CN106810557B - Heterocyclic compounds and their use - Google Patents

Heterocyclic compounds and their use Download PDF

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CN106810557B
CN106810557B CN201510848048.2A CN201510848048A CN106810557B CN 106810557 B CN106810557 B CN 106810557B CN 201510848048 A CN201510848048 A CN 201510848048A CN 106810557 B CN106810557 B CN 106810557B
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compound
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CN106810557A (en
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王勇
纪剑峰
刘欣
张先
张景忠
张迪
戴鹏
张秀玲
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Nanjing Shenghe pharmaceutical research and Development Co., Ltd
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Nanjing Shenghe Pharmaceutical Research And Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a heterocyclic compound and application thereof, in particular to a compound shown in a formula I, or an isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in medicines for treating virus infectious diseases. The partial compound of the invention has better capability of inhibiting HCV virus and is very hopeful to become HCV therapeutic agent.

Description

Heterocyclic compounds and their use
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a heterocyclic compound or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in preparation of a medicament for treating viral infectious diseases.
Background
Hepatitis C Virus (HCV) infection is a worldwide epidemic with more than 2 billion of chronic infected people worldwide, with a 3.2% rate of infection in china, and the top three worldwide. The clinical manifestations of hepatitis c virus infection are diverse, mild to inflammation and severe to cirrhosis and liver cancer. Chronic hepatitis c may also be associated with certain extrahepatic manifestations, including rheumatoid arthritis, keratoconjunctivitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-cell lymphoma, and delayed porphyria cutanea dermalis, which may be the result of an abnormal immune response in the body. When the hepatitis C cirrhosis is in the decompensation stage, various complications can appear, such as ascites abdominal infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatic failure and the like.
HCV belongs to the flaviviridae family of viruses of the hepacivirus genus, which has a gene structure similar to that of the other two genera in the flaviviridae family, namely pestivirus and flavivirus. Currently, standard methods of treating HCV infection are interferon and ribavirin combination therapy. However, only 50% of the patients respond to this method, and interferons have significant side effects such as influenza-like symptoms, weight loss, and fatigue weakness, while interferon and ribavirin combination therapy produces considerable side effects including hemolysis, anemia, and fatigue.
Drugs that have been developed for the treatment of HCV infection include protease inhibitors, thiazolidine derivatives, thiazolidine and benzanilide, phenanthrenequinone, helicase inhibitors, nucleoside polymerase inhibitors and gliotoxin, antisense phosphorothioate oligonucleotides, ribozymes, and nucleoside analogs, among others.
Although current anti-HCV infection drugs have achieved some clinical success, there is still a need to develop more structural classes of compounds to achieve superior efficacy against HCV infection.
Disclosure of Invention
One object of the present invention is to provide a compound having the structure of general formula I or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
Figure BDA0000860217820000021
wherein:
cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl optionally substituted with one or more halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro, cyano;
R1、R3together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R2Is hydrogen or alkylA group or an alkoxy group; or R2、R3Together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R1Is hydrogen, alkyl or alkoxy;
R4、R5each independently is hydrogen or alkyl;
X1is N (R)6) Or O, R6Selected from H and alkyl, said alkyl being optionally substituted with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl or heteroaryl groups;
X2is selected from C (R)7) And N (R)8) (ii) a If X2Is selected from C (R)7) Then X3Is selected from C (R)9) And X2、X3The dotted bonds between represent double bonds; if X2Is selected from N (R)8) Then X3Is a carbonyl group, and X2、X3The dotted bonds between represent single bonds; r7、R8、R9Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro and cyano;
m is 0, 1,2 or 3.
It is another object of the present invention to provide a process for preparing a compound of formula I of the present invention or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
It is a further object of the present invention to provide a composition comprising a compound of formula I of the present invention or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof and a pharmaceutically acceptable carrier, and a composition comprising a compound of formula I of the present invention or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof and another drug or drugs against viral infectious diseases.
The invention also aims to provide a method for treating virus infectious diseases, in particular to diseases caused by hepatitis C virus infection by using the compound of the general formula I or the stereoisomer, the pharmaceutically acceptable salt, the solvate or the prodrug thereof, and application of the compound of the general formula I or the stereoisomer, the pharmaceutically acceptable salt, the solvate or the prodrug thereof in preparing medicines for treating virus infectious diseases, in particular to diseases caused by hepatitis C virus infection.
