CN106543162B - The quinoline derivatives and its preparation method and application of 3- heterocyclic substituted - Google Patents

The quinoline derivatives and its preparation method and application of 3- heterocyclic substituted Download PDF

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CN106543162B
CN106543162B CN201510616827.XA CN201510616827A CN106543162B CN 106543162 B CN106543162 B CN 106543162B CN 201510616827 A CN201510616827 A CN 201510616827A CN 106543162 B CN106543162 B CN 106543162B
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methyl
base
hydroxyl
methoxyl group
methylquinoline
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CN106543162A (en
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宫平
刘亚婧
赵燕芳
翟鑫
冯国兵
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The present invention relates to quinoline derivatives new shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein substituent R1、R2、R3, n there is the meaning that provides in the description.Has the function of strong inhibition HBV DNA replication dna the invention further relates to the compound of general formula I, and the purposes of such compound and its pharmaceutically acceptable salt, hydrate, solvate or prodrug in the drug that preparation treats due to HBV infection diseases caused is further related to, especially the purposes in preparation treatment and/or preventing viral hepatitis B medicament.

Description

The quinoline derivatives and its preparation method and application of 3- heterocyclic substituted
Technical field:
The present invention relates to quinoline derivatives and its pharmaceutically acceptable salt, hydration that new 3- position heterocycle replaces Object, solvate or its prodrug, their preparation method, the compound as made from equivalent means and contain the compound Pharmaceutical composition.The invention further relates to such compounds and its pharmaceutically acceptable salt, hydrate, solvate or prodrug to exist The purposes in the drug of hepatitis b virus infected diseases caused is treated in preparation.
Technical background:
Virus B hepatitis be by caused by hepatitis B (HBV), based on liver inflammatory lesion, and more devices can be caused A kind of disease of official's damage.Hepatitis B is widely current in countries in the world, and main infringement children and person between twenty and fifty, small number of patients can be converted into Cirrhosis or liver cancer.Therefore, it has become the worldwide disease for seriously threatening human health and China's current popular is the widest A kind of general, harmfulness most serious disease.Virus B hepatitis can fall ill throughout the year without certain epizootic modeling, but more Category distributes.
Hepatitis B becomes the main reason for hepatopathy is lethal.It is counted according to WHO, global about 2,000,000,000 people once infected HBV, wherein 400,000,000 Artificial Patients with Chronic HBV Infection, there are about ten thousand people of 50-70, to die of hepatic failure caused by HBV infection, cirrhosis and Primary Hepatic thin every year Born of the same parents' cancer.HBV infection is presented the situation of distribution on global, and China belongs to the Endemic Area HBV high, hepatitis B have in China " the first disease of China " it Claim, there are about 30,000,000 chronic hepatitis B patients, 1.2 hundred million hepatitis carriers.
Hepatitis type B virus abbreviation hepatitis B.It is a kind of DNA virus, belongs to Hepadnaviridae (hepadnavividae).According to currently known, HBV just only has neurological susceptibility to people and orangutan, causes virus B hepatitis disease Disease.Complete hepatitis B can also be referred to as red Na particle (Dane) at graininess.Hepatitis B breeds duplication in liver, but It is to be acted on without apparent coup injury liver cell.Hepatitis B is a kind of retrovirus, and the process of reverse transcription is to utilize What the archaeal dna polymerase of virus itself carried out.But due to hepatitis B replication need by pregenome RNA intermediate, It is easy to become at minus-strand dna, thus compared with other DNA virus using the archaeal dna polymerase reverse transcription that virus itself lacks check and correction enzymatic activity It is different.
The antigen of HBV has 3 kinds: surface antigen, core antigen and e antigen.Surface antigen is largely present in the infected's blood In, it is the outstanding feature of HBV infection and detection.It has antigenicity, can induce the Anti-HBs antibody that body generates specific protective, And prepare the main ingredient of vaccine.
