CN106810557A - Heterocyclic compound and its application - Google Patents

Heterocyclic compound and its application Download PDF

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Publication number
CN106810557A
CN106810557A CN201510848048.2A CN201510848048A CN106810557A CN 106810557 A CN106810557 A CN 106810557A CN 201510848048 A CN201510848048 A CN 201510848048A CN 106810557 A CN106810557 A CN 106810557A
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alkyl
amino
compound
alkoxy
acyl
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CN106810557B (en
Inventor
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 Sanhome Pharmaceutical 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

Abstract

The invention belongs to medicinal chemistry arts, it is related to heterocycle compound and its application, specifically, the present invention provides the compound or its isomers, pharmaceutically acceptable salt, solvate or prodrug shown in Formulas I, the purposes that their preparation method and the pharmaceutical composition containing these compounds and these compounds or composition are used to treat in the medicine of disease of viral infection.Part of compounds of the invention has the ability for preferably suppressing HCV virus, promises to be very much HCV therapy agent.

Description

Heterocyclic compound and its application
Technical field
The invention belongs to medicinal chemistry arts, and in particular to heterocyclic compound or its stereoisomer, pharmaceutically may be used The salt of receiving, solvate or prodrug, their preparation method and the pharmaceutical composition containing these compounds With the purposes of these compounds or composition in the medicine for preparing treatment disease of viral infection.
Background technology
HCV (HCV) infection is the disease of world-wide prevalence, and global chronic infection has surpassed Cross 200,000,000, Chinese infection rate is 3.2%, rank the world first three.The clinical manifestation of infection with hepatitis C virus is more Sample, gently to inflammation, weight to cirrhosis, liver cancer.Chronic hepatitis C can also be showed concurrently outside some livers, Including rheumatoid arthritis, drying property conjunctivokeratitis, lichen planus, glomerulonephritis, mixed type Cryoglobulinemia, B cell lymphoma and porphyria cutanea tarda etc., it may be possible to body abnormal immune Caused by reaction.During hepatitis cirrhosis patients in decompensation, various complication, such as ascites abdominal cavity infection can occur, UGB, hepatic encephalopathy, hepatorenal syndrome, hepatic failure etc. are showed.
HCV belongs to flaviviridae hepatovirus virus, and it is pestivirus with two other category in flaviviridae Category is similar with the gene structure of Flavivirus.At present, treatment HCV infection standard method have interferon and Interferon and ribavirin combination therapy.But, only 50% curer has reaction, and interferon to the method With obvious side effect, such as flu-like symptoms, body weight lower and fatigue and weak, and interferon Then produce sizable side effect with ribavirin combination therapy, including haemolysis, anemia and tired etc..
The medicine for treating HCV infection developed includes protease inhibitors, tetrahydrothiazole derivates, thiophene Oxazolidine and N- benzanilides, phenanthrenequione, helicase inhibitors, nucleoside polymerase inhibitor and gliotoxin, Antisense phosphorothioate ester oligonucleotides, ribozyme and nucleoside analog etc..
Although the medicine of current HCV-Ab IgG infection clinically achieves some successes, there is still a need for opening The compound for sending out structure type more, curative effect is infected to obtain more excellent HCV-Ab IgG.
The content of the invention
It is an object of the present invention to provide compound or its stereoisomer, medicine that a class has general formula I Acceptable salt, solvate or prodrug on,
Wherein：
Cy is selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, described cycloalkyl, Heterocyclylalkyl, virtue Base and heteroaryl optionally by one or more halogens, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, Halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino Acyl group, nitro, cyano group substitution；
R1、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them2It is hydrogen, alkyl Or alkoxy；Or R2、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them1 It is hydrogen, alkyl or alkoxy；
R4、R5Each stand alone as hydrogen or alkyl；
X1It is N (R6) or O, R6Selected from H and alkyl, the alkyl is optionally by one or more alkyl, ring Alkyl, Heterocyclylalkyl, alkoxy, alkyl amino, halogen, hydroxyl, amino, nitro, cyano group, alkyl acyl The substitution of base, aminoacyl, alkylamino acyl group, sulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl；
X2Selected from C (R7) and N (R8)；If X2Selected from C (R7), then X3Selected from C (R9), and X2、X3Between The key of dotted line represent double bond；If X2Selected from N (R8), then X3It is carbonyl, and X2、X3Between dotted line Key represent singly-bound；R7、R8、R9Independently selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, heterocycle Alkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl Acyl group, aminoacyl, alkylaminoacyl, nitro and cyano group；
M is 0,1,2 or 3.
It is a further object to provide prepare compounds of formula I of the invention or its stereoisomer, The method of pharmaceutically acceptable salt, solvate or prodrug.
It is also another object of the present invention to provide comprising compounds of formula I of the invention or its stereoisomer, The composition of pharmaceutically acceptable salt, solvate or prodrug and pharmaceutically acceptable carrier, and comprising this The compounds of formula I of invention or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug and Another composition of the medicine of or various viral infection resisting diseases.
It is of the invention that offer compounds of formula I of the invention or its stereoisomer, pharmacy are provided Upper acceptable salt, solvate or prodrug treatment disease of viral infection, especially treat HCV The method of disease that infection causes, and compounds of formula I of the invention or its stereoisomer, pharmaceutically Acceptable salt, solvate or prodrug are being prepared for treating disease of viral infection, especially treat the third type Application in the medicine of the disease that hepatites virus infections cause.
