CN115197240B - Quinoline compound, synthesis method, pharmaceutical composition and application - Google Patents

Quinoline compound, synthesis method, pharmaceutical composition and application Download PDF

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CN115197240B
CN115197240B CN202110770732.9A CN202110770732A CN115197240B CN 115197240 B CN115197240 B CN 115197240B CN 202110770732 A CN202110770732 A CN 202110770732A CN 115197240 B CN115197240 B CN 115197240B
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quinoline
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salts
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王文龙
慕旭阳
李佳
周宇波
许磊
王智佳
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Shanghai Institute of Materia Medica of CAS
Jiangnan University
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Jiangnan University
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    • A61P25/00—Drugs for disorders of the nervous system
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention discloses a quinoline compound, a synthesis method, a pharmaceutical composition and application thereof, belonging to the technical field of medicines and preparation and application thereof. The quinoline compounds with the structure shown in the general formula I have the biological activity of activating protein tyrosine phosphatase SHP1, can be used as tool compounds for researching biological function relevance of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provide a new means for preventing and treating cancers, metabolism and immune diseases.

Description

Quinoline compound, synthesis method, pharmaceutical composition and application
Technical Field
The invention belongs to the technical field of medicines and preparation and application thereof, and particularly relates to a quinoline compound, a synthesis method, a pharmaceutical composition and application thereof.
Background
Protein tyrosine phosphatase 1 (SHP-1) containing Src homology 2 domain is a non-receptor protein tyrosine phosphatase widely existing in vivo, and consists of two SH2 domains (N-SH 2 and C-SH 2), a PTP domain with catalytic activity, a proline-rich group and a tyrosine phosphorylation tail. SHP-1 is present mainly in hematopoietic and epithelial cells and controls sig by down-regulating cellular signaling processes, particularly in the nuclear transcription and transcription activator (STAT) pathways, and is therefore widely recognized as a tumor suppressor. Overactivation of oncogenic STAT3 was observed in diffuse large B-cell lymphoma (DLBCL), the most common non-hodgkin lymphoma, with high aggressiveness and heterogeneity. Blocking STAT3 pathway is a potential therapeutic strategy for DLBCL. Mutation resulting in loss of function of SHP-1 promotes deregulation of STAT3 in DLBCL. Down-regulation of expression occurs in approximately 50% of primary DLBCL tumors. Thus, increasing SHP-1 activity represents a potentially promising strategy for DLBCL therapy. Enzyme activators are generally more difficult to develop than enzyme inhibitors. To our knowledge, reported compounds that directly activate SHP-1 are all kinase inhibitors, including dovitinib, nintedanib, regorafenib, sorafenib and derivatives thereof, and specific structures are shown below:
there is a great need to develop potent and specific SHP-1 activators with structural diversity, with significantly less number and structural diversity than modulators of other subtypes in the family.
Disclosure of Invention
The invention provides a quinoline compound shown in the following general formula I and a preparation method thereof, wherein the quinoline compound has the biological activity of activating protein tyrosine phosphatase SHP1, can be used as a tool compound for researching the biological function relevance of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provides a new means for preventing and treating cancers, metabolism and immune diseases.
A quinoline compound shown in a general formula I or pharmaceutically acceptable salt thereof,
wherein,represents a single bond or a double bond; x is X 1 Selected from none (H), S, O, NH; x is X 2 Selected from none (H), CH, CNH 2 A thiophene ring;
R 1 is selected from the group consisting of the following,represents the site of attachment:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group.
In one embodiment of the invention, R 2 ，R 3 ，R 4 ，R 5 Are independently selected from-F, -Cl, -Br, -H, -CF 3 、 -CH 3 、-OCH 3
In one embodiment of the present invention, the quinoline compound has a structure represented by the following formula II, formula III, formula IV, formula V, formula VI, formula VII:
wherein R is 1 ，R 2 ，R 3 ，R 4 ，R 5 Respectively as defined above.
In one embodiment of the invention, when X 1 Is S, X 2 In the case of CH, the quinoline compound has a structure of thieno [2,3-b ] shown in formula II]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
wherein R is 1 ：
R 2 ，R 3 ，R 4 ，R 5 Independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
in one embodiment of the invention, when X 1 Is O, X 2 When CH is adopted, the structure of the quinoline compound is furo [2,3-b ] shown in the formula III]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 independently selected from:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
in one embodiment of the invention, when X 1 Is NH, X 2 In the case of CH, quinoline compoundsIs pyrrolo [2,3-b ] of formula IV]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
wherein R is 1 Selected from:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
in one embodiment of the invention, when X 1 Is S, X 2 Is CNH 2 In the case of quinoline compounds, the structure of the quinoline compounds is 3-aminothiophene [2,3-b ] shown in formula V]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 selected from:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
/>
in one embodiment of the invention, when X 1 X is nothing 2 In the case of 4-thienyl, the structure of the quinoline compound is a 4- (quinoline-3-yl) thiophene-2-carboxamide derivative shown in a formula VI or pharmaceutically acceptable salt thereof,
R 1 selected from:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
/>
/>
in one embodiment of the invention, X 1 Is S, X 2 In the absence, the structure of the quinoline compound is a 2- (quinoline-2-yl thio) acetamide derivative shown in a formula VII or pharmaceutically acceptable salt thereof,
R 1 selected from:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group; specifically selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
/>
/>
in one embodiment of the invention, the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, metaphosphate, nitric acid and sulfate, acetate, benzenesulfonate, benzoate, citrate, ethanesulfonate, fumarate, gluconate, glycolate, isethionate, lactate, lactobionate, maleate, malate, methanesulfonate, succinate, p-toluenesulfonate and tartrate, ammonium salts, alkali metal salts, alkaline earth metal salts, tromethamine salts, diethanolamine salts, lysine salts, ethylenediamine salts.
The invention also provides a method for preparing the quinoline compound shown in the formula II, wherein the reaction route is as follows:
wherein, reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Ethyl thioglycolate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
reflux the mixture of the compound II-1 and acetic anhydride in a solvent, neutralizing the reaction solution with an inorganic alkali solution after the reaction is completed, filtering, and washing a filter cake to obtain a solid compound II-2, and directly throwing the solid compound II-2 into the next step; dissolving the compound II-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating the reaction solution, monitoring the reaction, reversely dripping the reaction solution into cold water, carrying out suction filtration, washing a filter cake and drying to obtain the compound II-3; heating DMF solution of the compound II-3, triethylamine and ethyl thioglycolate, monitoring the reaction, reversely dripping the DMF solution into cold water after the reaction is finished, carrying out suction filtration, washing a filter cake and drying to obtain the compound II-4; hydrolyzing the ethanol solution of the compound II-4 by using lithium hydroxide, adding acid to adjust the pH to be acidic, filtering, washing and drying a filter cake to obtain the compound II-5; heating a dimethylformamide solution of a compound II-5, an organic base 6, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and after the reaction is completed, dripping the reaction liquid into water, carrying out suction filtration, and recrystallizing a filter cake to obtain the compound II-7.
