CN115073436A - Quinazoline benzamide compound and derivative, pharmaceutical composition and application thereof - Google Patents

Quinazoline benzamide compound and derivative, pharmaceutical composition and application thereof Download PDF

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CN115073436A
CN115073436A CN202210830689.5A CN202210830689A CN115073436A CN 115073436 A CN115073436 A CN 115073436A CN 202210830689 A CN202210830689 A CN 202210830689A CN 115073436 A CN115073436 A CN 115073436A
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quinazoline
benzamide
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benzamide compound
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龙久思
焦龙华
黄玉龙
赵祖龙
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Suzhou Shi'an Dingtai Biomedical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention provides a quinazoline benzamide compound, a derivative, a pharmaceutical composition and application thereof, and relates to the technical field of medicines. The invention provides a quinazoline benzamide compound which has a structure shown in a formula I:
Figure DDA0003745507250000011
r is-NHR 1 Or azaheterocyclyl, -NHR 1 In R 1 Including any of the following structures:
Figure DDA0003745507250000012
IC of quinazoline benzamide compound provided by the invention to JNK1 50 IC as low as 2.8nM for JNK2 50 IC as low as 4.6nM for JNK3 50 The JNK inhibitor has high JNK inhibitory activity as low as 5.1nM, can improve the immune system capability and has high anti-tumor pharmacological activity, and has good application prospect in treating and/or preventing respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors and diabetes as the JNK inhibitor.

Description

Quinazoline benzamide compound and derivative, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a quinazoline benzamide compound, a derivative, a pharmaceutical composition and application thereof.
Background
Jun amino terminal kinases (JNK) are members of the mitogen-activated protein kinase family. JNK is activated by a three-level kinase pattern including MAP kinases, and MAP kinases. JNK can be activated by factors including cytokines, pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and alterations in the metabolic environment. At least 40 JNK downstream proteins are known, wherein c-Jun is a characteristic downstream protein, and can be combined with JunB, JunD or Fos to participate in the formation of transcription factors and realize various biological effects including cell metabolism, proliferation, differentiation and the like.
c-JNK is a mitogen-activated protein kinase family member together with p38 and Extracellular Regulated Kinases (ERK), c-JNK has 3 different genes (JNK1, JNK2, JNK3) that encode 10 splice variants, JNK1, JNK2 are expressed in a wide variety of tissues, whereas JNK3 is expressed mainly in neurons. Members of the JNK family are activated by pro-inflammatory cytokines such as tumor necrosis factor (TNF- α) and interleukin-1 β (IL-1 β), and activated JNK generates cellular activity signals by phosphorylating specific substrates (e.g., transcription factors such as c-Jun, activin-1 family members, etc.). Studies have shown that these signals induced or transmitted by JNK play important roles in inflammation, T cell function, apoptosis and cell survival, with neuronal apoptosis being associated with over-activated expression of JNK3 kinase.
Research shows that the JNK inhibitor can inhibit cell death caused by ischemia and other stress-induced apoptosis reaction, and can be used for treating respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors, diabetes and the like. However, the variety of JNK inhibitors is still to be enriched.
Disclosure of Invention
In view of the above, the present invention aims to provide a quinazoline benzamide compound and a derivative thereof, a pharmaceutical composition and an application thereof, and the quinazoline benzamide compound and the derivative thereof provided by the present invention have a high JNK inhibitory activity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a quinazoline benzamide compound which has a structure shown in a formula I:
Figure RE-GDA0003805511730000021
in the formula I, R is-NHR 1 Or an azaheterocyclyl group;
the-NHR 1 In R 1 Including any of the following structures:
Figure RE-GDA0003805511730000022
preferably, the azaheterocyclyl group includes any one of the following structures:
Figure RE-GDA0003805511730000023
preferably, the quinazoline benzamide compound has any one of the following structures:
Figure RE-GDA0003805511730000024
Figure RE-GDA0003805511730000031
the invention provides a preparation method of a quinazoline benzamide compound in the technical scheme, which comprises the following steps:
carrying out condensation reaction on a compound VII and a compound VIII to obtain the quinazoline benzamide compound;
Figure RE-GDA0003805511730000032
the compound VIII is NH 2 R 1 Or a nitrogen heterocyclic compound.
Preferably, the preparation method of the compound VII comprises the following steps:
carrying out condensation reaction on the compound II and the compound III to obtain a compound IV;
carrying out coupling reaction on the compound IV and a compound V to obtain a compound VI;
carrying out hydrolysis reaction on the compound VI to obtain a compound VII;
Figure RE-GDA0003805511730000041
the invention provides a quinazoline benzamide compound derivative which comprises a pharmaceutically acceptable salt, a stereoisomer, a hydrate, a solvate or an isotope compound of the quinazoline benzamide compound in the technical scheme or the quinazoline benzamide compound prepared by the preparation method in the technical scheme.
The invention provides a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is one or more of a quinazoline benzamide compound in the technical scheme, a quinazoline benzamide compound prepared by the preparation method in the technical scheme and a quinazoline benzamide compound derivative in the technical scheme.
Preferably, the pharmaceutically acceptable excipients include a pharmaceutically acceptable carrier and/or diluent.
The invention provides a quinazoline benzamide compound in the technical scheme, a quinazoline benzamide compound prepared by the preparation method in the technical scheme, a quinazoline benzamide compound derivative in the technical scheme or an application of a pharmaceutical composition in the technical scheme in preparation of a JNK inhibitor.
Preferably, the JNK inhibitor is a JNK inhibitor for treating and/or preventing one or more of a respiratory disease, fatty liver, liver fibrosis, chronic inflammatory disease, neurodegenerative disease, tumor, and diabetes.