For above-mentioned purpose, the present invention provides following technical scheme：
Wherein：
Cy is selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, described cycloalkyl, Heterocyclylalkyl, virtue Base and heteroaryl optionally by one or more halogens, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, Halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino Acyl group, nitro, cyano group substitution；
R1、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them2It is hydrogen, alkyl Or alkoxy；Or R2、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them1 It is hydrogen, alkyl or alkoxy；R4、R5Each stand alone as hydrogen or alkyl；
X1It is N (R6) or O, R6Selected from H and alkyl, the alkyl is optionally by one or more alkyl, ring Alkyl, Heterocyclylalkyl, alkoxy, alkyl amino, halogen, hydroxyl, amino, nitro, cyano group, alkyl acyl The substitution of base, aminoacyl, alkylamino acyl group, sulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl；
X2Selected from C (R7) and N (R8)；If X2Selected from C (R7), then X3Selected from C (R9), and X2、X3Between The key of dotted line represent double bond；If X2Selected from N (R8), then X3It is carbonyl, and X2、X3Between dotted line Key represent singly-bound；R7、R8、R9Independently selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, heterocycle Alkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl Acyl group, aminoacyl, alkylaminoacyl, nitro and cyano group；
M is 0,1,2 or 3.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
Cy is selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, the cycloalkyl, Heterocyclylalkyl, aryl Can be by one or more halogens, hydroxyl, amino, carboxyl, cyano group, nitro, C with heteroaryl1-6Alkyl, C3-8 Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Alkoxy, halo C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6 Alkyl, carboxyl C1-6Alkyl, cyano group C1-6Alkyl, nitro C1-6Alkyl, cycloalkyl C1-6Alkyl, C3-8It is miscellaneous Cycloalkyl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, list C1-6Alkyl amino, list C1-6Alkyl amino C1-6 Alkyl, double C1-6Alkyl amino, double C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkyl acyl Base C1-6Alkyl, C1-6Alkoxyacyl, C1-6Alkoxyacyl C1-6Alkyl, C1-6Alkyl acyl epoxide, C1-6Alkyl acyl epoxide C1-6Alkyl, aminoacyl, aminoacyl C1-6Alkyl, list C1-6Alkyl amino acyl Base, list C1-6Alkylaminoacyl C1-6Alkyl, double C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl C1-6Alkyl, C1-6Alkyl acylamino or C1-6Alkyl acylamino C1-6Alkyl replaces；
It is further preferred that Cy is selected from C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C6-10Aryl, C6-10Heteroaryl Base, the cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can by one or more halogens, hydroxyl, amino, Carboxyl, cyano group, nitro, C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Alkoxy, halo C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano group C1-6Alkyl, nitro C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C3-8Heterocyclylalkyl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, Single C1-6Alkyl amino, list C1-6Alkyl amino C1-6Alkyl, double C1-6Alkyl amino, double C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkyl acyl C1-6Alkyl, C1-6Alkoxyacyl, C1-6Alkoxy Acyl group C1-6Alkyl, C1-6Alkyl acyl epoxide, C1-6Alkyl acyl epoxide C1-6Alkyl, aminoacyl, ammonia Base acyl group C1-6Alkyl, list C1-6Alkylaminoacyl, list C1-6Alkylaminoacyl C1-6Alkyl, double C1-6 Alkylaminoacyl, double C1-6Alkylaminoacyl C1-6Alkyl, C1-6Alkyl acylamino or C1-6Alkyl acyl Base amino C1-6Alkyl replaces；
It is further preferred that Cy is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, piperazine Piperazine base, morpholinyl, nafoxidine base, tetrahydrofuran base, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrroles Base, thienyl, furyl, indyl, isoindolyl and quinolyl, the cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, piperidyl, piperazinyl, morpholinyl, nafoxidine base, tetrahydrofuran base, phenyl, naphthyl, Pyridine radicals, pyrimidine radicals, pyrrole radicals, thienyl, furyl, indyl, isoindolyl and quinolyl can be by one Individual or multiple halogens, hydroxyl, amino, carboxyl, cyano group, nitro, C1-6Alkyl, C3-8Cycloalkyl, C3-8 Heterocyclylalkyl, C1-6Alkoxy, halo C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6 Alkyl, cyano group C1-6Alkyl, nitro C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C3-8Heterocyclylalkyl C1-6 Alkyl, C1-6Alkoxy C1-6Alkyl, list C1-6Alkyl amino, list C1-6Alkyl amino C1-6Alkyl, double C1-6 Alkyl amino, double C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkyl acyl C1-6Alkyl, C1-6Alkoxyacyl, C1-6Alkoxyacyl C1-6Alkyl, C1-6Alkyl acyl epoxide, C1-6Alkyl acyl oxygen Base C1-6Alkyl, aminoacyl, aminoacyl C1-6Alkyl, list C1-6Alkylaminoacyl, list C1-6Alkyl Aminoacyl C1-6Alkyl, double C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl C1-6Alkyl, C1-6 Alkyl acylamino or C1-6Alkyl acylamino C1-6Alkyl replaces.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
R1It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R2、R3Constituted together with the atom being connected with them 2,3- Dihydrobenzofuranes；Or R2It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R1、R3With they institute The atom of connection constitutes 2,3- Dihydrobenzofuranes together；R4、R5Each stand alone as hydrogen or C1-6Alkyl；
It is further preferred that R1It is hydrogen, C1-3Alkyl or C1-3Alkoxy, and R2、R3It is connected with them Atom constitute 2,3- Dihydrobenzofuranes together；Or R2It is hydrogen, C1-3Alkyl or C1-3Alkoxy, and R1、R32,3- Dihydrobenzofuranes are constituted together with the atom being connected with them；R4、R5It is respectively hydrogen, C1-3 Alkyl；
It is further preferred that R1It is hydrogen, methoxyl group, ethyoxyl, propoxyl group, and R2、R3With they institute The atom of connection constitutes 2,3- Dihydrobenzofuranes together；Or R2It is hydrogen, methoxyl group, ethyoxyl, the third oxygen Base, and R1、R32,3- Dihydrobenzofuranes are constituted together with the atom being connected with them；R4、R5Each solely Stand is hydrogen, methyl, ethyl, propyl group.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
X1It is N (R6), R6Selected from H and C1-6Alkyl, the alkyl is optionally by one or more alkyl, ring Alkyl, Heterocyclylalkyl, alkoxy, alkyl amino, halogen, hydroxyl, amino, nitro, cyano group, alkyl acyl The substitution of base, aminoacyl, alkylamino acyl group, sulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl；
It is further preferred that R6Selected from H and C1-3Alkyl, described alkyl and cycloalkyl can by one or Multiple C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Alkoxy, C1-6Alkyl amino, halogen, Hydroxyl, amino, nitro, cyano group, C1-6Alkyl acyl, aminoacyl, C1-6Alkylamino acyl group, sulfonyl, The substitution of sulfinyl, sulfydryl, aryl or heteroaryl.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
X2Selected from C (R7), X3Selected from C (R9), and X2、X3Between the key of dotted line represent double bond.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
X2Selected from N (R8), X3It is carbonyl, and X2、X3Between the key of dotted line represent singly-bound.