The invention also provides a method for preparing the quinoline compound shown in the formula III, wherein the reaction route is as follows:
wherein, reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
the mixture of the compound III-1 and acetic anhydride is refluxed in a solvent, after the reaction is completed, the reaction solution is neutralized by inorganic alkali solution, the filtration is carried out, and the filter cake is washed to obtain a solid compound III-2 which is directly put into the next step; dissolving a compound III-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating a reaction solution, monitoring the reaction, reversely dripping the reaction solution into cold water, carrying out suction filtration, washing a filter cake, drying, floating the compound in 70% acetic acid for reflux, cooling, carrying out suction filtration, and washing with water to obtain a compound III-3; heating DMF solution of the compound III-3, triethylamine and ethyl thioglycolate, monitoring the reaction, reversely dripping the DMF solution into cold water, carrying out suction filtration, washing a filter cake and drying to obtain the compound III-4; hydrolyzing the ethanol solution of the compound III-4 by using lithium hydroxide, adding acid to adjust the pH to be acidic, filtering, washing and drying a filter cake to obtain the compound III-5; heating a dimethylformamide solution of a compound III-5, an organic base 6, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine, and after the reaction is completed, dripping the reaction liquid into water, carrying out suction filtration, and recrystallizing a filter cake to obtain the compound III-7.
The invention also provides a method for preparing the quinoline compound shown in the formula IV, wherein the reaction route is as follows:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Isocyanoacetic acid ethyl ester, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
reflux the mixture of the compound IV-1 and acetic anhydride in a solvent, neutralizing the reaction solution with an inorganic alkali solution after the reaction is completed, performing suction filtration, and washing a filter cake to obtain a solid compound IV-2, and directly throwing the solid compound IV-2 into the next step; dissolving the compound IV-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating the reaction solution, monitoring the reaction, reversely dripping the reaction solution into cold water, carrying out suction filtration, washing a filter cake and drying to obtain the compound IV-3; heating a DMSO solution of the compound IV-3, potassium carbonate and ethyl isocyanoacetate, adding catalytic amount of cuprous iodide, monitoring the completion of the reaction, performing suction filtration, reversely dripping filtrate into cold water, performing suction filtration, washing a filter cake and drying to obtain the compound IV-4; hydrolyzing the ethanol solution of the compound IV-4 by using lithium hydroxide, adding acid to adjust the pH to be acidic, filtering, washing and drying a filter cake to obtain the compound IV-5; heating a dimethylformamide solution of the compound IV-5, organic base 6, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine, and after the reaction is completed, dripping the reaction liquid into water, filtering, and recrystallizing a filter cake to obtain the compound IV-7.
The invention also provides a method for preparing the quinoline compound shown in the formula V, wherein the reaction route is as follows:
(1) Important intermediate preparation:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, chloroform and thionyl chloride; d) Thiourea, ethanol;
(2) Preparation of quinoline compounds:
reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 ℃.
Wherein, the step (1) comprises the following steps:
the mixture of the compound V-1 and acetic anhydride is refluxed in a solvent, after the reaction is completed, the reaction solution is neutralized by inorganic alkali solution, the filtration is carried out, and the filter cake is washed to obtain a solid compound V-2 which is directly put into the next step; dissolving the compound V-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating the reaction solution, monitoring the reaction, reversely dripping the reaction solution into cold water, carrying out suction filtration, washing a filter cake and drying to obtain the compound V-3. Mixing tetrahydrofuran solution of the compound V-3 with aqueous solution of hydroxylamine hydrochloride, stirring at room temperature, concentrating to remove solvent after complete reaction, washing with water, dissolving solid in chloroform, adding thionyl chloride, refluxing and stirring, concentrating to remove organic solvent after complete reaction, recrystallizing with ethanol to obtain the compound V-4, dissolving the compound V-4 and thiourea in ethanol, refluxing and reacting for 1h, cooling, adding water, precipitating, and filtering to obtain the solid V-5.
The step (2) comprises the following steps:
dissolving an amino compound 6 in dichloromethane, adding chloroacetic anhydride, concentrating a reaction solution after the reaction is completed, and performing alkali washing to obtain a product V-7, dissolving the V-7 and the V-5 in a proper amount of DMF, adding triethylamine, reacting at 90 ℃, adding water after the completion, and separating out solids to obtain a compound V-8.
The invention also provides a method for preparing the quinoline compound shown in the formula VI, wherein the reaction route is as follows:
reagents and conditions: a) The bisboronic acid pinacol ester, the tetraphenylphosphine palladium, the potassium carbonate, the water, the 1, 4-dioxane and the temperature of 80 ℃; b) Substituted 2-bromoquinoline, tetraphenylphosphine palladium, potassium carbonate, water, 1, 4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
dissolving a compound VI-1, pinacol biborate, tetraphenylphosphine palladium and potassium carbonate in a mixed solution of 1, 4-dioxane and water, refluxing and heating, and after the reaction is completed, spin-drying an organic solvent and extracting with ethyl acetate; concentrating the organic phase, and purifying by a chromatographic column to obtain a compound VI-2; dissolving VI-2, various substituted 2-bromoquinolines, tetraphenylphosphine palladium and potassium carbonate in a mixed solution of 1, 4-dioxane and water, heating under reflux, and after the reaction is completed, spin-drying an organic solvent and extracting with ethyl acetate; the organic phase was concentrated and purified by column chromatography to give compound VI-3. Hydrolyzing a methanol solution of the compound VI-4 by using lithium hydroxide, adding acid to adjust the pH to be acidic, filtering, washing and drying a filter cake to obtain the compound VI-4; heating a dimethylformamide solution of a compound VI-4, an organic base 6, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate and N, N-diisopropylethylamine, and after the reaction is completed, dripping the reaction liquid into water, carrying out suction filtration, and recrystallizing a filter cake to obtain the compound VI-5.