The invention provides a quinazoline benzamide compound which has a structure shown in a formula I:
Figure RE-GDA0003805511730000042
in the formula I, R is-NHR 1 Or an azaheterocyclyl group; the-NHR 1 In R 1 Including any of the following structures:
Figure RE-GDA0003805511730000051
the quinazoline benzamide compound provided by the invention has high JNK inhibitory activity, can improve the capability of an immune system, has high anti-tumor pharmacological activity, and has good application prospect when being used as a JNK inhibitor in treating and/or preventing respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors and diabetes. As shown in the test results of the examples, the IC of the quinazoline benzamide compound provided by the invention on JNK1 50 IC as low as 2.8nM for JNK2 50 IC as low as 4.6nM for JNK3 50 As low as 5.1nM, the quinazoline benzamide compound provided by the invention has high JNK inhibitory activity.
The invention provides the preparation method of the quinazoline benzamide compound in the technical scheme, and the preparation method provided by the invention is simple to operate, low in production cost and suitable for large-scale production.
The invention provides a quinazoline benzamide compound derivative which comprises pharmaceutically acceptable salts, stereoisomers, hydrates, solvates or isotopic compounds of the quinazoline benzamide compound, has high JNK inhibitory activity, can improve the capability of an immune system, has high anti-tumor physical activity, and can treat and/or prevent respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors and diabetes by taking one or more compounds, pharmaceutically acceptable salts, stereoisomers, hydrates, solvates or isotopic compounds thereof with a therapeutically effective dose as JNK inhibitors to patients needing the treatment or prevention.
The invention provides a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is one or more of a quinazoline benzamide compound in the technical scheme, a quinazoline benzamide compound prepared by the preparation method in the technical scheme and a quinazoline benzamide compound derivative in the technical scheme. The pharmaceutical composition provided by the invention has high JNK inhibitory activity, can improve the immune system capability, has high anti-tumor pharmacological activity, and has good application prospects in treatment and/or prevention of respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors and diabetes mellitus.
Detailed Description
The invention provides a quinazoline benzamide compound which has a structure shown in a formula I:
Figure RE-GDA0003805511730000061
in the formula I, R is-NHR 1 Or an azaheterocyclyl group;
the-NHR 1 In R 1 Including any of the following structures:
Figure RE-GDA0003805511730000062
wherein the content of the first and second substances,
Figure RE-GDA0003805511730000063
the group attached by the medium double bond is CH.
In the present invention, the azaheterocyclyl group preferably includes any one of the following structures:
Figure RE-GDA0003805511730000064
in the present invention, the quinazoline benzamide compound is preferably at least one of the compounds shown in table 1 (denoted as compound 1 to compound 15):
TABLE 1 preferred classes of quinazoline benzamides having the structure shown in formula I
Figure RE-GDA0003805511730000065
Figure RE-GDA0003805511730000071
The invention provides a preparation method of a quinazoline benzamide compound in the technical scheme, which comprises the following steps:
carrying out condensation reaction on a compound VII and a compound VIII to obtain the quinazoline benzamide compound;
Figure RE-GDA0003805511730000072
the compound VIII is NH 2 R 1 Or a nitrogen heterocyclic compound, said NH 2 R 1 In R 1 And said-NHR 1 In R 1 The same is true.
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
In the present invention, the preparation method of the compound VII preferably includes the steps of:
carrying out condensation reaction on the compound II and the compound III to obtain a compound IV;
carrying out coupling reaction on the compound IV and the compound V to obtain a compound VI;
carrying out hydrolysis reaction on the compound VI to obtain a compound VII;
Figure RE-GDA0003805511730000081
according to the invention, a compound II and a compound III are subjected to condensation reaction (denoted as a first condensation reaction) to obtain a compound IV. In the invention, the molar ratio of the compound II to the compound III is preferably (0.8-2): 1, more preferably 1: 1. In a specific embodiment of the present invention, the condensation reaction of compound II with compound III is preferably: mixing the compound II, the compound III, an alkaline reagent and an organic solvent, and carrying out condensation reaction. In the present invention, the alkaline agent preferably includes alkali metal carbonate, alkali metal hydroxide and alkali metal alkoxide, more preferably includes at least one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and sodium tert-butoxide; the molar ratio of the compound II to the basic agent is preferably 1: (1-2), more preferably 1: (1.2-1.5). In the present invention, the organic solvent preferably includes at least one of tetrahydrofuran, dioxane, toluene, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide, and the amount of the organic solvent is not particularly limited in the present invention, and it is sufficient to ensure that the condensation reaction proceeds smoothly, and in a specific embodiment of the present invention, the ratio of the amount of the substance of the compound II to the volume of the organic solvent is preferably 0.1 mol: 200 mL. The mixing is not particularly limited, and the raw materials can be uniformly mixed, specifically, stirred and mixed. In the invention, the temperature of the condensation reaction is preferably 20-100 ℃, more preferably 50-80 ℃, and the time of the condensation reaction is preferably 4-24 h, more preferably 8-15 h; in a particular embodiment of the invention, the progress of the reaction is preferably checked by TLC. After completion of the condensation reaction, the present invention preferably further comprises a post-treatment, which preferably comprises: adding water into the obtained condensation reaction liquid to quench the reaction, extracting by an organic solvent, concentrating the obtained organic phase, and separating by column chromatography to obtain a compound IV. The amount of the quenching reaction water is not particularly limited, and the condensation reaction can be quenched. In the invention, the organic solvent for extraction preferably comprises ethyl acetate or dichloromethane, the number of times of extraction is preferably 2-3, and the obtained extraction liquids are combined to obtain an organic phase. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. The eluent for column chromatography separation is not particularly limited, and is based on the separation of a target product, specifically, the eluent is an ester-ether mixed solvent or a methanol-dichloromethane mixed solvent, wherein an ester in the ester-ether mixed solvent preferably comprises ethyl acetate, an ether in the ester-ether mixed solvent preferably comprises petroleum ether, and the volume ratio of the ester to the ether in the ester-ether mixed solvent is preferably 1: 1-100; the volume ratio of methanol to dichloromethane in the methanol-dichloromethane mixed solvent is preferably 1: 5 to 100.
