layer chromatography, adding acetone for quenching, extracting with ethyl acetate, and drying with anhydrous sodium sulfateDrying, concentration, column chromatography (25:1 petroleum ether/ethyl acetate) gave compound 18(32mg, yield 20.1%).
The following compounds were prepared according to the preparation method in example 5, except for appropriately substituting the corresponding reaction compounds.
Figure BDA0001217551720000192
Figure BDA0001217551720000201
Figure BDA0001217551720000211
Example 6 (exemplified by compound 19):
Figure BDA0001217551720000212
reagents and conditions a) triphosgene, dichloroethane, ethyl 4-piperidinecarboxylate.
Under ice-bath conditions, a solution of compound 17(75mg, 0.5mmol) in 1, 2-dichloroethane (2mL) was slowly added to a solution of triphosgene (74mg, 0.25mmol) in 1, 2-dichloroethane (2mL), after completion of the addition, the mixture was stirred at room temperature for 0.5h, then placed in a 75 ℃ oil bath for reaction for 3h, and after completion of the reaction monitored by thin layer chromatography, the reaction mixture was cooled to room temperature. Adding 4-piperidinecarboxylic acid ethyl ester (78.5mg, 0.5mmol) in 1, 2-dichloroethane (1mL), stirring at room temperature for 15min, monitoring reaction completion by thin layer chromatography, spin-drying the reaction solution, dissolving in water, and adding saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (3:1 petroleum ether/ethyl acetate) to obtain compound 19(50.1mg, yield 30.0%).
The following compounds were prepared according to the preparation method in example 6, except for appropriately substituting the corresponding reaction compounds.
Figure BDA0001217551720000213
Figure BDA0001217551720000221
Example 7:
Figure BDA0001217551720000231
reagents and conditions a) bromine water, acetic acid.
Br was added under ice-bath conditions2A solution of (30. mu.L, 0.667mmol) in acetic acid (0.5mL) was slowly added to a solution of compound 15(100mg, 0.667mmol) in acetic acid (3 mL). After the addition, the reaction is carried out for 10min at normal temperature, and after the completion of the reaction is monitored by thin layer chromatography, saturated NaHCO is added3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (20:1 petroleum ether/ethyl acetate) to obtain compound 20(30mg, yield 19.6%) and compound 21(13mg, yield 6.3%).
Figure BDA0001217551720000232
Example 8:
Figure BDA0001217551720000233
reagents and conditions a) sodium hydroxide, water.
Adding NaOH aqueous solution (1N, 1mL) into ethanol (1mL) solution of compound 17(100mg, 0.667mmol), heating to 90 deg.C, reacting for 1h, TLC to follow and determine the completion degree of the reaction, extracting with ethyl acetate after the reaction is completed, drying with anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (8:1 petroleum ether/ethyl acetate) to obtain compound 22(13mg, yield 13%).1HNMR(400MHz,DMSO-d6):10.58(s,1H),7.94(d,J＝9.6Hz,1H),7.36(dd,J＝9.6Hz,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H)；13C NMR(100MHz,CDCl3):151.88,148.67,142.99,117.15,113.47,92.47.
Example 9:
Figure BDA0001217551720000241
reagents and conditions a) acetic anhydride; b) potassium nitrate, sulfuric acid; c) iron powder, ammonium chloride, ethanol and water.
Under the ice-bath condition, acetic anhydride (2.5mL, 26.5mmol) is slowly added into a 1, 4-dioxane (18mL) solution of the compound 17(2g, 13.25mmol) to react for 4h at room temperature, after the reaction is monitored by thin layer chromatography, water is added to quench, a solid is separated out, the filtration is carried out, the solid is washed by water, and the compound 23(2.2g, the yield is 86.3%) is obtained after drying.1H NMR(400MHz,CDCl3):8.41(s,1H),7.93(d,J＝9.2Hz,1H),7.58(dd,J＝9.2Hz,J＝2.0Hz,1H),7.41(s,1H),2.27(s,3H)；13C NMR(100MHz,CDCl3):169.88,155.61,151.70,140.93,125.94,121.72,106.83,24.72.
Under the ice-bath condition, KNO is added3(390mg, 4.81mmol) of H2SO4(1.5mL) solution was added slowly to compound 23(750mg, 3.89mmol) in H2SO4(7.5mL) in solution. After the addition was completed, the reaction was carried out at 40 ℃ for 5 hours, and after completion of the reaction as monitored by thin layer chromatography, the reaction mixture was taken out and cooled, poured slowly into ice water (50mL), and a solid precipitated, filtered with suction, washed with water, and dried to obtain compound 24(610mg, yield 80.1%).1H NMR(400MHz,DMSO-d6):9.04(s,2H),8.04(d,J＝9.2Hz,1H),7.46(d,J＝9.2Hz,1H)；13C NMR(100MHz,DMSO-d6):151.28,150.33,149.93,128.70,127.81,127.50.