The invention also provides a method for preparing the quinoline compound shown in the formula VII, wherein the reaction route is as follows:
reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
The specific process comprises the following steps:
dissolving a compound VII-3 in methylene dichloride, dropwise adding bromoacetyl bromide, stirring at room temperature for reaction, spinning the solvent, washing with water and extracting with ethyl acetate after the reaction is completed, thus obtaining a compound VII-4; dissolving a compound VII-2 and a compound VII-4 in N, N-dimethylformamide, adding potassium carbonate, and stirring at 60 ℃ for reaction; after the reaction is completed, ethyl acetate is added for dilution, and the N, N dimethylformamide is washed away by water, and the organic phase chromatographic column is purified to obtain the compound VII-5.
The invention also provides application of the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof in preparation of a protein tyrosine phosphatase SHP1 activator.
The invention also provides application of the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof in preparing medicaments for preventing and treating cancers, metabolic and immune diseases, cardiovascular diseases and neurological diseases.
The invention also provides a pharmaceutical composition, which comprises the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof, and optional pharmaceutically acceptable auxiliary materials.
The invention also provides a medicine for preventing and treating cancers, metabolic and immune diseases, cardiovascular diseases or neurological diseases, which comprises quinoline compounds shown in the general formula I or pharmaceutically acceptable salts thereof and optional pharmaceutically acceptable auxiliary materials.
The beneficial effects are that:
the quinoline compound or the pharmaceutically acceptable salt thereof has the bioactivity of activating protein tyrosine phosphatase SHP1, can be used as a tool compound for researching the biological function association of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provides a new means for preventing and treating cancers, metabolism and immune diseases.
Drawings
FIG. 1 is a plot of concentration versus fold activation for compounds CD-13, XY-5, XY-6 (left to right).
FIG. 2 is a graph comparing CD-13 effect on STAT3 (Y705) phosphorylation; (A) Protein expression of STAT3 (Y705) and STAT3 was detected 4 hours after OCI-Ly10, OCI-Ly10R and DHL-2 cells were treated with different CD-13 concentrations, respectively, GAPDH as an internal control; (B) Protein expression of STAT3 (Y705) and STAT3 was examined after treatment of OCI-Ly10, OCI-Ly10R and DHL2 cells with 40. Mu.M CD-13 for various periods of time, GAPDH being an internal control.
Detailed Description
The preparation process of the following examples:
reaction procedure 1, preparation of quinolines of formula II:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Ethyl thioglycolate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: and adding the compound II-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring that the reaction is complete, slowly dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral, filtering the solid, washing and drying to obtain the compound II-2. Dissolving the compound II-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), refluxing at 90 ℃ for reaction overnight, monitoring that the reaction is complete, slowly dripping the reaction solution into ice water, leaching after the solid is completely separated out, washing and drying the filter cake to obtain the compound II-3. Compound II-3 (1 eq) was dissolved in 10ml of DMF, triethylamine (6 eq) and ethyl thioglycolate (1.2 eq) were added, the reaction system was warmed to 90℃and reacted for 1h. After the reaction is monitored to be complete, the reaction liquid is dripped into cold water, and after the solid is completely separated out, the suction filtration is carried out, and the filter cake is washed and dried to obtain the compound II-4. Dissolving the compound II-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the monitoring reaction is complete, concentrating the reaction liquid, adding dilute hydrochloric acid to adjust the pH to 5-6, carrying out suction filtration, washing and drying a filter cake to obtain the compound II-5. Compound II-5 (1 eq) was dissolved in DMF (20 ml) and HATU (1.5 eq), DIPEA (1.5 eq) and organic amine 6 (1.2 eq) were added in order. The reaction system was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed, ethyl acetate: the solid was recrystallized from petroleum ether=1:5 mixed solvent to give pure compound II-7.
Reaction procedure 2, preparation of quinolines of formula III:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: and adding the compound III-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring that the reaction is complete, slowly dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral, filtering the solid, washing and drying to obtain the compound III-2. Dissolving the compound III-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), carrying out reflux reaction at 90 ℃ for overnight, slowly dripping the reaction solution into ice water after monitoring the reaction, carrying out suction filtration after the solid is completely separated out, floating the solid in 70% acetic acid solution (20 ml), carrying out reflux stirring for 10 hours, cooling, carrying out suction filtration, washing and drying a filter cake to obtain the compound III-3. Compound III-3 (1 eq) was dissolved in 10ml of DMF, triethylamine (6 eq) and ethyl bromoacetate (1.2 eq) were added, the reaction system was warmed to 90℃and reacted for 1h. After the reaction is monitored to be complete, the reaction liquid is dripped into cold water, and after the solid is completely separated out, the suction filtration is carried out, and the filter cake is washed and dried to obtain the compound III-4. Dissolving the compound III-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the monitoring reaction is complete, concentrating the reaction liquid, adding dilute hydrochloric acid to adjust the pH to 5-6, carrying out suction filtration, washing and drying a filter cake to obtain the compound III-5. Compound III-5 (1 eq) was dissolved in DMF (20 ml) and HATU (1.5 eq), DIPEA (1.5 eq) and organic amine 6 (1.2 eq) were added in sequence. The reaction system was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed, ethyl acetate: the solid was recrystallized from petroleum ether=1:5 mixed solvent to give pure compound III-7.
Reaction procedure 3, preparation of quinolines of formula IV:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Isocyanoacetic acid ethyl ester, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: and adding the compound IV-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring that the reaction is complete, slowly dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral, filtering the solid, washing and drying to obtain the compound IV-2. Dissolving the compound IV-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), refluxing at 90 ℃ for reaction overnight, monitoring that the reaction is complete, slowly dripping the reaction solution into ice water, leaching after the solid is completely separated out, washing and drying a filter cake to obtain the compound IV-3. Compound IV-3 (1 eq) was dissolved in 10ml DMSO and K was added 2 CO 3 (3 eq) and ethyl isocyanoacetate (1.2 eq), and CuI (0.1 eq) were reacted for 1h at 90 ℃. And after the monitoring reaction is completed, carrying out suction filtration, dripping filtrate into cold water, carrying out suction filtration after the solid is completely separated out, washing and drying a filter cake to obtain the compound IV-4. Dissolving the compound IV-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the monitoring reaction is complete, concentrating the reaction liquid, adding dilute hydrochloric acid to adjust the pH to 5-6, carrying out suction filtration, washing and drying a filter cake to obtain the compound IV-5. Compound IV-5 (1 eq) was dissolved in DMF (20 ml) and HATU (1.5 eq), DIPEA (1.5 eq) and organic amine IV-6 (1.2 eq) were added in sequence. The reaction system was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed, ethyl acetate: petroleum ether=1:5 mixed solvent weightThe solid was crystallized to give pure compound IV-7.