Aiming at the above purpose, the invention provides the following technical scheme:
Figure BDA0000860217820000031
wherein:
cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl optionally substituted with one or more halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro, cyano;
R1、R3together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R2Is hydrogen, alkyl or alkoxy; or R2、R3Together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R1Is hydrogen, alkyl or alkoxy; r4、R5Each independently is hydrogen or alkyl;
X1is N (R)6) Or O, R6Selected from H and alkyl, said alkyl being optionally substituted with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl or heteroaryl groups;
X2is selected from C (R)7) And N (R)8) (ii) a If X2Is selected from C (R)7) Then X3Is selected from C (R)9) And X2、X3Virtual in betweenThe bonds of the lines represent double bonds; if X2Is selected from N (R)8) Then X3Is a carbonyl group, and X2、X3The dotted bonds between represent single bonds; r7、R8、R9Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro and cyano;
m is 0, 1,2 or 3.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which may be substituted with one or more halogens, hydroxy, amino, carboxyl, cyano, nitro, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl, cycloalkyl C1-6Alkyl radical, C3-8Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino radical, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino, di-C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkyl acyl radical, C1-6Alkyl acyl radical C1-6Alkyl radical, C1-6Alkoxyacyl group, C1-6Alkoxy acyl radical C1-6Alkyl radical, C1-6Alkyl acyloxy, C1-6Alkyl acyloxy radical C1-6Alkyl, aminoacyl C1-6Alkyl, mono C1-6Alkylaminoacyl, mono C1-6Alkylaminoacyl radical C1-6Alkyl, di-C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl radical C1-6Alkyl radical, C1-6Alkylacylamino or C1-6Alkylacylamino C1-6Alkyl substitution;
further preferably, Cy is selected from C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C6-10Aryl radical, C6-10Heteroaryl, said cycloalkyl, heterocycloalkyl, aryl and heteroaryl being optionally substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino radical, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino, di-C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkyl acyl radical, C1-6Alkyl acyl radical C1-6Alkyl radical, C1-6Alkoxyacyl group, C1-6Alkoxy acyl radical C1-6Alkyl radical, C1-6Alkyl acyloxy, C1-6Alkyl acyloxy radical C1-6Alkyl, aminoacyl C1-6Alkyl, mono C1-6Alkylaminoacyl, mono C1-6Alkylaminoacyl radical C1-6Alkyl, di-C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl radical C1-6Alkyl radical, C1-6Alkylacylamino or C1-6Alkylacylamino C1-6Alkyl substitution;
still further preferably, Cy is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrolyl, tetrahydrofuryl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, thienyl, furyl, indolyl, isoindolyl and quinolinyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrolyl, tetrahydrofuryl, phenyl, naphthyl, pyridinyl, pyrimidineThe radicals, pyrrolyl, thienyl, furyl, indolyl, isoindolyl and quinolinyl may be substituted by one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Heterocycloalkyl radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, mono C1-6Alkylamino radical, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino, di-C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkyl acyl radical, C1-6Alkyl acyl radical C1-6Alkyl radical, C1-6Alkoxyacyl group, C1-6Alkoxy acyl radical C1-6Alkyl radical, C1-6Alkyl acyloxy, C1-6Alkyl acyloxy radical C1-6Alkyl, aminoacyl C1-6Alkyl, mono C1-6Alkylaminoacyl, mono C1-6Alkylaminoacyl radical C1-6Alkyl, di-C1-6Alkylaminoacyl, di-C1-6Alkylaminoacyl radical C1-6Alkyl radical, C1-6Alkylacylamino or C1-6Alkylacylamino C1-6Alkyl substitution.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
R1is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R2、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; or R2Is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R1、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; r4、R5Each independently is hydrogen or C1-6An alkyl group;
further preferably, R1Is hydrogen, C1-3Alkyl or C1-3Alkoxy, and R2、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; or R2Is hydrogen, C1-3Alkyl or C1-3Alkoxy, and R1、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; r4、R5Each is hydrogen or C1-3An alkyl group;
even more preferably, R1Is hydrogen, methoxy, ethoxy, propoxy, and R2、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; or R2Is hydrogen, methoxy, ethoxy, propoxy, and R1、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; r4、R5Each independently hydrogen, methyl, ethyl, propyl.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
X1is N (R)6)，R6Selected from H and C1-6Alkyl optionally substituted with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, halo, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, or heteroaryl;
further preferably, R6Selected from H and C1-3Alkyl, said alkyl and cycloalkyl groups being optionally substituted by one or more C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogen, hydroxy, amino, nitro, cyano, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl, or heteroaryl substitution.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
X2is selected from C (R)7)，X3Is selected from C (R)9) And X2、X3The dotted bonds between represent double bonds.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
X2is selected from N (R)8)，X3Is a carbonyl group, and X2、X3The dotted bonds between represent single bonds.
In some preferred embodiments, the present invention provides a compound of formula I of the present invention, or an isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
cy is phenyl, optionally substituted with one or more halogen, hydroxy, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro, cyano;
R1is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R2、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran; or R2Is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R1、R3Together with the atoms to which they are attached form 2, 3-dihydrobenzofuran;
R4、R5each independently is hydrogen or C1-6An alkyl group;
X1is N (R)6)，R6Selected from H and C1-6An alkyl group;
X2is selected from C (R)7) And N (R)8) (ii) a If X2Is selected from C (R)7) Then X3Is selected from C (R)9) And X2、X3The dotted bonds between represent double bonds; if X2Is selected from N (R)8) Then X3Is C (O), and X2、X3BetweenThe bond of the dotted line of (a) represents a single bond; r7、R8、R9Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro and cyano;
m is 0, 1,2 or 3.