Will contain compound 24(100mg, 0.510mmol) and NH4Placing Cl (109mg, 2.04mmol) solution of ethanol and water (2:1, 2mL) in 90 deg.C oil bath, reflux reacting for 30min, adding iron powder (114mg, 2.04mmol), stirring under reflux for 3 hr, monitoring reaction, vacuum filtering, washing filter residue with ethanol, and filtering with saturated NaHCO3Adjusting alkali, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (1:1 petroleum ether/ethyl acetate) to obtain compound 25(16mg, yield 18.9%).1H NMR(400MHz,DMSO-d6):7.26(d,J＝8.8Hz,1H),7.18(d,J＝9.2Hz,1H),5.12(s,2H),4.95(s,2H)；13C NMR(100MHz,DMSO-d6):150.61,148.79,130.86,126.78,120.61,108.85.
Example 10: test for inhibition of SHP2 Activity by Compounds
1) Materials: SHP2, using colibacillus expression system to obtain GST fusion protein; substrate, pNPP.
2) The process is to detect the enzyme activity in 96-well or 384-well flat-bottom transparent microwell plates by light absorption detection. The free product obtained by hydrolysis of the substrate pNPP by SHP2 has strong light absorption at 405 nm. The change of the light absorption intensity at 405nm is monitored by a microplate reader, and the initial reaction speed is calculated. The control compound used in the experiment was Na3VO4。
3) Sample treatment: the samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within a range that did not affect the detection activity.
4) Data processing and results description:
the activity of the sample is tested under a single concentration condition, e.g., 20. mu.g/ml, for primary screening. For samples that exhibit activity under certain conditions, e.g., an Inhibition% Inhibition greater than 50, the activity dose dependence, i.e., IC, is tested50Values (only IC50 values in the table below) were obtained by non-linear fitting of sample concentrations to sample activity, calculated as Graphpad Prism 4 using software, and sigmoidal dose-response (variable slope) as the model used for fitting, and for most inhibitor screening models, the bottom and top of the fitted curves were set at 0 and 100. In general, each sample was tested with multiple wells (n.gtoreq.2) and the results were expressed as Standard Deviation (SD) or Standard Error (SE). Generally, each test has a reported compound as a reference. All data are credible, accurate and correct as far as possible within the knowledge capability range.
Table 1: activity data for compounds inhibiting SHP2
Name (R) IC50(μg/mL) Name (R) IC50(μg/mL)
CXY-151 5.90±0.76 CXY-175 0.39±0.17
CXY-152 >20 CXY-247 13.06±3.70
CXY-241 6.39±0.38 CXY-265 1.54±0.33
CXY-247-1 5.90±0.53 CXY-215 3.34±0.46
CXY-247-2 15.41±1.83 CXY-177 1.31±0.41
CXY-242 7.41±1.55 CXY-196 >20
CXY-231 >20 CXY-307 >20
CXY-207 >20 CXY-308 9.77±2.02
CXY-193 >20 CXY-231-1 5.96±0.73
CXY-276 8.33±0.60 CXY-251 3.51±0.50
CXY-277-1 3.15±0.11 CXY-227-1 >20
CXY-334 2.59±0.44 CXY-166 13.99±2.71
CXY-205 6.14±1.87 CXY-229 7.47±0.48
CXY-277 >20 CXY-295 >20
CXY-257 >20 CXY-245 15.78±1.53
CXY-281 >20 CXY-338 >20
CXY-261 >20
Cell screening model: selecting cancer cells (such as MDA-MB-435, Hela, A549, HCT116, HL-60 and the like), treating the cancer cells with EGF, analyzing the phosphorylation levels of SHP2 and ERK1/2 by Western Blot, carrying out semiquantitative analysis by Bandscan software, and determining the treatment concentration, time and other parameters of the EGF. Experiments show that the compound CXY-175 has certain inhibitory activity on tumor cells such as A549, Hela, HCT116, HL-60 and the like, and has an effect on the phosphorylation level of ERK 1/2.

Claims (6)

1. A benzothiadiazole compound represented by the general formula I:
Figure FDA0002600354840000011
wherein R is1is-NH2；
R2Selected from: vinyl, phenyl, benzyltriazolyl, substituted or unsubstituted ethynyl, wherein the substituents for substitution of ethynyl are selected from C1-4 alkyl, tri (C1-C4 alkyl) silyl, C3-C5 cycloalkyl and phenyl.
2. A benzothiadiazole-based compound selected from the group consisting of:
Figure FDA0002600354840000012
Figure FDA0002600354840000021
3. use of the benzothiadiazole-type compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of a medicament for the prevention and/or treatment of cancer, metabolic and immune diseases, cardiovascular diseases and neurological diseases.
4. Use of the benzothiadiazole-based compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for preparing a protein tyrosine phosphatase SHP2 inhibitor.
5. A pharmaceutical composition comprising a therapeutically effective amount of the benzothiadiazole-type compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is for the prevention and/or treatment of cancer, metabolic and immune diseases, cardiovascular diseases and neurological diseases.
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