Reaction procedure 4, preparation of quinolines of formula V:
(1) Preparation of important intermediates
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, chloroform and thionyl chloride; d) Thiourea, ethanol
The preparation process comprises the following steps: and adding the compound V-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring that the reaction is complete, slowly dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral, filtering the solid, washing and drying to obtain the compound V-2. Dissolving the compound V-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), refluxing at 90 ℃ for reaction overnight, monitoring that the reaction is complete, slowly dripping the reaction solution into ice water, leaching after the solid is completely separated out, washing and drying a filter cake to obtain the compound V-3. Mixing tetrahydrofuran solution of the compound V-3 (1 eq) with aqueous solution of hydroxylamine hydrochloride (1 eq), stirring at room temperature, concentrating to remove solvent after the reaction is complete, washing with water, dissolving solid in chloroform, adding thionyl chloride (1 eq), stirring under reflux, concentrating to remove organic solvent after the reaction is complete, recrystallizing with ethanol to obtain the compound V-4, dissolving the compound V-4 (1 eq) and thiourea (2 eq) in ethanol, carrying out reflux reaction for 1h, cooling, adding water, precipitating, and carrying out suction filtration to obtain the solid V-5.
(2) Synthesizing a quinoline structure:
reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 DEG C
Dissolving an amino compound V-6 (1 eq) in dichloromethane, adding chloroacetic anhydride (1.5 eq), concentrating the reaction solution after the reaction is completed, slowly dripping a saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, extracting and concentrating by ethyl acetate to obtain a product V-7, dissolving V-7 (1.5 eq) and V-5 (1 eq) in a proper amount of DMF, adding triethylamine (3 eq), reacting at 90 ℃, adding water after the completion of the reaction, and separating out solids to obtain the compound V-8.
Reaction procedure 5, preparation of quinolines of formula VI:
reagents and conditions: a) The bisboronic acid pinacol ester, the tetraphenylphosphine palladium, the potassium carbonate, the water, the 1, 4-dioxane and the temperature of 80 ℃; b) Substituted 2-bromoquinoline, tetraphenylphosphine palladium, potassium carbonate, water, 1, 4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound VI-1 (1 eq) and pinacol diboronate (1.2 eq), tetraphenylphosphine palladium (0.05 eq), and potassium carbonate (2 eq) were dissolved in a mixed solution of 1, 4-dioxane (8 mL) and water (2 mL), heated under reflux, and after the reaction was completed, the organic solvent was dried, and ethyl acetate was extracted. The organic phase was concentrated and purified by column chromatography to give compound VI-2. VI-2 (1 eq) was dissolved in a mixed solution of 1, 4-dioxane (8 mL) and water (2 mL) with various substituted 2-bromoquinolines (1 eq), tetraphenylphosphine palladium (0.05 eq), and potassium carbonate (2 eq), heated under reflux, and after the reaction was completed, the organic solvent was dried by spinning, and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give compound VI-3. A methanol solution of compound VI-3 (1 eq) was hydrolyzed with lithium hydroxide (8 eq), the pH was adjusted to acidity by adding acid, suction filtration, washing and drying the filter cake to obtain compound VI-4. A dimethylformamide solution (10 mL) of compound VI-4 (1 eq), organic base 6 (1.2 eq), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.2 eq) and N, N-diisopropylethylamine (2 eq) was heated, and after completion of the reaction, the reaction liquid was dropped into water, suction filtration and the cake was recrystallized to obtain compound VI-5.
Reaction procedure 6, preparation of quinolines of formula VII:
reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
The compound VII-1 (1 eq) and thiourea (1.5 eq) were dissolved in ethanol (5 mL) and refluxed, and after the reaction was completed, the solvent was dried by spin-drying, and washed with water to obtain the compound VII-2. Compound VII-3 (1 eq) was dissolved in methylene chloride (5 mL), bromoacetyl bromide (1.3 eq) was added dropwise, the reaction was stirred at room temperature, after the reaction was completed, the solvent was dried by spinning, washed with water and extracted with ethyl acetate, to obtain compound VII-4. Compound VII-2 (1 eq) and compound VII-4 (1 eq) were dissolved in N, N dimethylformamide (5 mL), and potassium carbonate (3 eq) was added thereto to stir the reaction at 60 ℃. After the reaction is completed, ethyl acetate is added for dilution, and the N, N dimethylformamide is washed away by water, and the organic phase chromatographic column is purified to obtain the compound VII-5.
Example 1
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) N, N-dimethylformamide, phosphorus oxychloride, 90 ℃; c) DMF, ethyl thioglycolate, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound II-1 (5.35 g,0.05 mol) was dissolved in acetic anhydride (7.5 g,0.075 mol), stirred well, reacted at 40℃until the reaction was completed, and then a saturated sodium hydrogencarbonate solution was added dropwise to the reaction solution until the reaction solution became neutral. The solid was suction filtered, washed and dried to give compound II-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/zcalcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Compound II-2 (5 g,0.03 mol) was dissolvedN, N-dimethylformamide (5.1 g,0.07 mol) was added to an excessive amount of phosphorus oxychloride (41.2 g,0.27 mol), the reaction was refluxed overnight at 90℃and, after completion of the reaction, the reaction solution was slowly dropped into ice water, and a large amount of solid was precipitated, filtered off with suction, washed and dried to give Compound II-3 (5.5 g, yield 80%). 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70(dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
Compound II-3 (5 g,0.024 mol) was dissolved in 20ml of DMF, and triethylamine (14.8 g,0.15 mol) and ethyl thioglycolate (3.5 g,0.03 mol) were added thereto, and the reaction system was warmed to 90℃and reacted for 1 hour. After the completion of the reaction was monitored, the reaction solution was dropped into ice water, a large amount of solids were precipitated, and the mixture was suction-filtered, washed and dried to obtain Compound II-4 (5.5 g, yield 83%). 1 H NMR(400MHz,CDCl 3 )δ8.56(s,1H),8.09(s,1H),8.05(d,J＝8.7Hz,1H),7.73(s,1H),7.63 (dd,J＝8.7,2.0Hz,1H),4.45(q,J＝7.1Hz,2H),2.61–2.55(m,3H),1.45(t,J＝7.1Hz,3H).MS(ESI):m/z calcd.For C 15 H 13 NO 2 S[M+H] + 272.0,found 272.0[M+H] +
Compound II-4 (3 g, 0.0111 mol) was dissolved in ethanol, and lithium hydroxide (0.83 g,0.033 mol) was added thereto, followed by stirring with heating. After the completion of the reaction was monitored, the reaction mixture was concentrated and then added with diluted hydrochloric acid to adjust the pH to 5-6, followed by suction filtration, washing and drying of the cake to give Compound II-5 (2 g, yield 73%). 1 H NMR(400MHz,Chloroform-d)δ10.90(s,1H),8.35(t,J＝1.6Hz, 1H),8.11(d,J＝1.4Hz,1H),8.04(d,J＝7.5Hz,1H),7.63(t,J＝1.5Hz,1H),7.51(dd,J＝7.5,1.4Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 13 H 9 NO 2 S[M+H] + 244.0,found 244.1[M+H] + .