In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
R7、R8、R9each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, nitro and cyano;
further preferably, R7、R8、R9Each independently selected from hydrogen, halogen, hydroxy, C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Heterocycloalkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, amino, C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, nitro and cyano;
even more preferably, R7、R8、R9Each independently selected from hydrogen, halogen, hydroxy, C1-3Alkyl radical, C3-6Cycloalkyl radical, C3-6Heterocycloalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, amino, C1-3Alkylamino radical, C1-3Alkylacylamino group, C1-3Alkyl acyl, amino acyl, C1-3Alkylaminoacyl, nitro and cyano.
In some embodiments, the present invention provides the following specific compounds:
Figure BDA0000860217820000071
in another aspect, the present invention provides a process for the preparation of a compound of formula I according to the invention, comprising the steps of:
Figure BDA0000860217820000072
a) carrying out an esterification reaction on the compound of the formula (1) and alcohol under the catalysis of acid to obtain a compound of a formula (2);
b) carrying out substitution and condensation reaction on the compound of the formula (2) to obtain a compound of a formula (3);
c) reacting the compound of formula (3) with copper halide to obtain a halogenated compound of formula (4);
d) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain a compound shown in a formula (5);
e) carrying out Curtius rearrangement reaction and decarboxylation reaction on the compound shown in the formula (5) to obtain an amino compound shown in the formula (6);
f) the compound of the formula (6) is subjected to a ring-increasing reaction to prepare a condensed ring compound of a formula (7);
g) the compound of formula (7) is prepared into the compound of formula (8) by a common preparation method;
h) the compound of the formula (8) is subjected to a Suzuki reaction to prepare the compound of the formula (I).
Wherein X is halogen, preferably selected from chlorine and bromine, M is alkyl, preferably selected from C1-6Alkyl radical, R1、R2、R3、R4、R5、X1、X2、X3Cy and m are as defined above for formula I.
In a third aspect, the present invention provides a pharmaceutical composition, which comprises the compound represented by the general formula I of the present invention, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, and a pharmaceutically acceptable carrier.
The compound of formula I of the present invention or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical formulation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a method of treating a subject suffering from a viral infectious disease with a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of the invention, comprising administering to the subject a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula I, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, in an amount effective to reduce the viral load of the virus in the subject. In one embodiment, the present invention provides a method for treating and/or preventing a viral infection, such as an HCV viral infection, comprising administering to a subject in need of such treatment a compound of the present invention, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof. In another embodiment, the present invention provides a method of inhibiting a viral infection, such as an HCV viral infection, comprising contacting the virus with a therapeutically effective amount of a compound of the present invention, or a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition thereof.
In another aspect, the present invention provides an application of the compound represented by the general formula I, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof in preventing or treating viral infection, especially HCV viral infection diseases, and an application in preparing a medicament for preventing and/or treating viral infection diseases, especially an application in preparing a medicament for preventing and/or treating HCV viral infection, such as HCV viral hepatitis diseases. Examples of such diseases are acute hepatitis c, chronic hepatitis c and mixed infections of hepatitis c and hepatitis b or hepatitis d.
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
"stereoisomer" in the present invention means an isomer produced by spatially different arrangement of atoms in a molecule. Including cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present invention. Individual stereoisomers of the compounds of the invention may be substantially free of other isomers or may be mixed, for example, as racemates or with all other stereoisomers.
The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, such as, but not limited to: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
"solvate" in the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. In the case of water, the solvate is often referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, and the like.
The "prodrug" in the present invention means a compound which is converted into a compound of the formula (i) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into a compound of the formula (i) by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into a compound of the formula (i) by a hydrolysis reaction of gastric acid or the like, or the like.
"pharmaceutical composition" in the present invention is intended to encompass a mixture comprising any one of the compounds described herein, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
By "pharmaceutically acceptable carrier" in the context of the present invention is meant a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.
"alkyl" in the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment. "haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen atom.
The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group, preferably a hydrocarbon group of 8 or less carbon atoms. "C" of the invention3-8Cycloalkyl radicals "areRefers to cyclic saturated hydrocarbon groups containing 3 to 8 carbon atoms. "C" of the invention3-6Cycloalkyl "means a straight or branched chain saturated hydrocarbon group containing 3 to 6 carbon atoms.
"alkoxy" in the present invention means-O-alkyl.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine.
"alkylamino" in the context of the present invention means-NH-alkyl or-N- (alkyl).
"Alkylacyl" in the present invention means-C (O) -alkyl.
"aminoacyl" in the context of the present invention is intended to mean-C (O) -NH2The term "alkylaminoacyl" refers to-C (O) -NH-alkyl or-C (O) -N- (alkyl).
The "sulfonyl group" in the present invention means-S (O)2-alkyl, the term "sulfinyl" refers to-s (o) -alkyl.
"aryl" in the context of the present invention refers to an aromatic hydrocarbon radical containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.