Core antigen is made of 183 or 185 amino acid, hyperphosphorylation, is the unique of hepatitis B virus core particles Structural proteins.It just since it is present in Dane granular core body structure surface, is covered by surface antigen, therefore is not easy to examine in blood circulation Out.Core antigen has strongly immunogenic, can induce very strong humoral immunity and cellular immunity, stimulation body generates anti-HBc.
E antigen is soluble protein, and infectiousness is strong, free to be present in blood, although being found very early, in pathology On be considered hbv replication to have a strong infective index, but its function is unclear.The appearance of anti-HBe is prognosis Good sign.
Summary of the invention:
The object of the present invention is to provide a kind of new quinoline derivatives and preparation method thereof and its is pharmaceutically acceptable Salt, hydrate, solvate or prodrug, the pharmaceutical composition using the compound as active constituent is further related to, as antiviral Agent, to hepatitis B have significant inhibiting effect and they be used as anti-hepatitis virus agent and treat and prevent hepatitis B In application.The invention further relates to their preparation methods.Compound shown in its structural formula as I and its pharmaceutically acceptable Salt, hydrate, solvate or prodrug.
Wherein:
R1For 5-10 circle heterocyclic ring base, 5-10 unit's heteroaryl, the heterocycle or heteroaryl contain 1-3 and are selected from N, O or S Hetero atom, and optional 0-3 identical or different R of the heterocycle or heteroaryl4Replace；
R4For C1-C6Alkyl, C3-C7Naphthenic base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl, C1-C6Alkoxy, phenyl, benzyl, Free, at salt, esterification, acylated carboxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C10Alkyl, C3-C7Naphthenic base, C1-C4Alkoxy, C2- C10Alkenyl and C2-C10Alkynyl, they can be by 0-3 identical or different R5Optionally replace；
Or R2And R3It is formed together 5-10 circle heterocyclic ring base or 5-10 unit's heteroaryl with the nitrogen-atoms being connect with them, it is described Heterocycle or heteroaryl in addition to R2And R3Outside the nitrogen-atoms of connection, the hetero atom of N, O or S are optionally selected from containing 0-4, in addition to R2And R3Outside the nitrogen-atoms connected, the heterocycle optionally includes 0-2 carbon-carbon double bond or three key, the heterocycle and heteroaryl Base is optionally by 0-3 identical or different R5Replace；
R5For C1-C6Alkyl, C3-C7Naphthenic base, hydroxyl, halogen, C1-C6Alkoxy, trifluoromethyl, trifluoromethoxy, nitre Base；
N is the integer of 0-2, and n can be 0,1 or 2；
Ar is 6-10 member aryl, 5-10 unit's heteroaryl, wherein the heteroaryl contains the 1-3 miscellaneous originals for being selected from N, O or S Son, and Ar can optionally 1-3 identical or different R6Replace；
R6For C1-C6Alkyl, C3-C7Naphthenic base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl, C1-C6Alkoxy, C1-C6Alkene oxygen Base, C1-C6Alkynyloxy group, sulfydryl, C1-C6Alkane sulfydryl, C1-C6Alkene sulfydryl, phenyl, benzyl are free, at salt, esterification, acylated Carboxyl, halogen, optionally by hydroxyl, amino or halogenated C1-C6Alkyl or C1-C6Alkoxy, nitro, cyano, amino or two (C1-C6Alkyl) replace amino.