After the compound IV is obtained, the compound IV and the compound V are subjected to coupling reaction to obtain a compound VI. In the invention, the molar ratio of the compound IV to the compound V is preferably (0.8-2): 1, more preferably 1: 1. In a particular embodiment of the invention, the coupling reaction of compound IV with compound V is preferably: and mixing the compound IV, the compound V, a catalyst, an alkaline reagent and an organic solvent to perform coupling reaction. In the present invention, the catalyst preferably comprises palladium triphenylphosphine (Pd (PPh) 3 ) 4 ) Palladium acetate (Pd (OAc) 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) And 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (Pd (dppf) Cl 2 ) At least one of; the molar ratio of compound IV to catalyst is preferably 1: (0.04 to 0.2), more preferably 1: (0.045-0.1). In the present invention, the basic agent preferably includes at least one of an alkali metal carbonate, an alkali metal acetate, an alkali metal alkoxide, and an alkali metal phosphate, and more preferably includes at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and potassium phosphate; the molar ratio of the compound IV to the alkaline reagent is preferably (1-2): 1, more preferably 1.2: 1. In the present invention, the organic solvent preferably includes at least one of dioxane, N-dimethylformamide, N-dimethylacetamide, toluene, and ethylene glycol dimethyl ether, and the amount of the organic solvent is not particularly limited in the present invention, and it is sufficient to ensure that the coupling reaction proceeds smoothly. The mixing is not particularly limited, and the raw materials can be uniformly mixed, specifically, stirred and mixed. In the invention, the temperature of the coupling reaction is preferably 60-120 ℃, more preferably 80-100 ℃, and the time of the coupling reaction is preferably 4-24 hours, more preferably 10-20 hours; in a particular embodiment of the invention, the progress of the reaction is preferably checked by TLC. After completion of the coupling reaction, the present invention preferably further comprises a post-treatment, which preferably comprises: adding water into the obtained coupling reaction liquid to quench the reaction, extracting with organic solvent, and obtaining the organic phaseAnd concentrating the phases, and performing column chromatography separation to obtain a compound VI. The amount of water for quenching reaction is not particularly limited, and the coupling reaction can be quenched. In the invention, the organic solvent for extraction preferably comprises ethyl acetate or dichloromethane, the number of times of extraction is preferably 2-3, and the obtained extraction liquids are combined to obtain an organic phase. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. The eluent for column chromatography separation is not particularly limited, and is based on the separation of a target product, specifically, the eluent is an ester-ether mixed solvent or a methanol-dichloromethane mixed solvent, wherein an ester in the ester-ether mixed solvent preferably comprises ethyl acetate, an ether in the ester-ether mixed solvent preferably comprises petroleum ether, and the volume ratio of the ester to the ether in the ester-ether mixed solvent is preferably 1: 1-100; the volume ratio of methanol to dichloromethane in the methanol-dichloromethane mixed solvent is preferably 1: 5 to 100.
After the compound VI is obtained, the compound VI is subjected to hydrolysis reaction to obtain a compound VII. In a particular embodiment of the invention, said compound VI is preferably subjected to a hydrolysis reaction: and mixing the compound VI, an alkaline reagent and a solvent to perform hydrolysis reaction. In the present invention, the alkaline agent preferably includes an alkali metal hydroxide, more preferably includes at least one of sodium hydroxide, lithium hydroxide, and potassium oxide; the molar ratio of said compound VI to the basic agent is preferably 1: (1 to 4), more preferably 1: (2-3). In the present invention, the solvent preferably includes an alcohol solvent or an organic solvent-water mixed solvent, and the alcohol solvent preferably includes methanol and/or ethanol; the organic solvent in the organic solvent-water mixed solvent preferably comprises at least one of dioxane, ethanol and tetrahydrofuran, and the volume fraction of the organic solvent in the organic solvent-water mixed solvent is not particularly limited and can be in any proportion; the dosage of the solvent is not specially limited, and the hydrolysis reaction can be ensured to be smoothly carried out; in a particular embodiment of the invention, the ratio of the amount of said substance of compound VI to the volume of solvent is preferably 1 mol: 8.2-8.3L. The mixing is not particularly limited, and the raw materials can be uniformly mixed, specifically, stirred and mixed. In the invention, the temperature of the hydrolysis reaction is preferably 20-80 ℃, more preferably 25-50 ℃, and the time of the hydrolysis reaction is preferably 2-12 h, more preferably 5-8 h. After completion of the hydrolysis reaction, the present invention preferably further comprises a post-treatment, which preferably comprises: and removing the organic solvent in the obtained hydrolysis reaction liquid, adjusting the pH value to 5-6, extracting with the organic solvent, concentrating the obtained organic phase, and performing column chromatography separation to obtain a compound VII. The organic solvent removal method of the present invention is not particularly limited, and any method known to those skilled in the art for removing organic solvent may be used, such as distillation under reduced pressure. In the present invention, the pH adjusting acid preferably includes hydrochloric acid; the concentration of the hydrochloric acid is preferably 5-20 wt%, and more preferably 10-15 wt%. In the invention, the organic solvent for extraction preferably comprises ethyl acetate or dichloromethane, the number of times of extraction is preferably 2-3, and the obtained extraction liquids are combined to obtain an organic phase. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. The eluent for column chromatography separation is not particularly limited, and is based on the separation of a target product, specifically, the eluent is an ester-ether mixed solvent or a methanol-dichloromethane mixed solvent, wherein an ester in the ester-ether mixed solvent preferably comprises ethyl acetate, an ether in the ester-ether mixed solvent preferably comprises petroleum ether, and the volume ratio of the ester to the ether in the ester-ether mixed solvent is preferably 1: 1-100; the volume ratio of methanol to dichloromethane in the methanol-dichloromethane mixed solvent is preferably 1: 5 to 100.