The term "heteroaryl" as used herein refers to an aromatic group wherein at least one carbon atom of the aromatic group is replaced by a heteroatom. The heteroatom is O, S, N. For example, heteroaryl groups described herein include, but are not limited to, pyridyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl.
"Heterocycloalkyl" as used herein refers to a saturated cyclic group containing at least one heteroatom, wherein the heteroatom is N, O or S.
The "-NHMs" in the present invention is an abbreviation for methylsulfonylamino group.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.
EXAMPLE 1N- (4- (4-methoxy-3, 3-dimethyl-9- (2-oxo-1, 2-dihydropyridin-3-yl) -2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
Figure BDA0000860217820000111
Step 14 preparation of methyl bromo-3, 5-dihydroxybenzoate
4-bromo-3, 5-dihydroxybenzoic acid (111.2g) was dissolved in methanol (400mL), concentrated sulfuric acid (8mL) was added, and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was poured into water, filtered and dried to obtain the title compound as a white solid. ESI-MS M/z [ M + H ]]+＝247.0.
Step 24 preparation of methyl bromo-3-hydroxy-5- (2-methacryloyloxy) benzoate
Methyl 4-bromo-3, 5-dihydroxybenzoate (116g) obtained in step 1 of example 1 was dissolved in acetone (500mL), potassium carbonate (64.8g) was added, the temperature was raised to reflux, 3-bromo-2-methylpropene (76.1g) was added dropwise, and the mixture was refluxed for 3 hours. Filtration, concentration and column chromatography gave the title compound as a white solid. ESI-MS M/z [ M + H ]]+＝301.0.
Step 34 preparation of methyl-hydroxy-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylate
Methyl 4-bromo-3-hydroxy-5- (2-methacryloyloxy) benzoate (47.7g) obtained in step 2 of example 1 was dissolved in DMF/H2To O (40:1) (470mL) were added palladium acetate (1.78g), tetraethylammonium chloride monohydrate (34.9g), sodium acetate (32.5g), and sodium formate (12.9g), and the mixture was reacted at 90 ℃ for 6 hours under an argon atmosphere. After the reaction is completed, ethyl acetate is added for filtration, saturated saline is added for extraction, organic layers are combined, dried by anhydrous sodium sulfate, concentrated and purified by column chromatography, and the title compound is obtained. ESI-MS M/z [ M + H ]]+＝223.
Step 47 preparation of bromo-4-hydroxy-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylic acid methyl ester
Methyl 4-hydroxy-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylate (18.6g) obtained in step 3 of example 1 was dissolved in acetonitrile (180mL), copper bromide (37.4g) was added, stirring was carried out overnight, ethyl acetate was added, filtration, concentration and column chromatography purification were carried out to obtain the title compound as a white solid. ESI-MS m/z:[M+H]+＝315.
Step preparation of 57-bromo-4-hydroxymethyl-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylic acid
Methyl 7-bromo-4-hydroxy-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylate (12.5g) obtained in step 4 of example 1 was dissolved in DMF (125mL), cooled to 0 deg.C, NaH (60%, 2.17g) was added, stirring at 0 deg.C for 30min, iodomethane (8.87g) was added dropwise, reaction was carried out for 2H, ethyl acetate and water were added for extraction, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the concentrate was treated with THF/H2O (1:1, 120mL) was dissolved, NaOH (6.67g) was added, reflux was taken for 8h, concentrated to remove THF, pH was adjusted to 3-4 with concentrated HCl, filtered, and dried to give the title compound as a white solid. ESI-MS M/z [ M + H ]]+＝301.
Step 67 preparation of bromo-4-hydroxymethyl-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-amino
7-bromo-4-hydroxymethyl-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-carboxylic acid (13g) obtained in step 5 of example 1 was dissolved in tert-butanol (100mL), and triethylamine (4.8g) and DPPA (13.1g) were added and refluxed for 4 hours. After the reaction is finished, concentrating to remove tert-butyl alcohol, adding ethyl acetate to dissolve, and sequentially using 1M citric acid and saturated NaHCO3Washed with saturated brine, concentrated, dried, added with HCl in ethyl acetate, stirred overnight, filtered, diluted with petroleum ether: ethyl acetate ═ 2:1 the combined solution was washed to give the title compound as a grey solid. ESI-MS M/z [ M + H ]]+＝272.
Step 76, preparation of 9, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinoline
2-Bromoacrolein (1.2g) was dissolved in acetic acid (35mL), and Br was added dropwise2(1.07g) in acetic acid (35mL), and stirred at room temperature for 15 min. The title compound was obtained as a pale yellow solid by adding 7-bromo-4-hydroxymethyl-3, 3-dimethyl-2, 3-dihydrobenzofuran-6-amino group (2.3g) obtained in step 6 of example 1 to the above solution, reacting at 60 ℃ for about 0.5h, concentrating to remove acetic acid, adding ethyl acetate, extracting with saturated aqueous sodium bicarbonate solution, combining the organic layers, concentrating, and purifying by column chromatography. ESI-MS M/z [ M + H ]]+＝386.