Present invention is preferably related to quinolines shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvents Compound or prodrug,
Wherein,
R1For 5-8 circle heterocyclic ring base, 5-6 unit's heteroaryl, the heterocycle or heteroaryl contain 1-3 and are selected from the miscellaneous of N, O or S Atom, and the heterocycle or the optional 0-1 R of heteroaryl4Replace；It is preferred that R1For 5-6 circle heterocyclic ring base, the heterocycle contains 1-3 are selected from the hetero atom of N, O or S, and the optional 0-1 R of the heterocycle4Replace；It is highly preferred that R1For oxadiazoles base, thiophene Diazole, the optional 0-1 R of heterocycle4Replace；
R4For C1-C2Alkyl, C3-C4Naphthenic base, C1-C3Alkoxy, phenyl, benzyl, free, at salt, esterification, acyl The carboxyl of change, halogen, trifluoromethyl；It is preferred that R4For C1-C2Alkyl, C3-C4Naphthenic base, phenyl, benzyl, free, at salt, ester Carboxyl change, acylated；It is further preferable that R4For methyl, phenyl；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C6Alkyl, C3-C5Naphthenic base, C1-C3Alkoxy, they It can be by 0-3 identical or different R5Optionally replace；
Or R2And R3It is formed together 5-7 circle heterocyclic ring base or 5-6 unit's heteroaryl with the nitrogen-atoms being connect with them, it is described miscellaneous Ring group and heteroaryl in addition to R2And R3Outside the nitrogen-atoms of connection, the hetero atom of N, O and S are optionally selected from containing 0-3, in addition to R2 And R3Outside the nitrogen-atoms connected, the heterocycle optionally includes 0-2 carbon-carbon double bond, the heterocycle and heteroaryl optionally quilt 0-2 identical or different R5Replace；
Preferably, R2And R3It is identical or different, separately it is selected from hydrogen, C1-C3Alkyl, C3-C5Naphthenic base, they can be with By 0-2 identical or different R5Optionally replace；
Or R2And R3It is formed together 5-6 circle heterocyclic ring base or 5-6 unit's heteroaryl with the nitrogen-atoms being connect with them, it is described miscellaneous Ring group in addition to R2And R3Outside the nitrogen-atoms of connection, the hetero atom of N, O and S, the heterocycle or miscellaneous are optionally selected from containing 0-3 Aryl is optionally by 0-1 R5Replace；
It is highly preferred that R2And R3It is identical or different, separately it is selected from methyl, ethyl；
R2And R3With the nitrogen-atoms being connect with them be formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl, 1- imidazole radicals, they can be by 1 R5Optionally replace；
Most preferably, R2And R3It is identical or different, separately it is selected from methyl, ethyl；
R2And R3With the nitrogen-atoms being connect with them be formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl, 1- imidazole radicals, they can be by 1 R5Optionally replace；
R5For C1-C4Alkyl, C3-C5Naphthenic base, hydroxyl, halogen, C1-C4Alkoxy；Preferably, R5For C1-C3Alkyl, hydroxyl Base, halogen, C1-C3Alkoxy；It is highly preferred that R5For methyl, ethyl；
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, And optional 0-2 identical or different R of Ar6Replace；
Preferably, Ar is 6-7 member aryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Ar Optional 0-2 identical or different R6Replace；
It is highly preferred that Ar is 6-7 member aryl, and Ar optional 0-1 identical or different R6Replace；
Most preferably, Ar is phenyl.
R6For C1-C4Alkyl, C3-C6Naphthenic base, C2-C4Alkenyl, hydroxyl, C1-C4Alkoxy, sulfydryl, phenyl, benzyl dissociate , carboxyl at salt, esterification, acylated, halogen, optionally by hydroxyl, amino or halogenated C1-C4Alkyl or two (C1-C3Alkane Base) replace amino；
Preferably, R6For C1-C3Alkyl, phenyl, benzyl, halogen, amino；
It is highly preferred that R6For C1-C3Alkyl.