After a compound VII is obtained, the compound VII and a compound VIII are subjected to condensation reaction (marked as a second condensation reaction) to obtain the quinazoline benzamide compound. In the invention, the molar ratio of the compound VII to the compound VIII is preferably (1-2): 1, more preferably 1: 1. In a particular embodiment of the invention, the condensation reaction of compound VII with compound VIII is preferably: mixing a compound VII, a compound VIII, a condensing agent, an alkaline reagent and an organic solvent, and carrying out condensation reaction. In the present invention, the condensing agent preferably includes at least one of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI. HCl), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU); the molar ratio of the compound VII to the catalyst is preferably 1: (1 to 3), more preferably 1: (1-2). In the present invention, the basic agent preferably includes at least one of triethylamine, N-Diisopropylethylamine (DIPEA), and morpholine; the molar ratio of the compound VII to the basic agent is preferably 1: (1-5), more preferably 1: (1.5 to 3). In the invention, the organic solvent preferably comprises at least one of dimethylformamide, diethylformamide and dichloromethane, and the dosage of the organic solvent is not particularly limited, so that the condensation reaction can be smoothly carried out; in a specific embodiment of the present invention, the ratio of the amount of the substance of the compound VII to the volume of the organic solvent is preferably 1 mmol: 30 mL. The mixing is not particularly limited, and the raw materials can be uniformly mixed, specifically, stirred and mixed. In the invention, the temperature of the condensation reaction is preferably 0-60 ℃, more preferably 20-50 ℃, and the time of the condensation reaction is preferably 2-8 h, more preferably 3-6 h; in a particular embodiment of the invention, the progress of the reaction is preferably checked by TLC. After completion of the condensation reaction, the present invention preferably further comprises a post-treatment, which preferably comprises: adding water into the obtained condensation reaction liquid for quenching reaction, extracting by using an organic solvent, concentrating the obtained organic phase, and then carrying out column chromatography separation to obtain the quinazoline benzamide compound. The amount of the water for quenching reaction is not particularly limited, and the condensation reaction can be quenched. In the invention, the organic solvent for extraction preferably comprises ethyl acetate or dichloromethane, the number of times of extraction is preferably 2-3, and the obtained extraction liquids are combined to obtain an organic phase. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. The eluent for column chromatography separation is not particularly limited, and is based on the separation of a target product, specifically, the eluent is an ester-ether mixed solvent or a methanol-dichloromethane mixed solvent, wherein an ester in the ester-ether mixed solvent preferably comprises ethyl acetate, an ether in the ester-ether mixed solvent preferably comprises petroleum ether, and the volume ratio of the ester to the ether in the ester-ether mixed solvent is preferably 1: 1-100; the volume ratio of methanol to dichloromethane in the methanol-dichloromethane mixed solvent is preferably 1: 5 to 100.
The invention provides a quinazoline benzamide compound derivative which comprises a pharmaceutically acceptable salt, a stereoisomer, a hydrate, a solvate or an isotope compound of the quinazoline benzamide compound in the technical scheme or the quinazoline benzamide compound prepared by the preparation method in the technical scheme.
In the present invention, the pharmaceutically acceptable salt preferably includes an inorganic acid salt or an organic acid salt, and the inorganic acid salt preferably includes a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a phosphate, a sulfate or a perchlorate; the organic acid salt preferably includes acetate, oxalate, (D) malate, (L) malate, maleate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, benzenesulfonate, benzoate, camphorsulfonate, citrate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, succinate, tartrate or malonate.
In the invention, the pharmaceutically acceptable salt of the quinazoline benzamide compound is preferably obtained by reacting a quinazoline benzamide compound derivative with an inorganic acid or an organic acid, or is obtained by replacing an acid proton in the quinazoline benzamide compound with a metal ion. In the present invention, the inorganic acid preferably includes hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, or perchloric acid; the organic acid preferably comprises acetic acid, oxalic acid, (D) malic acid, (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, or malonic acid. In the present invention, the metal ion preferably includes an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, and more preferably includes a sodium ion, a potassium ion, a rubidium ion, a cesium ion, a francium ion, a beryllium ion, a magnesium ion, a calcium ion, a strontium ion, a barium ion, a radium ion, or an aluminum ion. In the present invention, the organic base preferably includes ethanolamine, diethanolamine, triethanolamine, tromethamine or N-methylglucamine.
In the present invention, the stereoisomers of the quinazoline benzamide compound preferably include enantiomers and/or diastereomers, and the enantiomers preferably include at least one of d-isomer, l-isomer, (+) isomer and (-) isomer.
The hydrate, solvate or isotopic compound of the quinazoline benzamide compound in the present invention is not particularly limited, and any hydrate, solvate or isotopic compound known to those skilled in the art may be used.
The preparation method of the stereoisomer, hydrate, solvate or isotope compound of the quinazoline benzamide compound is not particularly limited, and the quinazoline benzamide compound can be prepared by a method well known to those skilled in the art.
The invention provides a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is one or more of a quinazoline benzamide compound in the technical scheme, a quinazoline benzamide compound prepared by the preparation method in the technical scheme and a quinazoline benzamide compound derivative in the technical scheme. In the present invention, the pharmaceutically acceptable excipients preferably include a pharmaceutically acceptable carrier and/or diluent; the pharmaceutically acceptable carrier and diluent used in the present invention are not particularly limited, and those known to those skilled in the art can be used. The pharmaceutical composition provided by the invention can promote effective active components (quinazoline benzamide compounds, and one or more of pharmaceutically acceptable salts, stereoisomers, hydrates, solvates and site compounds of the quinazoline benzamide compounds), and improve the bioavailability of the effective active components.