In some preferred embodiments, the present invention provide compounds of formula I of the invention or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
Cy is phenyl, its optionally by one or more halogens, hydroxyl, alkyl, cycloalkyl, haloalkyl, Alkoxy, halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl acyl, aminoacyl, Alkylaminoacyl, nitro, cyano group substitution；
R1It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R2、R3Constituted together with the atom being connected with them 2,3- Dihydrobenzofuranes；Or R2It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R1、R3With they institute The atom of connection constitutes 2,3- Dihydrobenzofuranes together；
R4、R5Each stand alone as hydrogen or C1-6Alkyl；
X1It is N (R6), R6Selected from H and C1-6Alkyl；
X2Selected from C (R7) and N (R8)；If X2Selected from C (R7), then X3Selected from C (R9), and X2、X3Between The key of dotted line represent double bond；If X2Selected from N (R8), then X3It is C (O), and X2、X3Between dotted line Key represent singly-bound；R7、R8、R9Independently selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, heterocycle Alkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl Acyl group, aminoacyl, alkylaminoacyl, nitro and cyano group；
M is 0,1,2 or 3.
In some specific embodiments, compound of the invention be compounds of formula I or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, wherein：
R7、R8、R9Be each independently selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, Heterocyclylalkyl, Haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl amino, alkyl acylamino, alkyl acyl, Aminoacyl, alkylaminoacyl, nitro and cyano group；
It is further preferred that R7、R8、R9It is each independently selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, C3-8 Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, amino, C1-6 Alkyl amino, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, Nitro and cyano group；
It is further preferred that R7、R8、R9It is each independently selected from hydrogen, halogen, hydroxyl, C1-3Alkyl, C3-6Cycloalkyl, C3-6Heterocyclylalkyl, C1-3Haloalkyl, C1-3Alkoxy, C1-3Halogenated alkoxy, amino, C1-3Alkyl amino, C1-3Alkyl acylamino, C1-3Alkyl acyl, aminoacyl, C1-3Alkylaminoacyl, Nitro and cyano group.
In some embodiments, the invention provides compound in detail below：
On the other hand, the present invention provides the preparation method of compound of Formula I of the invention, and the method includes following Step：
A) compound of formula (1) carries out esterification under acid catalysis with alcohol, obtains the compound of formula (2)；
B) compound of formula (3) is obtained by substitution, condensation reaction for the compound of formula (2)；
C) halogenated compound of formula (4) is obtained with copper halide reaction for the compound of formula (3)；
D) compound of formula (4) hydrolyze in the basic conditions formula (5) compound；
E) amino-compound of formula (6) is obtained by Curtius rearrangement reactions, decarboxylic reaction for the compound of formula (5)；
F) fused ring compound of formula (7) is obtained by annelation for the compound of formula (6)；
G) compound of formula (8) is obtained by commonly using preparation method for the compound of formula (7)；
H) compound of formula (I) is obtained by Suzuki reactions for the compound of formula (8).
Wherein, X is halogen, is preferably selected from chlorine, bromine, and M is alkyl, is preferably selected from C1-6Alkyl, R1、 R2、R3、R4、R5、X1、X2、X3, Cy, m be as defined in formula above I.
The third aspect, the present invention provide pharmaceutical composition, its include compound shown in formula I of the invention or its Stereoisomer, pharmaceutically acceptable salt, solvate or prodrug and pharmaceutically acceptable carrier.
Can be by compound shown in formula I of the invention or its stereoisomer, pharmaceutically acceptable salt, molten Agent compound or prodrug are prepared by mixing into pharmaceutical preparation with pharmaceutically acceptable carrier, diluent or excipient, with It is suitable for oral or parenteral.Medication includes, but are not limited to intracutaneous, intramuscular, intraperitoneal, vein Interior, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, for example by infusion or Inject, the approach absorbed by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) is applied.Administration Can be whole body or part.The example of oral administration preparation includes solid or liquid dosage form, specifically, Including tablet, pill, granula, pulvis, capsule, syrup, emulsion, supensoid agent etc..The preparation can lead to Methods known in the art preparation is crossed, and comprising the conventional use of carrier of field of pharmaceutical preparations, diluent or figuration Agent.
Fourth aspect, the present invention provides compound shown in formula I of the invention or its stereoisomer, pharmaceutically Acceptable salt, solvate or prodrug or medicine composite for curing viral infectious diseases of the invention are controlled The method for the treatment of person, including apply compounds of formula I or its stereoisomer, pharmaceutically to the subject Acceptable salt, solvate or prodrug or comprising compounds of formula I or its stereoisomer, pharmaceutically The pharmaceutical composition of acceptable salt, solvate or prodrug, effectively to reduce disease described in the subject The amount of the virus load of poison is applied.In one embodiment, the present invention is provided to treat and/or pre- diseases prevention The method of poison infection such as HCV virus infection, including give chemical combination of the invention to the individuality for needing this to treat Thing or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug or its pharmaceutical composition.Another In one embodiment, the present invention provides the method for suppressing virus infection such as HCV virus infection, including makes The virus and the compound of the invention of therapeutically effective amount or its stereoisomer, pharmaceutically acceptable salt, Solvate or prodrug or its pharmaceutical composition thereof.
On the other hand, the present invention provides compound shown in formula I of the invention or its stereoisomer, pharmaceutically Acceptable salt, solvate or prodrug are used to prevent or treat viral infection, especially HCV virus sense The application of disease, and the application in the medicine for preparing prevention and/or treatment viral infectious diseases are contaminated, it is special It is not to prepare prevention and/or treatment HCV virus infection, such as in the medicine of HCV virus hepatitis disease Using.The example of such disease has acute hepatitis C, chronic hepatitis C and hepatitis C and hepatitis B Or the mixed infection of hepatitis D.
Term is defined
Unless otherwise defined, all technologies used herein and scientific terminology have general with of the art The identical implication that logical technical staff is generally understood that.
" stereoisomer " in the present invention refers to that spatially arrangement mode is different produced by atom in molecule Isomers.Including cis-trans-isomer, enantiomter and rotamer.All stereoisomers are belonged to The scope of the present invention.The independent stereoisomer of compound of the invention can be substantially free of other isomers or can To be mixed into such as racemic modification, or mix with all other stereoisomer.