Compound II-5 (200 mg,0.82 mmol) was dissolved in DMF (20 ml) and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg,1.23 mmol), organic amine 6 (232.2 mg,0.98 mmol) were added sequentially. Reflux-reacting the mixture at 50deg.C, monitoring the reaction, and dripping the reaction solution into cold waterThe solid was filtered off with suction and washed with ethyl acetate: petroleum ether=1:5 mixed solvent recrystallises the solid to give pure compound II-7 (156 mg, yield 41.1%). 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.46(t,J＝1.5Hz,1H),8.25(d,J＝1.4Hz,1H), 8.16(d,J＝7.5Hz,1H),8.06–7.86(m,2H),7.68(t,J＝1.5Hz,1H),7.66–7.56(m,2H),7.51(dd,J＝7.5,1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),2.50 (s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 27 N 3 O 3 S[M+H] + 462.2, found462.2[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 1, except that the corresponding reaction compounds were appropriately replaced.
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Example 2
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) N, N-dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound III-1 (5.35 g,0.05 mol) was dissolved in acetic anhydride (7.5 g,0.075 mol), stirred well, reacted at 40℃until the reaction was completed, and then a saturated sodium bicarbonate solution was added dropwise to the reaction solution until the reaction solution became neutral. The solid was suction filtered, washed and dried to give compound III-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/z calcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Compound III-2 (5 g,0.03 mol) was dissolved in an excessive amount of phosphorus oxychloride (41.2 g,0.27 mol), N-dimethylformamide (5.1 g,0.07 mol) was added, the reaction was refluxed overnight at 90℃and after the completion of the reaction was monitored, the reaction solution was slowly dropped into ice water, a large amount of solids were precipitated, suction filtration was performed, the solids were floated in 30ml of a 70% acetic acid solution, heated and refluxed for 10 hours, cooled, suction filtration was performed, and washing and drying were performed to obtain compound III-3 (5.1 g, yield 81.27%). 1 H NMR(400MHz, Chloroform-d)δ10.14(d,J＝0.8Hz,1H),9.26(s,1H),8.42(d,J＝1.0Hz,1H),7.91(d,J＝7.7Hz,1H),7.53(d,J＝1.5Hz,1H),7.34(dd,J＝7.5,1.4Hz,1H),2.30(s,3H).MS(ESI):m/z calcd. For C 11 H 9 NO 2 [M+H] + 188.1,found 188.0[M+H] + .
Compound III-3 (4.5 g,0.024 mol) was dissolved in 20ml of DMF, and triethylamine (14.8 g,0.15 mol) and ethyl bromoacetate (5.0 g,0.03 mol) were added thereto, and the reaction system was warmed to 90℃and reacted for 1 hour. After monitoring the completion of the reaction, the reaction liquid was dropped into ice water, a large amount of solids were precipitated, and the compound III-4 (4.9 g, yield 79%) was obtained after suction filtration, washing and drying. 1 H NMR(400MHz,Chloroform-d)δ8.20(t,J＝1.6Hz,1H),7.99(d,J＝7.5Hz,1H),7.62(t,J＝ 1.6Hz,1H),7.51(dd,J＝7.5,1.5Hz,1H),7.42(d,J＝1.5Hz,1H),4.30(q,J＝8.0Hz,2H),2.50(s,3H),1.32(t,J＝8.0Hz,3H).MS(ESI):m/z calcd.For C 15 H 13 NO 3 [M+H] + 256.0,found 256.0[M+H] + .
Compound III-4 (2.8 g, 0.0111 mol) was dissolved in ethanol, and lithium hydroxide (0.83 g,0.033 mol) was added thereto, followed by stirring with heating. After the completion of the reaction was monitored, the reaction mixture was concentrated and then added with diluted hydrochloric acid to adjust the pH to 5-6, followed by suction filtration, washing and drying of the cake to give Compound III-5 (1.7 g, yield 68%). 1 H NMR(400MHz,Chloroform-d)δ12.54(s,1H),8.21(t,J ＝1.6Hz,1H),7.99(d,J＝7.5Hz,1H),7.62(t,J＝1.6Hz,1H),7.57–7.47(m,2H),2.50(s,3H).MS(ESI):m/z calcd.For C 13 H 9 NO 3 [M+H] + 228.0,found 228.0[M+H] + .
Compound III-5 (187 mg,0.82 mmol) was dissolved in DMF (20 ml) and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg,1.23 mmol), organic amine II-6 (232.2 mg,0.98 mmol) were added sequentially. The mixture was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed with ethyl acetate: the solid was recrystallized from petroleum ether=1:5 mixed solvent to give pure compound III-7 (117 mg, yield 31.92%). 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J＝7.7Hz,1H),8.02–7.94(m,3H),7.69–7.57(m, 3H),7.51(dd,J＝7.5,1.5Hz,1H),7.33(d,J＝1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 27 N 3 O 4 [M+H] + 446.2,found446.2[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 2, except that the corresponding reaction compounds were appropriately replaced.