Present invention is preferably related to quinolines shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvents Compound or prodrug,
Wherein,
R1For 5-8 circle heterocyclic ring base, 5-6 unit's heteroaryl, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and And the heterocycle or the optional 0-1 R of heteroaryl4Replace；
R4For C1-C2Alkyl, C3-C4Naphthenic base, C1-C3Alkoxy, phenyl, benzyl, free, at salt, esterification, acyl The carboxyl of change, halogen, trifluoromethyl；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C6Alkyl, C3-C5Naphthenic base, C1-C3Alkoxy, they It can be by 0-3 identical or different R5Optionally replace；
Or R2And R3It is formed together 5-7 circle heterocyclic ring base or 5-6 unit's heteroaryl with the nitrogen-atoms being connect with them, it is described miscellaneous Ring group and heteroaryl in addition to R2And R3Outside the nitrogen-atoms of connection, the hetero atom of N, O and S are optionally selected from containing 0-3, in addition to R2 And R3Outside the nitrogen-atoms connected, the heterocycle optionally includes 0-2 carbon-carbon double bond, the heterocycle and heteroaryl optionally quilt 0-2 identical or different R5Replace；
R5For C1-C4Alkyl, C3-C5Naphthenic base, hydroxyl, halogen, C1-C4Alkoxy；
N is the integer of 0-2；
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, And optional 0-2 identical or different R of Ar6Replace；
R6For C1-C4Alkyl, C3-C6Naphthenic base, C2-C4Alkenyl, hydroxyl, C1-C4Alkoxy, sulfydryl, phenyl, benzyl dissociate , carboxyl at salt, esterification, acylated, halogen, optionally by hydroxyl, amino or halogenated C1-C4Alkyl or two (C1-C3Alkane Base) replace amino.
Present invention is preferably related to quinolines shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvents Compound or prodrug,
Wherein,
R1For 5-6 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the heterocycle Optional 0-1 R4Replace；
R4For C1-C2Alkyl, C3-C4Naphthenic base, phenyl, benzyl, free, at salt, esterification, acylated carboxyl；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C3Alkyl, C3-C5Naphthenic base, they can be by 0-2 Identical or different R5Optionally replace；
Or R2And R3It is formed together 5-6 circle heterocyclic ring base or 5-6 unit's heteroaryl with the nitrogen-atoms being connect with them, it is described miscellaneous Ring group in addition to R2And R3Outside the nitrogen-atoms of connection, the hetero atom of N, O and S, the heterocycle or miscellaneous are optionally selected from containing 0-3 Aryl is optionally by 0-1 R5Replace；
R5For C1-C3Alkyl, hydroxyl, halogen, C1-C3Alkoxy；
N is the integer of 0-2；
Ar is 6-7 member aryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0-2 of Ar A identical or different R6Replace；
R6For C1-C3Alkyl, phenyl, benzyl, halogen, amino.
Present invention is preferably related to quinoline compound shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvations Object or prodrug,
Wherein,
R1For oxadiazoles base, thiadiazoles, the optional 0-1 R of heterocycle4Replace；
R4For methyl, phenyl；
R2And R3It is identical or different, separately it is selected from methyl, ethyl；
R2And R3With the nitrogen-atoms being connect with them be formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl, 1- imidazole radicals, they can be by 1 R5Optionally replace；
R5For methyl, ethyl；
N is the integer of 0-2；
Ar is 6-7 member aryl, and Ar optional 0-1 identical or different R6Replace；
R6For C1-C3Alkyl.
Present invention is preferably related to quinoline compound shown in general formula I and its pharmaceutically acceptable salt, hydrate, solvations Object or prodrug,
Wherein,
R1For oxadiazoles base, thiadiazoles, the optional 0-1 R of heterocycle4Replace；
R4For methyl, phenyl；
R2And R3It is identical or different, separately it is selected from methyl, ethyl；
R2And R3With the nitrogen-atoms being connect with them be formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl, 1- imidazole radicals, they can be by 1 R5Optionally replace；
R5For methyl, ethyl；
N is the integer of 0-2；
Ar is phenyl.