Step 84 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -3-methyl-N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (1.2g), 3-methyl-4-boronic acid pinacol ester-N-phenylmethanesulfonamide (1.06g), sodium carbonate (0.98g) and Pd (PPh)3)4(0.36g) is dissolved in methanol/dichloromethane (2:1, 10mL), microwave-treated at 90 deg.C for 30min, reaction solution is concentrated, and column chromatography purification is carried out to obtain light yellow solid compound. ESI-MS M/z [ M + H ]]+＝491.
Step 9 preparation of N- (4- (4-methoxy-3, 3-dimethyl-9- (2-oxo-1, 2-dihydropyridin-3-yl) -2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 8 of example 1]Quinolyl) -3-methyl-N-phenylmethanesulfonamide (125mg), (2-oxo-1, 2-dihydropyridin-3-yl) boronic acid (42.35mg), sodium carbonate (81mg) and Pd (PPh)3)4(29.5mg) was dissolved in methanol/toluene (2:1, 2mL) and isolated by microwave at 120 ℃ for 65min to give the title compound as an off-white solid.1H-NMR(300MHz,DMSO-d6):δ1.52(s，6H，2CCH3)，2.29(s，3H，ArCH 3)，3.04(s，3H，SCH 3)，4.02(s，3H，OCH 3)，4.26(s，2H，CH2)，8.31(s，1H，NHS)，6.23-8.66(m，8H，8ArH)，11.55(s，1H，NHCO).ESI-MS m/z:[M+H]+＝506.2.
EXAMPLE 2N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
Figure BDA0000860217820000131
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 8 of example 1]Quinolyl) -3-methyl-N-phenylmethanesulfonamide (0.25g), 2, 6-dimethoxy-3-pyridineboronic acid (0.1g)Sodium carbonate (0.16g) and Pd (PPh)3)4(0.058g) was dissolved in methanol/toluene (2:1, 2mL), microwaved at 120 ℃ for 65min, concentrated and dissolved in acetic acid (2mL), HBr (0.2mL) was added, stirred at 60 ℃ for 1.5h before reaction was complete, concentrated and isolated as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.52(s，6H，2×CH3)，2.29(s，3H，CH3)，3.04(s，3H，CH3)，3.86(s，3H，OCH3),4.02(s，3H，OCH3)，4.26(s，2H，OCH2)，6.25(s，1H，NH)，6.25-8.66(m，7H，7ArH)，9.79(s，1H，NH).ESI-MS m/z:[M+H]+＝536.2.
EXAMPLE 3N- (4- (4-methoxy-9- (6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
Figure BDA0000860217820000132
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 8 of example 1]Quinolyl) -3-methyl-N-phenylmethanesulfonamide (250mg), 2-methoxy-6-methylpyridin-3-ylboronic acid (85.68mg), sodium carbonate (161.9mg) and Pd (PPh)3)4(58.8mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h, reacted completely, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.51(d，6H，2CCH3)，2.23(s，3H，NHCCH 3)，2.30(s，3H，ArCH 3)，3.04(s，3H，SCH 3)，4.01(s，3H，ArOCH 3)，4.25(d，2H，CH2)，6.04-8.66(m，7H，7ArH)，9.83(brs，1H，NHS)，11.55(s，1H，NHCO).ESI-MS m/z:[M+H]+＝520.2.
Example 4N- (4- (9- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
Figure BDA0000860217820000141
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 8 of example 1]Quinolyl) -3-methyl-N-phenylmethanesulfonamide (250mg), 2, 4-dimethoxypyrimidine-5-boronic acid (93.67mg), sodium carbonate (161.9mg) and Pd (PPh)3)4(58.8mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.51(d，6H，2CCH3)，2.29(s，3H，ArCH 3)，3.04(s，3H，SCH 3)，4.01(s，3H，ArOCH 3)，4.29(q，2H，CH2)，7.17-8.72(m，6H，6ArH)，9.81(brs，1H，NHS)，10.97(brs，1H，NHCH)，11.12(s，1H，CONHCO).ESI-MS m/z:[M-H]-＝521.2.
EXAMPLE 5N- (4- (9- (5-fluoro-2-oxo-1, 2-dihydropyridin-3-yl) -4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-methylphenyl) methanesulfonamide
Figure BDA0000860217820000151
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 8 of example 1]Quinolyl) -3-methyl-N-phenylmethanesulfonamide (250mg), 2-methoxy-5-fluoropyridine-3-boronic acid (85.68mg), sodium carbonate (161.9mg) and Pd (PPh)3)4(58.8mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.53(s，6H，2CCH3)，2.30(s，3H，ArCH 3)，3.04(s，3H，SCH 3)，4.03(s，3H，ArOCH 3)，4.30(s，2H，CH2)，7.17～8.70(m，7H，7ArH).ESI-MS m/z:[M-H]-＝522.1.