" pharmaceutically acceptable salt " in the present invention refers to the pharmacy that compound of the present invention is formed with acid Upper acceptable salt, described acid for example may be selected from, but be not limited to：Phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, maleic acid, malonic acid, mandelic acid, butanedioic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, P-methyl benzenesulfonic acid, malic acid, Loprazolam or its analog.
" solvate " in the present invention refers in a conventional sense solute (such as reactive compound, reactive compound Salt) and solvent (such as water) combination formed compound.Solvent refers to known to those of skill in the art or easy The solvent of determination.If water, then solvate is commonly referred to as hydrate, such as monohydrate, two hydrations Thing, trihydrate etc..
Under " prodrug " in the present invention refers to the physiological condition in organism, due to the reaction such as enzyme, hydrochloric acid in gastric juice and The compound of the compound of a conversion accepted way of doing sth (I), i.e., convert an accepted way of doing sth (I) by the oxidation of enzyme, reduction, hydrolysis etc. Compound compound and/or a conversion accepted way of doing sth such as the hydrolysis by hydrochloric acid in gastric juice etc. (I) compound chemical combination Thing etc..
" pharmaceutical composition " in the present invention refers to comprising any compound as herein described including corresponding Isomers, prodrug, solvate, pharmaceutically acceptable salt or its chemical forms of protection, and it is a kind of or The mixture of various pharmaceutically acceptable carriers.The purpose of Pharmaceutical composition be promote compound on organism body to Medicine.The composition is commonly used for preparing treatment and/or prevents by one or more medicine of kinase mediated disease Thing.
" pharmaceutically acceptable carrier " in the present invention refers to not cause obvious irritation to organism and do not do The bioactivity of given compound and the carrier of property are disturbed, comprising all of solvent, diluent or other figurations Agent, dispersant, surfactant isotonic agent, thickener or emulsifying agent, preservative, solid binder, lubrication Agent etc..Unless any conventional carrier medium is incompatible with the compounds of this invention.Can be as pharmaceutically acceptable Some examples of carrier include, but are not limited to carbohydrate, such as lactose, dextrose and saccharose；Starch, such as corn form sediment Powder and farina；Cellulose and its derivates, such as sodium carboxymethylcellulose and cellulose and acetic acid are fine Dimension element；Malt, gelatin etc..
" alkyl " in the present invention refers to the saturated fat hydrocarbyl group of straight or branched, preferably containing 1 to 6 carbon atom Straight or branched group, further preferably 1 to the 3 straight or branched group of carbon atom is unrestricted Property example include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, N-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- first Base butyl, 3- methyl butyls, n-hexyl etc..Alkyl can be it is substituted or unsubstituted, when substituted, Substitution base can be on any usable tie point." haloalkyl " of the invention refers at least by a halogen The alkyl of atom substitution.
" cycloalkyl " in the present invention refers to the saturated hydrocarbyl of ring-type, the alkyl below preferably 8 carbon atoms.This " the C of invention3-8Cycloalkyl " refers to contain the 3-8 cyclic saturated hydrocarbon base of carbon atom." C of the invention3-6Cycloalkanes Base " refers to contain the 3-6 saturated hydrocarbyl of the straight or branched of carbon atom.
" alkoxy " in the present invention refers to-O- alkyl.
" halogen " in the present invention refers to fluorine, chlorine, bromine, iodine.
" alkyl amino " in the present invention refers to-NH- alkyl or-N- (alkyl) (alkyl).
" alkyl acyl " in the present invention refers to-C (O)-alkyl.
" aminoacyl " in the present invention refers to-C (O)-NH2, term " alkylamino acyl group " refers to-C (O)-NH- alkane Base or-C (O)-N- (alkyl) (alkyl).
" sulfonyl " in the present invention refers to-S (O)2- alkyl, term " sulfinyl " refers to-S (O)-alkyl.
" aryl " in the present invention refers to the aromatic hydrocarbon group containing one or more phenyl ring.Suitable aryl includes benzene Base, naphthyl.
" heteroaryl " in the present invention refers to the armaticity that at least one carbon atom is substituted by hetero atom in aryl Group.Described hetero atom is O, S, N.For example, heteroaryl described herein include but is not limited to pyridine radicals, Pyrazolyl, oxazolyls, thiazolyl, thienyl, furyl, pyrrole radicals, isoxazolyls, isothiazolyl, miaow Oxazolyl, triazolyl, tetrazole radical, oxadiazolyls, thiadiazolyl group, pyrimidine radicals, pyridazinyl, pyrazinyl and triazine Base.
" Heterocyclylalkyl " in the present invention refers at least containing a heteroatomic saturated cyclic group, wherein miscellaneous original Son is N, O or S.
"-NHMs " in the present invention is the abbreviation of sulfonyloxy methyl amido.
Specific embodiment
Representational embodiment is in order to the present invention is better described, not for limitation protection of the invention below Scope.
The N- of embodiment 1 (4- (4- methoxyl group -3,3- dimethyl -9- (2- oxo -1,2- dihydropyridine -3- bases) -2,3- dihydro furans Mutter simultaneously [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides
The preparation of the bromo- 3,5- methyl dihydroxy benzoates of step 1 4-
Bromo- 3, the 5- dihydroxy-benzoic acids (111.2g) of 4- are dissolved in methyl alcohol (400mL), the concentrated sulfuric acid (8mL) is added, Backflow 5h.Cooling, reaction solution is poured into water, and is filtered, and is dried, and obtains white solid state title compound.ESI-MS m/z:[M+H]+=247.0.
The preparation of step 2 4- bromo- 3- hydroxyls -5- (2- metacryloxies) methyl benzoate
The bromo- 3,5- methyl dihydroxy benzoates (116g) of obtained 4- in the step 1 of embodiment 1 are dissolved in acetone In (500mL), potassium carbonate (64.8g) is added, is warming up to backflow, the bromo- 2- metering systems (76.1g) of 3- are added dropwise, Back flow reaction 3h.Filtering, concentration, column chromatography obtains white solid state title compound.ESI-MS m/z:[M+H]+=301.0.