The invention also provides the quinazoline benzamide compound in the technical scheme, the quinazoline benzamide compound prepared by the preparation method in the technical scheme, the quinazoline benzamide compound derivative in the technical scheme or the application of the pharmaceutical composition in the technical scheme in preparation of a JNK inhibitor. In the invention, the JNK inhibitor is preferably a JNK inhibitor for treating and/or preventing one or more of respiratory system diseases, fatty liver, hepatic fibrosis, chronic inflammatory diseases, neurodegenerative diseases, tumors and diabetes, and achieves the purpose of treatment by infusing one or more of pharmaceutically acceptable salts, stereoisomers, hydrates, solvates and site compounds of quinazoline benzamide compounds into a patient.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (tetrahydro-2H-pyran-4-yl) benzamide (Compound 1)
Figure RE-GDA0003805511730000141
(1) Compound 1a (i.e., compound II, 19.8g, 100.0mmol), compound 1b (i.e., compound III, 13.6g, 100.0mmol) and cesium carbonate (48.6g, 150.0mmol) were dissolved in DMF (200mL), heated to 80 ℃ and stirred for reaction for 8 hours, the reaction was detected by TLC, after completion of the reaction, water was added to quench the reaction, extracted with ethyl acetate (300mL × 2), the organic layer was concentrated, and column chromatography was performed to give compound 1c (i.e., compound IV, off-white solid, 19.5g, yield 65.4%).
(2) The compound 1c (19.0g, 63.8mmol), the compound 1d (i.e. the compound V, 9.6g, 63.8mmol), potassium carbonate (13.2g, 95.7mmol)), Pd (dppf) Cl were obtained as described above 2 (2.2g, 3.0mmol) was dissolved in DMF (300mL), heated to 80 ℃ and stirred for 12 hours, the reaction was detected by TLC, after completion of the reaction, water was added to quench the reaction, which was extracted with ethyl acetate (300 mL. times.2), the organic layer was concentrated and separated by column chromatography to give compound 1e (i.e., compound VI, off-white solid, 15.3g, 58.1% yield.
(3) Compound 1e (15.0g, 36.3mmol) was dissolved in methanol (300mL), sodium hydroxide (4.4g, 109.0mmol) was added at room temperature, the reaction was stirred for 6 hours, after completion of the reaction, methanol was removed under reduced pressure, pH was adjusted to 5-6 with dilute hydrochloric acid, extraction was performed with ethyl acetate (200mL × 2), organic layers were combined, dried, filtered, and separated by column chromatography to give compound 1f (i.e., compound VII, off-white solid, 10.7g, yield 73.8%).
(4) Dissolving intermediate 1f (298g, 1.0mmol), compound 1g (compound VIII, 101mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and performing column chromatography to obtain compound 1 (quasi-white solid, 311mg, yield of 64.5%); structural characterization data for compound 1: ESI (+) m/z 483.2, 1 H-NMR(500MHz,d 6 -DMSO)δ 9.92(s,1H),8.36–8.27(m,2H),8.09(dd,J＝8.0,1.6Hz,1H),7.90–7.75(m, 4H),7.69–7.62(m,2H),7.57–7.47(m,3H),7.40(t,J＝7.8Hz,1H),7.33– 7.25(m,2H),7.12(td,J＝7.6,1.5Hz,1H),3.82–3.66(m,3H),3.52(ddd,J＝ 11.5,7.2,5.0Hz,2H),1.98–1.77(m,4H)。
example 2
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (4-oxocyclohexyl) benzamide (Compound 2)
Figure RE-GDA0003805511730000151
Dissolving the intermediate 1f (298g, 1.0mmol), the compound 2a (the compound 2 a-15 a is the compound VIII, 113mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting by TLC, adding water (50ml) for quenching reaction after the reaction is finished, extracting by using ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain the compound 2 (an off-white solid, 285mg, the yield is 57.7%); structural characterization data for compound 2: ESI (+) m/z 495.2, 1 H-NMR(500MHz, d 6 -DMSO)δ9.92(s,1H),8.33(dd,J＝7.7,1.4Hz,1H),8.22(d,J＝9.1Hz,1H), 8.11(dd,J＝7.9,1.3Hz,1H),7.90–7.79(m,3H),7.79–7.71(m,2H),7.64– 7.57(m,2H),7.56–7.47(m,2H),7.43(t,J＝7.9Hz,1H),7.32–7.25(m,2H), 7.11(td,J＝7.7,1.6Hz,1H),3.96(dp,J＝9.0,5.7Hz,1H),2.50–2.37(m,4H), 1.88(dddd,J＝13.4,8.2,6.9,5.8Hz,2H),1.83–1.72(m,2H)。
example 3
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (4-methylenecyclohexane) benzamide (Compound 3)
Figure RE-GDA0003805511730000161
Dissolving intermediate 1f (298g, 1.0mmol), compound 3a (111mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography to obtain compound 3 (off-white solid, 269mg, yield 54.7%); structural characterization data for compound 3: ESI (+) m/z 493.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.33(dd,J＝ 7.8,1.3Hz,1H),8.23(d,J＝8.9Hz,1H),8.11(dd,J＝8.0,1.4Hz,1H),7.90– 7.81(m,3H),7.79–7.71(m,2H),7.62–7.40(m,5H),7.32–7.25(m,2H),7.11 (td,J＝7.7,1.6Hz,1H),4.72(p,J＝1.0Hz,2H),3.83(dp,J＝9.1,5.7Hz,1H), 2.30(tt,J＝7.5,1.0Hz,4H),1.62(dtd,J＝13.2,7.5,5.7Hz,2H),1.50(dtd,J＝ 13.1,7.4,5.7Hz,2H)。