Example 6N- (4- (9- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000152
Step 14 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (650mg), 4-boronic acid pinacol ester-N-phenylmethanesulfonamide (438.67mg), sodium carbonate (427mg) and Pd (PPh)3)4(155mg) was dissolved in methanol/dichloromethane (2:1, 10mL) and microwaved at 90 ℃ for 30 min. Column chromatography gave the title compound as a pale yellow solid. ESI-MS M/z [ M + H ]]+＝477.
Step 2 preparation of N- (4- (9- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 6]Quinolyl) -N-phenylmethanesulfonamide (120mg), 2, 4-dimethoxypyrimidine-5-boronic acid (53.4mg), sodium carbonate (80.2mg) and Pd (PPh)3)4(29mg) was dissolved in methanol/toluene (2:1), microwaved at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h, reacted completely, concentrated, and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.52(d，6H，2CH3)，2.85(s，3H，SCH 3)，4.05(s，3H，OCH 3)，4.28(q，2H，CH2)，7.18-9.02(m，7H，7ArH)，11.11(s，1H，CONHCO).ESI-MS m/z:[M+H]+＝508.9.
EXAMPLE 7N- (4- (4-methoxy-3, 3-dimethyl-9- (2-oxo-1, 2-dihydropyridin-3-yl) -2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000161
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 6]Quinolyl) -N-phenylmethanesulfonamide (100mg), (2-oxo-1, 2-dihydropyridin-3-yl) boronic acid (58.2mg), sodium carbonate (66mg) and Pd (PPh)3)4(24mg) was dissolved in methanol/toluene (2:1) and isolated in a microwave at 120 ℃ for 65min to give the title compound as a white solid.1H-NMR(500MHz,DMSO-d6):δ1.53(s，6H，2CH3)，2.89(s，3H，SCH 3)，4.06(s，3H，OCH 3)，4.26(s，2H，CH2)，6.23-8.97(m，9H，9ArH)，11.52(d，1H，NHCO).ESI-MS m/z:[M+H]+＝491.9.
EXAMPLE 8N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000162
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 6]Quinolyl) -N-phenylmethanesulfonamide (100mg), 2, 4-dimethoxypyridine-5-boronic acid (92mg), sodium carbonate (132mg) and Pd (PPh)3)4(48.4mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.52(s，6H，2CH3)，3.04(s，3H，SCH 3)，3.85(s，3H，NHCOCH 3)，4.06(s，3H，ArOCH 3)，4.26(s，2H，CH 2)，6.25-8.99(m，8H，8ArH).ESI-MS m/z:[M+H]+＝521.9.
Example 9N- (4- (4-methoxy-3, 3-dimethyl-9- (6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) -2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000171
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 6]Quinolyl) -N-phenylmethanesulfonamide (200mg), 2-methoxy-6-methylpyridin-3-ylboronic acid (84mg), sodium carbonate (132mg) and Pd (PPh)3)4(48.4mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(300MHz,DMSO-d6):δ1.52(s，6H，2CCH 3)，2.25(s，3H，ArCH 3)，3.04(s，3H，SCH 3)，4.06(s，3H，OCH 3)，4.25(s，2H，CH2)，6.04～8.99(m，8H，8ArH)，9.98(brs，1H，NHS)，11.55(s，1H，NHCO).ESI-MS m/z:[M+H]+＝505.9.
EXAMPLE 10N- (3-fluoro-4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000172
Step 14 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -3-fluoro-N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (250mg), 3-methyl-4-boronic acid pinacol ester-3-fluoro-N-phenylmethanesulfonamide (224mg), sodium carbonate (205mg) and Pd (PPh)3)4(74.6mg) was dissolved in methanol/dichloromethane (2:1, 10mL), subjected to microwave irradiation at 90 ℃ for 30min, the reaction mixture was concentrated, and purified by column chromatography to give the title compound as a pale yellow solid. ESI-MS M/z [ M + H ]]+＝495.
Step 2 preparation of N- (3-fluoro-4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 10]Quinolyl) -3-fluoro-N-phenylmethanesulfonamide (100mg), 2, 4-dimethoxypyridine-5-boronic acid (44.5mg), sodium carbonate (64.3mg) and Pd (PPh)3)4(23.4mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(500MHz,DMSO-d6):δ1.52(s，6H，2CH3)，3.06(s，3H，SCH 3)，3.85(s，3H，NHCOCH 3)，4.03(s，3H，ArOCH 3)，4.27(s，2H，OCH 2C)，6.25-8.99(m，7H，7ArH).ESI-MSm/z:[M+H]+＝540.1.
EXAMPLE 11N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-trifluoromethylphenyl) methanesulfonamide
Figure BDA0000860217820000181
Step 14 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -3-trifluoromethyl-N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (650mg), 4-boronic acid pinacol ester-3-trifluoromethyl-N-phenylmethanesulfonamide (735.7mg), sodium carbonate (427mg) and Pd (PPh)3)4(155mg) dissolved in methanol/dichloromethane (2:1, 10mL), microwaved at 90 ℃ for 30min, concentratedThe reaction solution is purified by column chromatography to obtain the title compound as a light yellow solid. ESI-MS M/z [ M + H ]]+＝545.