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Example 3
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 DEG CThe method comprises the steps of carrying out a first treatment on the surface of the c) Isocyanoacetic acid ethyl ester, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound IV-1 (5.35 g,0.05 mol) was dissolved in acetic anhydride (7.5 g,0.075 mol), stirred well, reacted at 40℃until the reaction was completed, and then a saturated sodium bicarbonate solution was added dropwise to the reaction solution until the reaction solution became neutral. The solid was suction filtered, washed and dried to give compound IV-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/zcalcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Compound IV-2 (5 g,0.03 mol) was dissolved in an excessive amount of phosphorus oxychloride (41.2 g,0.27 mol), N-dimethylformamide (5.1 g,0.07 mol) was added, the reaction was refluxed overnight at 90℃and after completion of the reaction, the reaction solution was slowly dropped into ice water, a large amount of solids were precipitated, and after suction filtration, washing and drying, compound IV-3 (5.5 g, yield 80%) was obtained. 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70(dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
Compound IV-3 (5 g,0.024 mol) was dissolved in 20ml DMSO solution and K was added 2 CO 3 (10.35 g,0.075 mol), ethyl isocyanoacetate (3.4 g,0.03 mol), cuI (0.46 g,2.4 mmol), and the reaction system was heated to 90℃and reacted for 1 hour. After the completion of the reaction was monitored, the filtrate was suction-filtered, and a large amount of solids was precipitated by dropping the filtrate into ice water, suction-filtered, washed and dried, followed by column chromatography (ethyl acetate: petroleum ether=20:1) to give compound IV-4 (3.1 g, yield 48.6%). 1 H NMR(400MHz, Chloroform-d)δ8.68(s,1H),8.33(t,J＝1.6Hz,1H),8.01(d,J＝7.5Hz,1H),7.62(t,J＝1.5Hz,1H),7.51(dd,J＝7.5,1.4Hz,1H),7.35(d,J＝1.5Hz,1H),4.37(q,J＝8.0Hz,2H),2.50(s,3H), 1.36(t,J＝8.0Hz,3H).MS(ESI):m/z calcd.For C 15 H 14 N 2 33/24O 2 [M+H] + 255.1,found 255.1[M+H] +
Compound IV-4 (3 g,0.012 mol) was dissolved in ethanol, and lithium hydroxide (0.89 g,0.036 mol) was added thereto, followed by heating and stirring. After monitoring the completion of the reaction, the reaction mixture was concentrated and then added with diluted hydrochloric acid to adjust the pH to 5-6, followed by suction filtration, washing and drying the cake to give Compound IV-5 (2.3 g, yield 86.2%). 1 H NMR(400MHz,Chloroform-d)δ10.60(s,1H),9.00(s,1H), 8.33(t,J＝1.6Hz,1H),8.02(d,J＝7.5Hz,1H),7.62(t,J＝1.5Hz,1H),7.51(dd,J＝7.5,1.4Hz,1H),7.44(d,J＝1.4Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 13 H 10 N 2 O 2 [M+H] + 227.0, found 227.1[M+H] + .X
Compound IV-5 (185 mg,0.82 mmol) was dissolved in DMF (20 ml) and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg,1.23 mmol), organic amine 6 (232.2 mg,0.98 mmol) were added sequentially. The mixture was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed with ethyl acetate: the solid was recrystallized from petroleum ether=1:5 mixed solvent to give pure compound IV-7 (117 mg, yield 32.2%). 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.44(t,J＝1.6Hz,1H),8.26(s,1H),8.14(d,J＝7.5Hz,1H),8.02–7.94(m,2H),7.66(t,J＝1.6Hz,1H),7.62–7.54(m,2H),7.51(dd,J＝7.5, 1.4Hz,1H),7.36(d,J＝1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 28 N 4 O 3 [M+H] + 445.2,found445.0[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 3, except that the corresponding reaction compounds were appropriately replaced.
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Example 4
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, chloroform and thionyl chloride; d) Thiourea, ethanol.
Compound V-1 (5.35 g,0.05 mol) was dissolved in acetic anhydride (7.5 g,0.075 mol), stirred well, reacted at 40℃until the reaction was completed, and then a saturated sodium bicarbonate solution was added dropwise to the reaction solution until the reaction solution became neutral. The solid was suction filtered, washed and dried to give compound V-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/zcalcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Compound V-2 (5 g,0.03 mol) was dissolved in an excessive amount of phosphorus oxychloride (41.2 g,0.27 mol), N-dimethylformamide (5.1 g,0.07 mol) was added, the reaction was refluxed overnight at 90℃and after completion of the reaction, the reaction solution was slowly dropped into ice water, a large amount of solids were precipitated, and after suction filtration, washing and drying, compound V-3 (5.5 g, yield 80%) was obtained. 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70(dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
A solution of Compound V-3 (1 g,4.88 mmol) in tetrahydrofuran (5 ml) was mixed with a solution of hydroxylamine hydrochloride (0.34 g,4.88 mmol) in water (1 ml), stirred at room temperature, after completion of the reaction, the solvent was removed by concentration, the solid was washed with water, dissolved in chloroform, thionyl chloride (0.58 g,4.88 mmol) was added, stirred at reflux after completion of the reaction, the organic solvent was removed by concentration, and ethanol (5 ml) was recrystallized to give Compound V-4 (0.89 g, yield 90%). 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J＝1.4 Hz,1H),7.96(d,J＝7.5Hz,1H),7.73(dd,J＝7.6,1.6Hz,1H),7.61(t,J＝1.6Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 7 ClN 2 [M+H] + 203.0,found 203.0[M+H] + .
Compound V-4 (0.89 g,4.4 mmol) and thiourea (0.67 g,8.8 mmol) were dissolved in ethanol (10 ml), and reacted under reflux for 1h, cooled, then water was added, and precipitation was observed, and suction filtration was performed to obtain solid V-5 (0.81 g, yield 92%). 1 H NMR(400MHz, Chloroform-d)δ12.04(s,1H),9.58(s,1H),8.33(d,J＝7.7Hz,1H),7.76(d,J＝1.8Hz,1H),7.06(dd,J＝7.5,1.5Hz,1H),2.30(s,3H).MS(ESI):m/z calcd.For C 11 H 8 N 2 S[M+H] + 201.0,found 201.0[M+H] + .
Reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 ℃.
Amino compound V-6 (200 mg,0.85 mmol) was dissolved in dichloromethane (15 ml), chloroacetic anhydride (222 mg, 1.3 mmol) was added, after the reaction was completed at normal temperature, the reaction solution was concentrated, and saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution until the reaction solution became neutral, extraction was performed with ethyl acetate, and the organic phase was concentrated to give product V-7 (260 mg, yield 98%). 1 H NMR(400MHz, Chloroform-d)δ10.10(s,1H),7.87–7.79(m,2H),7.51–7.43(m,2H),4.34–4.26(m,4H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 15 H 21 ClN 2 O 3 [M+H] + 313.1,found 313.1[M+H] + .
V-7 (200 mg,0.64 mmol) and IV-5 (128 mg,0.64 mmol) were dissolved in an appropriate amount of DMF, triethylamine (200 mg,2 mmol) was added, and after completion of the reaction at 90℃the reaction liquid was poured into ice water to give compound V-8 (98 mg, yield 32%) as a solid. 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.45(d,J＝1.4Hz,1H), 8.01–7.95(m,2H),7.79(d,J＝7.4Hz,1H),7.75–7.69(m,2H),7.62(t,J＝1.6Hz,1H),7.51(dd,J＝7.6,1.5Hz,1H),4.30(t,J＝4.7Hz,2H),3.50(s,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝4.7 Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 28 N 4 O 3 S[M+H] + 488.1,found 488.1[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 4, except that the corresponding reaction compounds were appropriately replaced.