example 4
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (1-methylpiperidin-4-yl) benzamide (Compound 4)
Figure RE-GDA0003805511730000162
Dissolving intermediate 1f (298g, 1.0mmol), compound 4a (114mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography to obtain compound 4 (an off-white solid, 294mg, yield 59.4%); structural characterization data for compound 4: ESI (+) m/z 496.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.33(dd,J＝ 8.0,1.5Hz,1H),8.26(d,J＝9.2Hz,1H),8.11(dd,J＝7.8,1.3Hz,1H),7.90– 7.71(m,5H),7.63–7.42(m,5H),7.32–7.25(m,2H),7.11(td,J＝7.7,1.5Hz, 1H),3.84(dp,J＝9.1,5.8Hz,1H),2.82(ddd,J＝12.1,8.0,5.7Hz,2H),2.34(s, 3H),2.24(ddd,J＝12.3,8.0,5.7Hz,2H),1.89–1.79(m,2H),1.69(ddt,J＝ 13.6,8.1,5.7Hz,2H)。
example 5
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (2-oxotetrahydro-2H-pyran-4-yl) benzamide (Compound 5)
Figure RE-GDA0003805511730000171
Dissolving intermediate 1f (298g, 1.0mmol), compound 5a (115mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting by TLC, adding water (50ml) after reaction to quench the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and separating by column chromatography to obtain compound 5 (off-white solid, 322 m)g, yield 64.9%); structural characterization data for compound 5: ESI (+) m/z 497.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.28(dd,J＝ 7.9,1.4Hz,1H),8.09(dd,J＝7.9,1.3Hz,1H),7.92–7.74(m,5H),7.66(s,1H), 7.58–7.47(m,4H),7.43(t,J＝7.9Hz,1H),7.32–7.25(m,2H),7.11(td,J＝ 7.7,1.6Hz,1H),4.23–4.05(m,3H),2.66–2.52(m,2H),2.15–1.96(m,2H)。
example 6
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (2-oxopiperidin-4-yl) benzamide (Compound 6)
Figure RE-GDA0003805511730000181
Dissolving intermediate 1f (298g, 1.0mmol), compound 6a (114mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 6 (white-like solid, 315mg, yield 63.6%); structural characterization data for compound 6: ESI (+) m/z 496.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.32(dd,J＝ 8.0,1.3Hz,1H),8.16–8.05(m,2H),7.90–7.71(m,5H),7.68(s,1H),7.62– 7.42(m,4H),7.32–7.24(m,2H),7.11(td,J＝7.7,1.5Hz,1H),6.98(t,J＝4.4 Hz,1H),3.97(dtt,J＝9.0,7.1,5.7Hz,1H),3.34–3.16(m,2H),2.67(dd,J＝ 16.6,7.1Hz,1H),2.42(dd,J＝16.5,7.1Hz,1H),1.95–1.85(m,1H),1.77– 1.67(m,1H)。
example 7
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (1, 1-disulfidetetrahydro-2H-thiopyran-4-yl) benzamide (Compound 7)
Figure RE-GDA0003805511730000182
Reacting intermediate 1f (298g, 1.0mmol),Dissolving compound 7a (149mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring, detecting by TLC, adding water (50ml) after reaction to quench the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and separating by column chromatography to obtain compound 7 (off-white solid, 288mg, yield 54.3%); structural characterization data for compound 7: ESI (+) m/z 531.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.34(dd,J＝ 8.0,1.6Hz,1H),8.21(d,J＝9.0Hz,1H),8.13(dd,J＝8.0,1.6Hz,1H),7.94– 7.81(m,2H),7.80–7.73(m,3H),7.68(s,1H),7.60–7.47(m,3H),7.41(t,J＝ 7.9Hz,1H),7.32–7.24(m,2H),7.12(td,J＝7.6,1.5Hz,1H),3.62(dp,J＝9.0, 5.7Hz,1H),3.13(t,J＝6.6Hz,4H),2.16(dtd,J＝12.3,6.7,5.8Hz,2H),2.04 (dtd,J＝12.2,6.6,5.7Hz,2H)。
example 8
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (3-oxocyclohexyl) benzamide (Compound 8)
Figure RE-GDA0003805511730000191
Dissolving intermediate 1f (298g, 1.0mmol), compound 8a (99mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 8 (off-white solid, 302mg, yield 61.1%); structural characterization data for compound 8: ESI (+) m/z 495.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.35–8.29 (m,2H),8.13(dd,J＝7.8,1.3Hz,1H),7.90–7.71(m,5H),7.68(s,1H),7.60– 7.41(m,4H),7.32–7.24(m,2H),7.11(td,J＝7.7,1.6Hz,1H),3.98(dtt,J＝ 8.9,7.0,5.6Hz,1H),2.57–2.33(m,4H),2.00–1.89(m,1H),1.79–1.61(m, 3H)。
example 9
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (3-oxocyclopentyl) benzamide (Compound 9)
Figure RE-GDA0003805511730000201
Dissolving intermediate 1f (298g, 1.0mmol), compound 9a (99mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 9 (off-white solid, 311mg, yield 64.8%); structural characterization data for compound 9: ESI (+) m/z 481.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.35–8.29 (m,2H),8.15(dd,J＝8.0,1.4Hz,1H),7.90–7.70(m,5H),7.65(d,J＝7.9Hz, 1H),7.60–7.41(m,4H),7.33–7.25(m,2H),7.12(td,J＝7.6,1.5Hz,1H),4.40 –4.29(m,1H),2.50–2.30(m,4H),1.94–1.78(m,2H)。
example 10
Synthesis of 3- ((4- ((2-aminocarbonylphenyl) amino) quinazolin-2-yl) amino) -N- (3-hydroxycyclopentyl) benzamide (Compound 10)
Figure RE-GDA0003805511730000202