Step 2 preparation of N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3-trifluoromethylphenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 11]Quinolyl) -3-trifluoromethyl-N-phenylmethanesulfonamide (100mg), 2, 4-dimethoxypyridine-5-boronic acid (44.5mg), sodium carbonate (64.3mg) and Pd (PPh)3)4(23.4mg) was dissolved in methanol/toluene (2:1), microwave-treated at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h before completion of the reaction, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(300MHz,DMSO-d6):δ1.53(s，6H，2CH3)，3.15(s，3H，SCH 3)，3.86(s，3H，NHCOCH 3)，4.0(s，3H，ArOCH 3)，4.31(s，2H，OCH 2C)，6.25-8.67(m，7H，7ArH)，10.32(s，1H，NHS).ESI-MS m/z:[M+H]+＝590.1.
EXAMPLE 12N- (3-methoxy-4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
Figure BDA0000860217820000191
Step 14 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -3-methoxy-N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (650mg), 4-boronic acid pinacol ester-3-methoxy-N-phenylmethanesulfonamide (735.7mg), sodium carbonate (427mg) and Pd (PPh)3)4(155mg) was dissolved in methanol/dichloromethane (2:1, 10mL) and microwaved at 90 ℃ for 30 min. Column chromatography gave the title compound as a pale yellow solid. ESI-MSm/z [ alpha ], [ alphaM+H]+＝507.
Step 2 preparation of N- (3-methoxy-4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) phenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 12]Quinolyl) -3-methoxy-N-phenylmethanesulfonamide (500mg), 2, 4-dimethoxypyridine-5-boronic acid (217mg), sodium carbonate (314mg) and Pd (PPh)3)4(114mg) was dissolved in methanol/toluene (2:1), microwaved at 120 ℃ for 65min, concentrated and dissolved in acetic acid, HBr was added, stirred at 60 ℃ for 1.5h, reacted completely, concentrated and isolated to give the title compound as an off-white solid.1H-NMR(300MHz,DMSO-d6):δ1.52(s，6H，2CH3)，3.07(s，3H，SCH 3)，3.80(s，3H，NHCOCH 3)，3.86(s，3H，COCH 3)，4.0(s，3H，ArOCH 3)，4.27(s，2H，OCH 2C)，6.25-8.77(m，7H，7ArH)，9.90(s，1H，NHS).ESI-MS m/z:[M+H]+＝552.2.
EXAMPLE 13N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3, 5-dimethylphenyl) methanesulfonamide
Figure BDA0000860217820000201
Step 14 preparation of (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolyl) -3, 5-dimethyl-N-phenylmethanesulfonamide
The 6, 9-dibromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3,2-g obtained in step 7 of example 1 was used]Quinoline (650mg), 4-boronic acid pinacol ester-3, 5-dimethyl-N-phenylmethanesulfonamide (545.9mg), sodium carbonate (427mg) and Pd (PPh)3)4(155mg) was dissolved in methanol/dichloromethane (2:1) (10mL), subjected to microwave chromatography at 90 ℃ for 30min, and subjected to column chromatography to give the title compound as a pale yellow solid. ESI-MS M/z [ M + H ]]+＝505.
Step 2 preparation of N- (4- (4-methoxy-9- (6-methoxy-2-oxo-1, 2-dihydropyridin-3-yl) -3, 3-dimethyl-2, 3-dihydrofuro [3,2-g ] quinolin-6-yl) -3, 5-dimethylphenyl) methanesulfonamide
4- (9-bromo-4-methoxy-3, 3-dimethyl-2, 3-dihydrofuro [3, 2-g) obtained in step 1 of example 13]Quinolyl) -3, 5-dimethyl-N-phenylmethanesulfonamide (300mg), 2, 4-dimethoxypyridine-5-boronic acid (130mg), sodium carbonate (68.64mg) and Pd (PPh)3)4(189mg) in methanol/toluene (2:1), microwave 65min at 120 deg.C, concentrate and dissolve in acetic acid, add HBr, stir at 60 deg.C for 1.5h before completing the reaction, concentrate to afford the title compound as an off-white solid.1H-NMR(300MHz,DMSO-d6):δ1.53(s，6H，2CH3)，2.01(s，6H，2ArCH 3)，3.05(s，3H，SCH 3)，3.84(s，3H，NHCOC 3H)，4.02(s，3H，ArOCH 3)，4.31(s，2H，OCH 2C)，6.25-8.58(m，6H，6ArH)，10.35(s，1H，NHS).ESI-MS m/z:[M+H]+＝550.2.