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Example 5
Reagents and conditions: a) The bisboronic acid pinacol ester, the tetraphenylphosphine palladium, the potassium carbonate, the water, the 1, 4-dioxane and the temperature of 80 ℃; b) 2-bromoquinoline, tetraphenylphosphine palladium, potassium carbonate, water, 1, 4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) Procaine, 2- (7-azabenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound VI-1 (2.21 g,10 mmol) was reacted with pinacol biborate (3.05 g,12 mol), tetrakis triphenylphosphine palladium (577 mg, 0.5 mmol),potassium carbonate (2.76 g,20 mmol) was dissolved in a mixture of 1, 4-dioxane (16 mL) and water (4 mL), heated under reflux, and after the reaction was completed, the organic solvent was dried by spinning, and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give compound VI-2 (2.52 g, 94%). 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J＝1.6Hz,1H), 7.40(d,J＝1.6Hz,1H),3.85(s,3H),1.28(s,12H).MS(ESI):m/z calcd.For C 12 H 18 BO 4 S[M+H] + 269.1,found 269.1[M+H] + .
VI-2 (1.34 g,5 mmol) and 2-bromoquinoline (1.04 g,5 mmol), tetrakis triphenylphosphine palladium (290 mg, 0.25 mmol), potassium carbonate (1.38 g,10 mmol) were dissolved in a mixed solution of 1, 4-dioxane (8 mL) and water (2 mL), heated under reflux, and after the reaction was completed, the organic solvent was dried, and ethyl acetate was extracted. The organic phase was concentrated and purified by column chromatography to give compound VI-3 (1.0 g, 74%). 1 H NMR(400MHz,Chloroform-d)δ8.28(dd,J＝7.6,1.6Hz,1H),8.19 (d,J＝1.6Hz,1H),8.17–8.04(m,2H),7.89–7.79(m,2H),7.72(td,J＝7.6,1.6Hz,1H),7.54(td,J＝7.6,1.6Hz,1H),3.85(s,3H).MS(ESI):m/z calcd.For C 15 H 12 NO 2 S[M+H] + 270.1,found 270.1[M+H] + .
A solution of compound VI-4 (0.8 g,3 mmol) in methanol was hydrolyzed with lithium hydroxide (0.6 g,24 mmol), the pH was adjusted to acidity with the addition of acid, and the cake was suction filtered, washed and dried to give compound VI-4 (0.72 g, 94%). 1 H NMR(400MHz,Chloroform-d)δ 10.90(s,1H),8.40(d,J＝1.6Hz,1H),8.34–8.24(m,2H),8.08(dd,J＝7.6,1.6Hz,1H),7.89–7.79(m,2H),7.72(td,J＝7.6,1.6Hz,1H),7.54(td,J＝7.6,1.6Hz,1H).MS(ESI):m/z calcd.For C 14 H 10 NO 2 S[M+H] + 256.1,found 256.1[M+H] + .
Compound VI-4 (210 mg,0.82 mmol) was dissolved in DMF (10 ml) and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg,1.23 mmol), organic amine V-6 (232.2 mg,0.98 mmol) was added sequentially. The mixture was heated to reflux at 50 ℃, after monitoring the reaction, the reaction liquid was dropped into cold water, suction filtered and the solid was washed with ethyl acetate: the solid was recrystallized from a petroleum ether=1:5 solvent mixture to give pure compound VI-5 (120mg, yield 30%). 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.46(d,J＝1.6Hz,1H),8.34(dd,J＝7.6,1.6 Hz,1H),8.17(dd,J＝7.6,1.6Hz,1H),8.04–7.91(m,4H),7.85(dt,J＝7.6,1.6Hz,1H),7.72(td,J＝7.6,1.6Hz,1H),7.54(td,J＝7.6,1.6Hz,1H),7.46–7.38(m,2H),4.30(t,J＝3.6Hz,2H), 2.89(q,J＝7.6Hz,4H),2.78(t,J＝3.6Hz,2H),1.09(t,J＝7.6Hz,6H).MS(ESI):m/z calcd.For C 27 H 28 N 3 O 3 S[M+H] + 474.2,found 474.1[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 5, except that the corresponding reaction compounds were appropriately replaced.
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Example 6
Reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
The compound VII-1 (2.07 g,10 mmol) and thiourea (1.14 g,15 mmol) are mixed and refluxed in ethanol (20 mL), and after the reaction is completed, the solvent is dried by spin, and the compound V is obtained by water washingII-2(1.58g，98％)。 1 H NMR(400MHz, Chloroform-d)δ8.02(dd,J＝7.2,1.6Hz,1H),7.79–7.64(m,3H),7.47–7.35(m,2H),3.29(s,1H)。MS(ESI):m/z calcd.For C 9 H 8 NS[M+H] + 162.0,found 162.0[M+H] + .
Compound VII-3 (1.18 g,5 mmol) was dissolved in dichloromethane (10 mL), bromoacetyl bromide (1.41 g,7 mmol) was added dropwise, the reaction was stirred at room temperature, after completion of the reaction, the solvent was dried, washed with water and extracted with ethyl acetate to give compound VII-4 (1.66 g, 83%). 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),7.87–7.79(m,2H),7.51– 7.43(m,2H),4.34–4.22(m,4H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.2Hz,2H),1.09(t,J＝8.0 Hz,6H)。MS(ESI):m/z calcd.For C 15 H 22 BrN 2 O 3 [M+H] + 357.1,found 357.1[M+H] + .
Compound VII-2 (161 mg,1 mmol) and compound VI-4 (356 mg,1 mmol) were dissolved in N, N dimethylformamide (5 mL), and potassium carbonate (414 mg,3 mmol) was added thereto, and the reaction was stirred at 60 ℃. After completion of the reaction, ethyl acetate was added for dilution, and N, N dimethylformamide was washed with water, and the organic phase was purified by column chromatography to give Compound VII-5 (280 mg, 64%). 1 H NMR(400MHz,Chloroform-d)δ9.50(s,1H),8.18(dd,J＝7.6,1.6Hz,1H),7.94(dd,J＝7.6, 1.6Hz,1H),7.87–7.79(m,2H),7.79–7.65(m,4H),7.69–7.59(m,1H),7.43(td,J＝7.6,1.6Hz,1H),4.30(t,J＝7.2Hz,2H),4.07(s,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.2Hz,2H),1.09(t, J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 24 H 28 N 2 O 3 S[M+H] + 438.2,found 438.2[M+H] + .