Dissolving intermediate 1f (298g, 1.0mmol), compound 10a (101mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 10 (off-white solid, 307mg, yield 63.7%); compound 10 structural characterization data: ESI (+) m/z 483.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.36– 8.26(m,2H),8.11(dd,J＝8.0,1.5Hz,1H),7.90–7.83(m,2H),7.83–7.73(m, 2H),7.68–7.60(m,3H),7.54–7.47(m,2H),7.43(t,J＝7.8Hz,1H),7.33–7.25(m,2H),7.12(td,J＝7.6,1.5Hz,1H),4.39(dtd,J＝12.5,6.8,5.9Hz,1H), 4.02(dtt,J＝9.1,6.6,5.6Hz,1H),2.42(d,J＝6.8Hz,1H),2.18(dt,J＝14.1,6.7 Hz,1H),1.99(dq,J＝13.0,5.8Hz,1H),1.86–1.61(m,4H)。
example 11
Synthesis of 2- ((2- ((3- (morpholine-4-carbonyl) phenyl) amino) quinazolin-4-yl) amino) benzamide (Compound 11)
Figure RE-GDA0003805511730000211
Dissolving intermediate 1f (298g, 1.0mmol), compound 11a (87mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 11 (off-white solid, 283mg, yield 60.5%); structural characterization data for compound 11: ESI (+) m/z 469.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.32(dd, J＝8.0,1.3Hz,1H),8.14(dd,J＝7.9,1.5Hz,1H),7.92(dd,J＝7.9,1.5Hz,1H), 7.85(ddd,J＝8.0,6.9,1.3Hz,1H),7.79–7.72(m,2H),7.68–7.62(m,2H), 7.54–7.44(m,3H),7.44–7.38(m,1H),7.34–7.25(m,2H),7.12(td,J＝7.7, 1.6Hz,1H),3.70–3.61(m,4H),3.52(dd,J＝6.7,5.4Hz,4H)。
example 12
Synthesis of 2- ((2- ((3- (4-methylpiperazine-1-carbonyl) phenyl) amino) quinazolin-4-yl) amino) benzamide (Compound 12)
Figure RE-GDA0003805511730000212
Dissolving intermediate 1f (298g, 1.0mmol), compound 12a (100mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting reaction by TLC, adding water (50ml) after reaction to quench reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and performing column chromatographyChromatography gave compound 12 (off-white solid, 289mg, 60.1% yield); structural characterization data for compound 12: ESI (+) m/z 482.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.32(dd, J＝8.0,1.6Hz,1H),8.12(dd,J＝7.7,1.4Hz,1H),7.90–7.81(m,2H),7.79– 7.73(m,2H),7.68–7.62(m,2H),7.54–7.44(m,3H),7.37(ddd,J＝7.9,1.9, 1.2Hz,1H),7.33–7.25(m,2H),7.12(td,J＝7.6,1.5Hz,1H),3.77(ddd,J＝ 11.7,6.5,4.1Hz,2H),3.39(ddd,J＝11.7,6.5,4.1Hz,2H),3.14(ddd,J＝11.9, 6.5,4.1Hz,2H),2.68(ddd,J＝11.9,6.5,4.1Hz,2H),2.27(s,3H)。
example 13
Synthesis of 2- ((2- ((3- (3-oxopiperidine-1-carbonyl) phenyl) amino) quinazolin-4-yl) amino) benzamide (Compound 13)
Figure RE-GDA0003805511730000221
Dissolving intermediate 1f (298g, 1.0mmol), compound 13a (99mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 13 (off-white solid, 312mg, yield 65.0%); structural characterization data for compound 13: ESI (+) m/z 481.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.33(dd, J＝8.0,1.6Hz,1H),8.11(dd,J＝8.0,1.6Hz,1H),7.90–7.81(m,2H),7.79– 7.72(m,2H),7.67–7.59(m,2H),7.54–7.46(m,2H),7.46–7.38(m,2H),7.33 –7.25(m,2H),7.12(td,J＝7.6,1.5Hz,1H),4.28(s,2H),3.44(dt,J＝11.7,5.9 Hz,1H),3.36(dt,J＝11.9,6.0Hz,1H),2.53–2.46(m,2H),1.89–1.80(m,2H)。
example 14
Synthesis of 2- ((2- ((3- (3-oxopyrrolidine-1-carbonyl) phenyl) amino) quinazolin-4-yl) amino) benzamide (Compound 14)
Figure RE-GDA0003805511730000231
Dissolving intermediate 1f (298g, 1.0mmol), compound 14a (85mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography to obtain compound 14 (off-white solid, 335mg, yield 71.9%); structural characterization data for compound 14: ESI (+) m/z 467.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.33(dd, J＝8.0,1.6Hz,1H),8.10(dd,J＝8.0,1.5Hz,1H),7.92(dd,J＝7.8,1.4Hz,1H), 7.85(ddd,J＝7.8,6.8,1.2Hz,1H),7.80–7.72(m,2H),7.68–7.60(m,2H), 7.54–7.47(m,2H),7.43–7.38(m,2H),7.33–7.25(m,2H),7.12(td,J＝7.7, 1.6Hz,1H),4.18(s,2H),3.81(t,J＝4.9Hz,2H),2.67–2.54(m,2H)。
example 15
Synthesis of 2- ((2- ((3- (3-hydroxypyrrolidine-1-carbonyl) phenyl) amino) quinazolin-4-yl) amino) benzamide (Compound 15)
Figure RE-GDA0003805511730000232
Dissolving intermediate 1f (298g, 1.0mmol), compound 15a (87mg, 1.0mmol) and DIPEA (194mg, 1.5mmol) in DMF (30ml), adding HATU (456mg, 1.2mmol) at room temperature, stirring for reaction, detecting the reaction by TLC, adding water (50ml) after the reaction is finished, quenching the reaction, extracting with ethyl acetate (2X50ml), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain compound 15 (off-white solid, 340mg, yield 72.6%); structural characterization data for compound 15: ESI (+) m/z 469.2, 1 H-NMR(500MHz,d 6 -DMSO)δ9.92(s,1H),8.33(dd, J＝7.7,1.5Hz,1H),8.12(dd,J＝7.8,1.3Hz,1H),7.92(dd,J＝7.8,1.4Hz,1H), 7.85(ddd,J＝7.9,6.8,1.3Hz,1H),7.79–7.72(m,2H),7.68–7.58(m,2H), 7.54–7.40(m,3H),7.39–7.25(m,3H),7.12(td,J＝7.7,1.6Hz,1H),4.44– 4.34(m,1H),3.72–3.61(m,2H),3.55–3.44(m,2H),3.12(d,J＝6.6Hz,1H), 2.15(dtd,J＝13.1,6.2,5.3Hz,1H),2.00(dtd,J＝13.2,6.2,5.3Hz,1H)。
test example 1
Biological evaluation
Determination of kinase Activity