The preparation of step 3 4- hydroxyl -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- methyl formates
By the bromo- 3- hydroxyls -5- of obtained 4- (2- metacryloxies) methyl benzoate (47.7 in the step 2 of embodiment 1 G) it is dissolved in DMF/H2O(40:1) in (470mL), palladium (1.78g), etamon chloride one is added to be hydrated Thing (34.9g), sodium acetate (32.5g), sodium formate (12.9g), under argon gas protection, 90 DEG C of reaction 6h.Reaction After completely, ethyl acetate filtering is added, add saturated aqueous common salt, extraction merges organic layer, anhydrous sodium sulfate Dry, concentration, column chromatography purifying obtains title compound.ESI-MS m/z:[M+H]+=223.
The preparation of the bromo- 4- hydroxyls -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- methyl formates of step 4 7-
By obtained 4- hydroxyls -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- methyl formates in the step 3 of embodiment 1 (18.6g) is dissolved in acetonitrile (180mL), adds copper bromide (37.4g), is stirred overnight, and adds ethyl acetate, mistake Filter, concentration, column chromatography purifying obtains white solid state title compound.ESI-MS m/z:[M+H]+=315.
The preparation of the bromo- 4- methylols -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- formic acid of step 5 7-
By the bromo- 4- hydroxyls -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- first of obtained 7- in the step 4 of embodiment 1 Sour methyl esters (12.5g) is dissolved in DMF (125mL), is cooled to 0 DEG C, adds NaH (60%, 2.17g), 30min is stirred at 0 DEG C, iodomethane (8.87g) is added dropwise, after reaction 2h, add ethyl acetate and water extraction, Organic layer anhydrous sodium sulfate drying, concentration, concentrate THF/H2O(1:1,120mL) dissolve, add NaOH (6.67g), flowed back 8h, and concentration removes THF, and concentrated hydrochloric acid regulation pH 3-4, filtering is dried, obtained White solid state title compound.ESI-MS m/z:[M+H]+=301.
The preparation of the bromo- 4- methylols -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- amino of step 6 7-
By the bromo- 4- methylols -3,3- dimethyl -2,3- Dihydrobenzofuranes -6- of obtained 7- in the step 5 of embodiment 1 Formic acid (13g) is dissolved in the tert-butyl alcohol (100mL), adds triethylamine (4.8g), DPPA (13.1g), backflow 4h. After completion of the reaction, concentration removes the tert-butyl alcohol, ethyl acetate dissolving is added, successively with 1M citric acids, saturation NaHCO3, saturated common salt water washing, concentration, dry, add HCl ethyl acetate solution, be stirred overnight, Filtering, uses petroleum ether：Ethyl acetate=2：1 mixed solution is washed, and obtains grey solid title compound.ESI-MS m/z:[M+H]+=272.
The preparation of the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of step 7 6,9- bis- simultaneously [3,2-g] quinoline
2- bromopropenes aldehyde (1.2g) are dissolved in acetic acid (35mL), Br is added dropwise2The acetum (35mL) of (1.07g), 15min is stirred at room temperature.By the bromo- 4- methylols -3,3- dimethyl -2,3- two of obtained 7- in the step 6 of embodiment 1 Hydrogen benzofuran -6- amino (2.3g) is added in above-mentioned solution, and 60 DEG C of reaction about 0.5h, concentration removes acetic acid, Ethyl acetate is added, saturated sodium bicarbonate aqueous solution extraction merges organic layer, and concentration, column chromatography purifying is obtained Faint yellow solid-state title compound.ESI-MS m/z:[M+H]+=386.
Step 8 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl) -3- methyl-N- benzene The preparation of base Methanesulfomide
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (1.2g), 3- methyl -4- pinacol borates-N- phenyl methanesulfonamides acid amides (1.06g), sodium carbonate (0.98 G) with Pd (PPh3)4(0.36g) is dissolved in ethanol/methylene (2:1,10mL), 90 DEG C of microwave 30min, concentration Reaction solution, column chromatography purifying, obtains faint yellow solid compounds.ESI-MS m/z:[M+H]+=491.
Step 9 N- (4- (4- methoxyl group -3,3- dimethyl -9- (2- oxo -1,2- dihydropyridine -3- bases) -2,3 dihydro furans And [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides preparation
By obtained 4- in the step 8 of embodiment 1, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methyl-N-phenyls Methanesulfomide (125mg), (2- oxo -1,2- dihydropyridine -3- bases) boric acid (42.35mg), sodium carbonate (81mg) and Pd (PPh3)4(29.5mg) is dissolved in methanol/toluene (2:1,2mL), 120 DEG C Microwave 65min, preparative separation obtains canescence solid-state title compound.1H-NMR(300MHz,DMSO-d6): δ 1.52 (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.
The N- of embodiment 2 (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl - 2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides
By obtained 4- in the step 8 of embodiment 1, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methyl-N-phenyls Methanesulfomide (0.25g), 2,6- dimethoxy -3- pyridine boronic acids (0.1g), Sodium carbonate (0.16g) and Pd (PPh3)4(0.058g) is dissolved in methanol/toluene (2:1,2mL), 120 DEG C of microwave 65min, Dissolved with acetic acid (2mL) after concentration, add HBr (0.2mL), reaction is complete after stirring 1.5h at 60 DEG C, Concentration, preparative separation obtains canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 3 (4- (4- methoxyl groups -9- (6- methyl -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides
By obtained 4- in the step 8 of embodiment 1, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methyl-N-phenyls Methanesulfomide (250mg), 2- methoxyl group -6- picoline -3- ylboronic acids (85.68mg), sodium carbonate (161.9mg) and Pd (PPh3)4(58.8mg) is dissolved in methanol/toluene (2:1), 120 DEG C Microwave 65min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, Concentration, preparative separation obtains canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.51 (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.
The N- of embodiment 4 (4- (9- (2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- bases) -4- methoxyl group -3,3- dimethyl -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides
By obtained 4- in the step 8 of embodiment 1, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methyl-N-phenyls Methanesulfomide (250mg), 2,4- dimethoxypyridin -5- boric acid (93.67 Mg), sodium carbonate (161.9mg) and Pd (PPh3)4(58.8mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwaves 65 Min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, concentration, system Back-up from canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.51 (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.