The preparation of the following compounds was referred to the preparation method in example 6, except that the corresponding reaction compounds were appropriately replaced.
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Experimental example 7: activated SHP1 Activity test of quinoline Compounds
1. SHP1 protein activity assay:
10uL of the compound was applied to 384 black flat bottom plates at various concentrations. Subsequently, 20ul of SHP1-GST fusion protein was added, and SHP1 protein was dissolved in 50mmol/L HEPES pH=7.2, 100mmol/L NaCl, 0.05% BSA, 1mM DTT at a concentration of 10nmol/L. After 15 minutes incubation at room temperature 20ul of substrate DiFUMP was added and the DiFUMP was dissolved in 50mmol/L HEPES pH=7.2, 100mmol/L NaCl, 0.05% BSA, 1mM DTT at a concentration of 25. Mu. Mol/L. The change of fluorescence is detected by a dynamic method under 355nm excitation and 460nm emission on a multifunctional enzyme-labeled instrument, and the value is read once every 1min for 10 times. And calculating the slope of the enzymatic reaction in unit time by using an Excel macro tool to obtain a corresponding SHP1 protein activity result.
2. Western immunoblotting:
the cells were collected at 800rpm/min for 3min. After removal of the supernatant medium, the cells were resuspended once more with pre-chilled PBS. The samples were placed on ice and cells lysed with RIPA for 30 min. After centrifugation at 12000rpm/min for 20 minutes, protein quantification was performed on the cell lysed supernatant. And (4) adding a 4xloading buffer while vibrating on the vortex vibrating instrument. After mixing, the mixture is placed on a metal dry bath instrument at 100 ℃ for 15 minutes to fully crack and denature the protein. Protein samples were added to the SDA-PAGE gel at 20 ug/well, electrophoresis conditions: constant current 20mA per gel. And stopping electrophoresis when the blue dye of the protein Marker is electrophoresed to the outer side of the gel, and placing the sponge cushion, the filter paper, the protein gel and the acetate fiber film NC into a transfer printing groove according to the sequence of a molecular biology operation manual. And transferring for a proper time according to the principle of 1KD protein transfer for 1 min. After the target protein is transferred onto an NC film, the NC film is developed by ponceau, and cut according to a protein Marker. The cut NC film was placed in a closed tank. Adding corresponding blocking solution, placing on a shaking table, and blocking at room temperature for 2 hr (checking protein change, blocking with 5% skimmed milk, and if checking protein phosphorylation change, blocking with 5% fetal bovine albumin). The blocking solution was removed and the NC membrane was washed twice with TBST for 5 minutes each. After addition of the corresponding primary antibody, the mixture was placed on a shaking table and incubated overnight at 4 ℃. The next day, NC membranes were washed 3 times with TBST on a shaker for 10 minutes each, followed by addition of the corresponding fluorescent secondary antibodies and shaking incubations at room temperature for 1 hour. The NC membrane was then washed 3 times with TBST for 10 minutes on a shaker. The membrane was placed on an infrared imaging system (Odyssey) instrument and different detection fluorescence channels were selected to scan the protein bands of interest according to the fluorescence properties of the secondary antibodies.
FIGS. 1 and 2 show that compounds of the invention have significant activation of dephosphorylation of shp1 and downstream STAT3 on OCI-Ly10, OCI-Ly10R and DHL-2 cells over the range of concentrations tested.
The results of the biological activity test of quinoline compounds of each structural type are shown in table 1.
TABLE 1 biological Activity results for different quinolines
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Claims (9)

1. The application of quinoline compounds shown in a general formula I or pharmaceutically acceptable salts thereof in preparing medicaments for preventing and treating cancers, metabolic and immune diseases, cardiovascular diseases and neurological diseases is to use quinoline compounds shown in the general formula I as protein tyrosine phosphatase SHP1 activators;
wherein X is 1 Selected from S, O, NH; x is X 2 Selected from CH, CNH 2 ；
R 1 Is selected from the group consisting of the following,represents the site of attachment:
R 2 ，R 3 ，R 4 ，R 5 independently selected from hydrogen, halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 A haloalkyl group.
2. The use according to claim 1, wherein when X is 1 Is S, X 2 In the case of CH, the quinoline compound has a structure of thieno [2,3-b ] shown in formula II]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 respectively as defined in claim 1.
3. The use according to claim 1, wherein when X is 1 Is O, X 2 When CH is adopted, the structure of the quinoline compound is furo [2,3-b ] shown in the formula III]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 respectively as defined in claim 1.
4. The use according to claim 1, wherein when X is 1 Is NH, X 2 When CH is adopted, the structure of the quinoline compound is pyrrolo [2,3-b ] shown in a formula IV]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 respectively as defined in claim 1.
5. The use according to claim 1, wherein when X is 1 Is S, X 2 Is CNH 2 In the case of quinoline compounds, the structure of the quinoline compounds is 3-aminothiophene [2,3-b ] shown in formula V]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 respectively as defined in claim 1.
6. The use according to claim 1, wherein the quinoline compound of formula I is specifically selected from:
7. a quinoline compound or a pharmaceutically acceptable salt thereof, said quinoline compound being selected from the following structures:
8. the quinoline compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, phosphate, metaphosphate, nitric acid and sulfate, acetate, benzenesulfonate, benzoate, citrate, ethanesulfonate, fumarate, gluconate, glycolate, isethionate, lactate, lactobionate, maleate, malate, methanesulfonate, succinate, p-toluenesulfonate and tartrate, ammonium salts, alkali metal salts, alkaline earth metal salts, tromethamine salts, diethanolamine salts, lysine salts, ethylenediamine salts.
9. A pharmaceutical composition comprising a quinoline compound according to claim 7, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable adjuvant.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2371444C1 (en) * 2008-01-24 2009-10-27 Андрей Александрович Иващенко FURO- AND THIENO[2,3-b]-QUINOLINE-2-CARBOXAMIDES, METHOD OF PRODUCTION AND ANTITUBERCULOUS ACTIVITY
CN102757447A (en) * 2011-07-05 2012-10-31 北京大学 Urea transporter inhibitors, and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2371444C1 (en) * 2008-01-24 2009-10-27 Андрей Александрович Иващенко FURO- AND THIENO[2,3-b]-QUINOLINE-2-CARBOXAMIDES, METHOD OF PRODUCTION AND ANTITUBERCULOUS ACTIVITY
CN102757447A (en) * 2011-07-05 2012-10-31 北京大学 Urea transporter inhibitors, and preparation method and application thereof

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Title
STN检索报告;ACS;STN检索报告 *

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