Diluting the compounds 1-15 prepared in the embodiments 1-15 into 10 different concentration gradients by DMSO for later use;
mu.L of the compound was transferred to a 96-well plate, and 100. mu.L of kinase buffer (50mM HEPES pH 7.5, 10mM MgCl) was added to the plate 2 0.015% Brij-35, 2mM DTT), transferring 5. mu.L to 384 well plates, adding 10. mu.L of kinase buffer containing JNK1, JNK2 or JNK3, incubating at room temperature for 10 minutes, adding 10. mu.L of peptide buffer containing FAM-labledpeptide and ATP, incubating at 28 ℃ for 2 hours, adding 25. mu.L of stop solution, terminating the reaction, electrophoretically separating the detection substrate and product, and calculating the IC of the compound 50 。
The test results are shown in table 2:
TABLE 2 kinase Activity test results (nM)
Figure RE-GDA0003805511730000241
Figure RE-GDA0003805511730000251
As can be seen from Table 2, JNK1 kinase activity of compounds 1-15 is stronger than that of Tanziser tib; the JNK2 kinase activity of compound 2, compound 4 and compound 10 was greater than that of Tanziser tib, and the JNK2 kinase activity of compound 7 was close to that of Tanziser tib; compound 2 and compound 10 had JNK3 kinase activity greater than that of Tanzisertib, and compound 7 had JNK3 kinase activity close to that of Tanzisertib; the quinazoline benzamide compound provided by the invention has anti-tumor pharmacological activity, and the derivative thereof also has anti-tumor pharmacological activity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.

Claims (10)

1. A quinazoline benzamide compound is characterized by having a structure shown in formula I:
Figure FDA0003745507230000011
in the formula I, R is-NHR 1 Or an azaheterocyclyl group;
the-NHR 1 In R 1 Including any of the following structures:
Figure FDA0003745507230000012
2. the quinazoline benzamide compound according to claim 1, wherein said azaheterocyclyl comprises any one of the following structures:
Figure FDA0003745507230000013
3. a quinazoline benzamide compound according to claim 1 or 2, characterized in that it has any of the following structures:
Figure FDA0003745507230000014
Figure FDA0003745507230000021
4. a method for producing a quinazoline benzamide compound according to any one of claims 1 to 3, characterized by comprising the steps of:
carrying out condensation reaction on a compound VII and a compound VIII to obtain the quinazoline benzamide compound;
Figure FDA0003745507230000022
compound VII;
the compound VIII is NH 2 R 1 Or a nitrogen heterocyclic compound.
5. The process according to claim 4, wherein the process for the preparation of compound VII comprises the steps of:
carrying out condensation reaction on the compound II and the compound III to obtain a compound IV;
carrying out coupling reaction on the compound IV and a compound V to obtain a compound VI;
carrying out hydrolysis reaction on the compound VI to obtain a compound VII;
Figure FDA0003745507230000031
6. a quinazoline benzamide compound derivative which comprises a pharmaceutically acceptable salt, a stereoisomer, a hydrate, a solvate or an isotopic compound of the quinazoline benzamide compound described in any one of claims 1 to 3 or the quinazoline benzamide compound prepared by the preparation method described in any one of claims 4 to 5.
7. A pharmaceutical composition is characterized by comprising an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is one or more of the quinazoline benzamide compound disclosed in any one of claims 1 to 3, the quinazoline benzamide compound prepared by the preparation method disclosed in any one of claims 4 to 5 and the quinazoline benzamide compound derivative disclosed in claim 6.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient comprising a pharmaceutically acceptable carrier and/or diluent.
9. Use of a quinazoline benzamide compound according to any one of claims 1 to 3, a quinazoline benzamide compound prepared by a preparation method according to any one of claims 4 to 5, a quinazoline benzamide compound derivative according to claim 6 or a pharmaceutical composition according to any one of claims 7 to 8 in the preparation of a JNK inhibitor.
10. The use according to claim 9, wherein the JNK inhibitor is a JNK inhibitor for the treatment and/or prevention of one or more of a respiratory disease, fatty liver, liver fibrosis, chronic inflammatory disease, neurodegenerative disease, tumor and diabetes.
CN202210830689.5A 2022-07-14 2022-07-14 Quinazoline benzamide compound and derivative, pharmaceutical composition and application thereof Withdrawn CN115073436A (en)

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