The N- of embodiment 5 (4- (9- (the fluoro- 2- oxos -1,2- dihydropyridines -3- bases of 5-) -4- methoxyl group -3,3- dimethyl -2,3- two Hydrogen furans simultaneously [3,2-g] quinoline -6- bases) -3- aminomethyl phenyls) methylsulfonamides
By obtained 4- in the step 8 of embodiment 1, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methyl-N-phenyls Methanesulfomide (250mg), 2- methoxyl group -5- fluorine pyridine -3- boric acid (85.68 Mg), sodium carbonate (161.9mg) and Pd (PPh3)4(58.8mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwaves 65 Min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, concentration, system Back-up from canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.53 (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.
The N- of embodiment 6 (4- (9- (2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- bases) -4- methoxyl group -3,3- dimethyl -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
Step 1 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl)-N- phenyl methanesulfonamides The preparation of acid amides
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (650mg), 4- pinacol borates-N- phenyl methanesulfonamides acid amides (438.67mg), sodium carbonate (427 ) and Pd (PPh mg3)4(155mg) is dissolved in ethanol/methylene (2:1,10mL), 90 DEG C of microwave 30min. Column chromatography obtains faint yellow solid-state title compound.ESI-MS m/z:[M+H]+=477.
Step 2 N- (4- (9- (2,4- dioxo -1,2,3,4- tetrahydropyrimidine -5- bases) -4- methoxyl group -3,3- dimethyl -2,3- two Hydrogen furans simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides preparation
By obtained 4- in the step 1 of embodiment 6, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl)-N- phenyl methanesulfonamides acid amides (120mg), 2,4- dimethoxypyridin -5- boric acid (53.4mg), carbon Sour sodium (80.2mg) and Pd (PPh3)4(29mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwave 65min, concentration Acetate dissolution is used afterwards, HBr is added, and reaction is complete after stirring 1.5h at 60 DEG C, and concentration, preparative separation is obtained Canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 7 (4- (4- methoxyl group -3,3- dimethyl -9- (2- oxo -1,2- dihydropyridine -3- bases) -2,3- dihydro furans Mutter simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
By obtained 4- in the step 1 of embodiment 6, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl)-N- phenyl methanesulfonamides acid amides (100mg), (2- oxo -1,2- dihydropyridine -3- bases) boric acid (58.2 Mg), sodium carbonate (66mg) and Pd (PPh3)4(24mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwave 65min, Preparative separation obtains white solid state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.53 (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.
The N- of embodiment 8 (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl - 2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
By obtained 4- in the step 1 of embodiment 6, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl)-N- phenyl methanesulfonamides acid amides (100mg), 2,4- dimethoxy-pyridine -5- boric acid (92mg), carbonic acid Sodium (132mg) and Pd (PPh3)4(48.4mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwave 65min, concentration Acetate dissolution is used afterwards, HBr is added, and reaction is complete after stirring 1.5h at 60 DEG C, and concentration, preparative separation is obtained Canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 9 (4- (4- methoxyl group -3,3- dimethyl -9- (6- methyl -2- oxo -1,2- dihydropyridine -3- bases) -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
By obtained 4- in the step 1 of embodiment 6, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl)-N- phenyl methanesulfonamides acid amides (200mg), 2- methoxyl groups -6- picoline -3- ylboronic acids (84mg), Sodium carbonate (132mg) and Pd (PPh3)4(48.4mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwave 65min, Acetate dissolution is used after concentration, HBr is added, reaction is complete after 60 DEG C of stirring 1.5h, concentration is prepared and divided From canescence solid-state title compound.1H-NMR(300MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 10 (the fluoro- 4- of 3- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- diformazans Base -2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
Step 1 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl) fluoro- N- phenyl of -3- The preparation of Methanesulfomide
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (250mg), the fluoro- N- phenyl methanesulfonamides acid amides (224mg) of 3- methyl -4- pinacol borates -3-, carbon Sour sodium (205mg) and Pd (PPh3)4(74.6mg) is dissolved in ethanol/methylene (2:1,10mL), 90 DEG C of microwaves 30min, concentration of reaction solution, column chromatography purifying obtains faint yellow solid-state title compound.ESI-MS m/z:[M+H]+=495.
Step 2 N- (the fluoro- 4- of 3- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl - 2,3 dihydro furan simultaneously [3,2-g] quinoline -6 base) phenyl) methylsulfonamides preparation
By obtained 4- in the step 1 of embodiment 10, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) the fluoro- N- phenyl methanesulfonamides acid amides (100mg) of -3-, 2,4- dimethoxy-pyridine -5- boric acid (44.5mg), Sodium carbonate (64.3mg) and Pd (PPh3)4(23.4mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwave 65min, Acetate dissolution is used after concentration, HBr is added, reaction is complete after 60 DEG C of stirring 1.5h, concentration is prepared and divided From canescence solid-state title compound.1H-NMR(500MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 11 (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl - 2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) -3- trifluoromethyls) methylsulfonamides
Step 1 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl) -3- trifluoromethyls The preparation of-N- phenyl methanesulfonamide acid amides
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (650mg), 4- pinacol borates -3- trifluoromethyls-N- phenyl methanesulfonamides acid amides (735.7mg), Sodium carbonate (427mg) and Pd (PPh3)4(155mg) is dissolved in ethanol/methylene (2:1,10mL), 90 DEG C it is micro- Ripple 30min, concentration of reaction solution, column chromatography purifying obtains faint yellow solid-state title compound.ESI-MS m/z:[M+H]+=545.
Step 2 N- (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) -3- trifluoromethyls) methylsulfonamides preparation
By obtained 4- in the step 1 of embodiment 11, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- trifluoromethyls-N- phenyl methanesulfonamides acid amides (100mg), 2,4- dimethoxy-pyridine -5- boric acid (44.5mg), sodium carbonate (64.3mg) and Pd (PPh3)4(23.4mg) is dissolved in methanol/toluene (2:1), 120 DEG C it is micro- Ripple 65min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, dense Contracting, preparative separation obtains canescence solid-state title compound.1H-NMR(300MHz,DMSO-d6):δ 1.53 (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.
The N- of embodiment 12 (3- methoxyl groups -4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- Dimethyl -2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides
Step 1 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl) -3- methoxyl groups-N- The preparation of phenyl methanesulfonamide acid amides
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (650mg), 4- pinacol borates -3- Methoxy-N-phenyls Methanesulfomide (735.7mg), carbon Sour sodium (427mg) and Pd (PPh3)4(155mg) is dissolved in ethanol/methylene (2:1,10mL), 90 DEG C of microwaves 30min.Column chromatography obtains faint yellow solid-state title compound.ESI-MSm/z:[M+H]+=507.