Evaluation of pharmacological Activity
Experimental example 1 test for migration of Activity in serum of Compound of the present invention
1. Experimental Material
1.1 reagent:
TABLE 1 list of reagents
Name of reagent Suppliers of goods
DMEM cell culture solution Invitrogen
Fetal bovine serum Corning
Human serum Sigma
Glutamine Invitrogen
Penicillin-streptomycin Hyclone
Non-essential amino acid additives Invitrogen
Screening for antibiotic G418 Invitrogen
Phosphate buffer Hyclone
Pancreatin Invitrogen
Dimethyl sulfoxide (DMSO) Sigma
Bright-Glo detection reagent Promega
1.2HCV 1a and 1b replicon cells:
HCV 1a and 1b replicon cells were prepared by stably transferring the HCV genotype 1a or 1b replicon into the Huh7 cell line. The Huh71a and 1b cell lines were provided by shanghai drug mingkude new drug development ltd as Huh7 cell lines containing HCV 1a or HCV 1b replicons with stable luciferase (Luc) reporters. It clones HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector through gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance selection, the HCV replicon stably replicated and the relevant protein and luciferase were stably expressed in huh7 cells. The cell model is used for in vitro screening of anti-HCV compounds. The anti-HCV activity of the compound was determined by examining the expression level of luciferase. See Lohmann V, et al 1999 reproduction of pathogenic hepatitis C viruses RNAs in a hepatoma cell line, science 285(5424):110-113.
1.3 Compounds: the compounds prepared in the above examples of the present invention were made into 10mM stock solutions in 100% DMSO, buffered in nitrogen gas cabinet.
2. Experimental methods
1) Compound treatment: DMSO stock solutions of example compounds of the invention were diluted and added to 96-well assay plates. The final concentration of the compound was up to 1. mu.M, and three-fold gradient dilutions were made for a total of 10 concentrations. The final concentration of DMSO was 0.5%.
2) Cell treatment: HCV-1a and HCV-1b replicon cells were seeded in the above 96-well cell plate, and the number of cells seeded per well was 8X 103Cells/well, then placed at 37 ℃ in 5% CO2Culturing in an incubator for 3 days.
3) anti-HCV replicon activity assay: luciferase luminescent substrate Bright-Glo was added to each well and Luminescence signal values were measured within 5 minutes using the chemiluminescence detection System Envision and raw data (RLU) was used for compound inhibition activity calculations.
4) Data processing: raw data were processed as percent inhibition using the following formula:
Figure BDA0000860217820000221
CPD (CPD): signal value of compound pore
HPE (Hundred percent effect) 100% effective control well signal value, only DMEM culture solution in the well
ZPE (zero percent effect) null effect control well signal values, compounds were replaced with 0.5% DMSO.
The percentage inhibition is introduced into GraphPad Prism software for data processing to obtain a curve corresponding to the compound and the inhibitory activity (EC) on HCV replicon50) Numerical values. Some data are shown in table 2.
TABLE 2
Figure BDA0000860217820000222
Figure BDA0000860217820000231
The experimental results show that the compound has better HCV virus inhibiting capacity and is very promising to be used as an HCV therapeutic agent.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims (5)

1. A compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:
Figure FDA0002708305960000011
wherein:
cy is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl,Piperazinyl, morpholinyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl, thienyl, furanyl, indolyl, isoindolyl and quinolinyl, which may be substituted with one or more halogen, hydroxy, amino, carboxy, cyano, nitro, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano C1-6Alkyl, nitro C1-6Alkyl substitution;
R1、R3together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R2Is hydrogen, C1-6Alkyl or C1-6An alkoxy group; or R2、R3Together with the atom to which they are attached form 2, 3-dihydrobenzofuran, and R1Is hydrogen, C1-6Alkyl or C1-6An alkoxy group;
R4、R5each independently is hydrogen or C1-6An alkyl group;
X1is N;
X2is selected from C (R)7) And N (R)8) Wherein if X2Is selected from C (R)7) Then X3Is selected from C (R)9) And X2、X3The dotted bonds between represent double bonds; if X2Is selected from N (R)8) Then X3Is a carbonyl group, and X2、X3The dotted bonds between represent single bonds; r7、R8、R9Independently selected from hydrogen, halogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, amino, C1-6Alkylamino radical, C1-6Alkylacylamino group, C1-6Alkyl acyl, amino acyl, C1-6Alkylaminoacyl, nitro and cyano; and
m is 0, 1,2 or 3.
2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from:
Figure FDA0002708305960000021
3. a pharmaceutical composition comprising a compound of any one of claims 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound according to any one of claims 1 or 2 or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment of a viral infectious disease.
5. The use according to claim 4, wherein the viral infectious disease is a disease caused by infection with hepatitis C virus.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041818A1 (en) * 2002-11-01 2004-05-21 Abbott Laboratories Anti-infective agents
WO2008082484A1 (en) * 2006-12-22 2008-07-10 Schering Corporation 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
CN102341382A (en) * 2009-03-06 2012-02-01 弗·哈夫曼-拉罗切有限公司 Heterocyclic antiviral compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041818A1 (en) * 2002-11-01 2004-05-21 Abbott Laboratories Anti-infective agents
WO2008082484A1 (en) * 2006-12-22 2008-07-10 Schering Corporation 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
CN102341382A (en) * 2009-03-06 2012-02-01 弗·哈夫曼-拉罗切有限公司 Heterocyclic antiviral compounds

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