Step 2 N- (3- methoxyl groups -4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- two Methyl -2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) phenyl) methylsulfonamides preparation
By obtained 4- in the step 1 of embodiment 12, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3- Methoxy-N-phenyls Methanesulfomide (500mg), 2,4- dimethoxy-pyridine -5- boric acid (217mg), sodium carbonate (314mg) and Pd (PPh3)4(114mg) is dissolved in methanol/toluene (2:1), 120 DEG C of microwaves 65min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, concentration, Preparative separation obtains canescence solid-state title compound.1H-NMR(300MHz,DMSO-d6):δ 1.52 (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.
The N- of embodiment 13 (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl - 2,3 dihydro furan simultaneously [3,2-g] quinoline -6- bases) -3,5- 3,5-dimethylphenyls) methylsulfonamides
Step 1 4- (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- simultaneously [3,2-g] quinolyl) -3,5- dimethyl The preparation of-N- phenyl methanesulfonamide acid amides
By the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of obtained 6,9- bis- in the step 7 of embodiment 1 simultaneously [3,2-g] quinoline (650mg), 4- pinacol borates -3,5- dimethyl-N-phenyls Methanesulfomide (545.9mg), carbon Sour sodium (427mg) and Pd (PPh3)4(155mg) is dissolved in ethanol/methylene (2:1) (10mL), 90 DEG C of microwaves 30min, column chromatography obtains faint yellow solid-state title compound.ESI-MS m/z:[M+H]+=505.
Step 2 N- (4- (4- methoxyl groups -9- (6- methoxyl group -2- oxo -1,2- dihydropyridine -3- bases) -3,3- dimethyl -2,3- Dihydrofuran simultaneously [3,2-g] quinoline -6- bases) -3,5- 3,5-dimethylphenyls) methylsulfonamides preparation
By obtained 4- in the step 1 of embodiment 13, (the bromo- 4- methoxyl groups -3,3- dimethyl -2,3 dihydro furans of 9- are simultaneously [3,2-g] quinolyl) -3,5- dimethyl-N-phenyls Methanesulfomide (300mg), 2,4- dimethoxy-pyridine -5- boric acid (130mg), sodium carbonate (68.64mg) and Pd (PPh3)4(189mg) is dissolved in methanol/toluene (2:1), 120 DEG C it is micro- Ripple 65min, uses acetate dissolution after concentration, add HBr, and reaction is complete after stirring 1.5h at 60 DEG C, dense Contracting, preparative separation obtains canescence solid-state title compound.1H-NMR(300MHz,DMSO-d6):δ 1.53 (s, 6H, 2CH3), 2.01 (s, 6H, 2ArCH 3), 3.05 (s, 3H, SCH 3), 3.84 (s, 3H, NHCOCH3 ), 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.
Pharmacological activity is evaluated
Activity skew test in the compound serum of the invention of experimental example 1
1. experiment material
1.1 reagents:
The reagent list of table 1.
Reagent name Supplier
DMEM cell culture fluids Invitrogen
Hyclone Corning
Human serum Sigma
Glutamine Invitrogen
Pen .- Strep Hyclone
Non-essential amino acid additive Invitrogen
Screening antibiotic G418 Invitrogen
Phosphate buffer Hyclone
Pancreatin Invitrogen
Dimethyl sulfoxide (DMSO) (DMSO) Sigma
Bright-Glo detection reagents Promega
1.2HCV 1a and 1b replicon cells:
HCV 1a are prepared by the way that HCV genotype 1a or 1b replicon stabilization are transferred into Huh7 cell lines With 1b replicon cells.Huh71a and 1b cell lines are carried by Shanghai Yaoming Kangde New Medicine Development Co., Ltd For being HCV 1a or HCV the 1b replicons comprising luciferase (Luc) report with stabilization Huh7 cell lines.It passes through gene recombination technology by HCV nonstructural protein genes, neo (G418 resistances) And luciferase reporter gene is cloned into pBR vector constructions.Then the carrier of HCV replicons will be carried Be transfected into huh7 cells, by G418 resistance screenings, HCV replicons can stablize replicate and GAP-associated protein GAP and Luciferase is expressed in huh7 cell inner stablities.The cell model is screened for HCV-Ab IgG Compound ira vitro. The activity of the HCV-Ab IgG of compound is determined by checking the expression of luciferase.Referring to Lohmann V, et al.1999.Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.Science.285(5424):110-113.
1.3 compounds：The compound prepared in above example of the present invention, 10mM is configured to 100%DMSO Mother liquor, in temporary nitrogen cabinet.
2. experimental technique
1) compound treatments：96 holes will be added to test after the DMSO mother liquors dilution of embodiments of the invention compound In plate.Final compound concentration is up to 1 μM, three times gradient dilution, totally 10 concentration.DMSO ends Concentration is 0.5%.
2) cells treatment：Planted in above-mentioned 96 porocyte plates into HCV-1a and HCV-1b replicon cells, often Hole inoculating cell number is 8 × 103Individual cells/well, is subsequently placed at 37 DEG C, 5%CO2Cultivated in incubator 3 days.
3) HCV-Ab IgGs replicon Activity determination：Add luciferase luminous substrate Bright-Glo per hole, used in 5 minutes Chemiluminescence detection system Envision detects Luminescence signal values, initial data (RLU) Calculated for compound inhibitory activity.
4) data processings：Using equation below by original data processing be suppression percentage：
CPD：The signal value of compound well
HPE(Hundred percent effect):100% useful effect control wells signal value, in hole only DMEM nutrient solutions
ZPE(Zero percent effect):Invalid effect control wells signal value, chemical combination is replaced with 0.5%DMSO Thing.
Suppression percentage importing GraphPad Prism softwares are carried out into data processing and draws the corresponding song of compound Line and the inhibitory activity (EC to HCV replicons50) numerical value.Partial data is shown in Table 2.
Table 2
Above experimental result can be seen that compound of the invention has the ability for preferably suppressing HCV virus, Promise to be very much HCV therapy agent.
Although being below described in detail to the present invention, however it is understood by skilled practitioners that without departing from On the premise of the spirit and scope of the present invention various modifications and changes can be carried out to the present invention.Right of the invention Scope is not limited to the detailed description made above, and should belong to claims.

Claims (10)

1. the compound or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug shown in a kind of formula I：
Wherein：
Cy is selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and described cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are appointed Choosing is by one or more halogens, hydroxyl, alkyl, cycloalkyl, haloalkyl, alkoxy, halogenated alkoxy, amino, alkyl The substitution of amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, nitro or cyano group；
R1、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them2It is hydrogen, alkyl or alkoxy；Or Person R2、R32,3- Dihydrobenzofuranes, and R are constituted together with the atom being connected with them1It is hydrogen, alkyl or alkoxy；
R4、R5Each stand alone as hydrogen or alkyl；
X1It is N (R6) or O, R6Selected from H and alkyl, the alkyl is optionally by one or more alkyl, cycloalkyl, heterocycle alkane Base, alkoxy, alkyl amino, halogen, hydroxyl, amino, nitro, cyano group, alkyl acyl, aminoacyl, alkylamino acyl The substitution of base, sulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl；
X2Selected from C (R7) and N (R8), if wherein X2Selected from C (R7), then X3Selected from C (R9), and X2、X3Between dotted line Key represent double bond；If X2Selected from N (R8), then X3It is carbonyl, and X2、X3Between the key of dotted line represent singly-bound；R7、 R8、R9Independently selected from hydrogen, halogen, hydroxyl, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, alkoxy, alkyl halide Epoxide, amino, alkyl amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, nitro and cyano group； With
M is 0,1,2 or 3.
2. compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug, Wherein Cy is selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and the cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl can By one or more halogens, hydroxyl, amino, carboxyl, cyano group, nitro, C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Alkoxy, halo C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano group C1-6Alkyl, Nitro C1-6Alkyl, cycloalkyl C1-6Alkyl, C3-8Heterocyclylalkyl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, list C1-6Alkyl Amino, list C1-6Alkyl amino C1-6Alkyl, double C1-6Alkyl amino, double C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl acyl, C1-6Alkyl acyl C1-6Alkyl, C1-6Alkoxyacyl, C1-6Alkoxyacyl C1-6Alkyl, C1-6Alkyl acyl epoxide, C1-6 Alkyl acyl epoxide C1-6Alkyl, aminoacyl, aminoacyl C1-6Alkyl, list C1-6Alkylaminoacyl, list C1-6Alkyl Aminoacyl C1-6Alkyl, double C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl C1-6Alkyl, C1-6Alkyl acylamino Or C1-6Alkyl acylamino C1-6Alkyl replaces.
3. compound according to claim 2 or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug, Wherein Cy be selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, piperazinyl, morpholinyl, nafoxidine base, Tetrahydrofuran base, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, thienyl, furyl, indyl, isoindolyl And quinolyl, the cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, piperidyl, piperazinyl, morpholinyl, nafoxidine base, Tetrahydrofuran base, phenyl, naphthyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, thienyl, furyl, indyl, isoindolyl Can be by one or more halogens, hydroxyl, amino, carboxyl, cyano group, nitro, C with quinolyl1-6Alkyl, C3-8Cycloalkyl, C3-8 Heterocyclylalkyl, C1-6Alkoxy, halo C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, cyano group C1-6Alkyl, nitro C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C3-8Heterocyclylalkyl C1-6Alkyl, C1-6Alkoxy C1-6Alkane Base, list C1-6Alkyl amino, list C1-6Alkyl amino C1-6Alkyl, double C1-6Alkyl amino, double C1-6Alkyl amino C1-6Alkane Base, C1-6Alkyl acyl, C1-6Alkyl acyl C1-6Alkyl, C1-6Alkoxyacyl, C1-6Alkoxyacyl C1-6Alkyl, C1-6 Alkyl acyl epoxide, C1-6Alkyl acyl epoxide C1-6Alkyl, aminoacyl, aminoacyl C1-6Alkyl, list C1-6Alkyl amino Acyl group, list C1-6Alkylaminoacyl C1-6Alkyl, double C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl C1-6Alkyl, C1-6Alkyl acylamino or C1-6Alkyl acylamino C1-6Alkyl replaces.
4. compound or its stereoisomer, pharmaceutically acceptable salt, solvent described in any one according to claim 1-3 Compound or prodrug, wherein R1It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R2、R3Constituted together with the atom being connected with them 2,3- Dihydrobenzofuranes；Or R2It is hydrogen, C1-6Alkyl or C1-6Alkoxy, and R1、R3The atom one being connected with them Rise and constitute 2,3- Dihydrobenzofuranes；R4、R5Each stand alone as hydrogen or C1-6Alkyl.
5. compound or its stereoisomer, pharmaceutically acceptable salt, solvent described in any one according to claim 1-3 Compound or prodrug, wherein X1It is N (R6), R6Selected from H and C1-6Alkyl, the alkyl is optionally by one or more C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C1-6Alkoxy, C1-6Alkyl amino, halogen, hydroxyl, amino, nitro, cyano group, C1-6Alkyl acyl, aminoacyl, C1-6The substitution of alkylamino acyl group, sulfonyl, sulfinyl, sulfydryl, aryl or heteroaryl.
6. compound or its stereoisomer, pharmaceutically acceptable salt, solvent described in any one according to claim 1-3 Compound or prodrug, wherein R7、R8、R9Independently selected from hydrogen, halogen, hydroxyl, C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocycle Alkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, amino, C1-6Alkyl amino, C1-6Alkyl acylamino, C1-6Alkyl acyl, aminoacyl, C1-6Alkylaminoacyl, nitro and cyano group.
7. compound according to claim 1 or its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug, Wherein described compound is selected from following compound：
8. a kind of pharmaceutical composition, compound or its stereoisomer, medicine described in its any one for including claim 1 to 7 Acceptable salt, solvate or prodrug and pharmaceutical acceptable carrier on.
9. it is compound described in any one of claim 1-7 or its stereoisomer, pharmaceutically acceptable salt, hydrate, molten The purposes of pharmaceutical composition described in agent compound or crystallization or claim 8 in the medicine for preparing treatment disease of viral infection.
10. purposes according to claim 9, wherein the disease that the disease of viral infection causes for 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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