Generalformulaⅰcompound and its pharmaceutically acceptable salt of the present invention, hydrate, solvate or prodrug preferably followingization Object is closed, but these compounds are not meant to any limitation of the invention:
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) first Base quinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (4- methyl-1-piperazine Piperazine base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (diformazan ammonia Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (diethylamino Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholine Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- methyl - 1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (dimethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (lignocaine) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (dimethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (lignocaine) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (dimethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (lignocaine) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (benzenesulfonyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (4- methyl-1- Piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (two Methylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (two Ethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- Pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- Piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- Morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- Methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (two Methylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (two Ethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- Pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- Piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- Morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- Methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (two Methylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (two Ethylamino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- Pyrrolidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- Piperidyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- Morpholinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- Methyl-1-piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) first Base quinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (2- methyl-1-miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazoles Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (2- methyl - 1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (2- methyl-1-imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (2- methyl-1-imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (2- methyl-1-imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (benzenesulfonyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (2- methyl-1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (2- Methyl-1-imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (2- Methyl-1-imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (2- Methyl-1-imidazole radicals) methylquinoline
Moreover, according to some usual methods of the art, I quinoline derivatives of above formula can be in the present invention Acid generates pharmaceutically acceptable salt.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, the salt with following sour addition Particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" naphthenic base " Refer to substituted or unsubstituted naphthenic base；" heteroaryl " refers to containing one or more selected from the heteroatomic monocycle of N, O, S or more The cyclic annular system of ring, cyclic annular system are armaticity, such as imidazole radicals, pyridyl group, pyrazolyl, (1,2,3)-and (1,2,4)-triazole Base, furyl, thienyl, pyrrole radicals, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthalene, quinolyl, isoquinolin Base, benzimidazolyl, benzoxazolyl etc.；" heterocycle " refers to containing one or more heteroatomic monocycles for being selected from N, O, S Or polycyclic cyclic annular system, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, pyrazolidinyl, imidazolidinyl and thiazolinyl Deng.
The present invention can the quinoline derivatives containing above formula I and its pharmaceutically acceptable salt, hydrate or solvation Object is prepared by mixing into composition as active ingredient, with pharmaceutically acceptable carrier or excipient, and is prepared into and clinically may be used The dosage form of receiving, above-mentioned pharmaceutically acceptable excipient refer to any diluent that can be used for pharmaceutical field, adjuvant and/or Carrier.Derivative of the invention can be applied in combination with other active ingredients, as long as they do not generate other unfavorable effects, example Such as allergic reaction.
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common figurations in drug field Agent.Several dosage form as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive, profit Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix etc.. Pharmaceutical preparation can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
Reactive compound of the invention or its officinal salt and its solvate can be used as unique antiviral class drug list It solely uses, or can be with the antiviral class Drug combination that has listed.
It is independent that reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-hbv drug Use, or can with listed anti-hbv drug (such as Lamivudine, Aldoforwe ester, Entecavir, Sebivo, Tenofovir disoproxil and clevudine etc.) it is used in combination.Combination therapy by by each therapeutic component simultaneously, sequence or separate administration To realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It should be appreciated that the range of following examples and preparation example does not limit the scope of the invention in any way.
Following synthetic route describes the preparation of I derivative of formula of the invention, and all raw materials are all by these roads Mode described in line, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or it is commercially available.The present invention All final derivatives be all to be prepared by method described in these routes or by similar method, these sides Method is that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these routes definition as follows or Such as the definition in claim.
Type I compound according to the invention, works as R2And R3It is identical or different, separately it is selected from methyl, ethyl；R2With R3It is formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；N=0；R1For oxadiazoles base and by 1 R4When substitution, compound The preparation method of A-10 such as route A, other substituent groups are as defined in the claims.
Type I compound according to the invention, works as R2And R3It is identical or different, separately it is selected from methyl, ethyl；R2With R3It is formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；N=0；R1For oxadiazoles base and by 0 R4When substitution, compound The preparation method of A-10 such as route B, other substituent groups are as defined in the claims.
Type I compound according to the invention, works as R2And R3It is identical or different, separately it is selected from methyl, ethyl；R2With R3It is formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；N=0；R1When for thiadiazolyl group, the preparation method of compound C-3 Such as route C, other substituent groups are as defined in the claims.
Type I compound according to the invention, works as R2And R3It is identical or different, separately it is selected from methyl, ethyl；R2With R3It is formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；When n=1, the preparation method of compound D-2 such as route D, other are taken Dai Ji is as defined in the claims.
Type I compound according to the invention, works as R2And R3It is identical or different, separately it is selected from methyl, ethyl；R2With R3It is formed together 1- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrolidinyl with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；When n=2, the preparation method of compound E-1 such as route E, other are taken Dai Ji is as defined in the claims.
Type I compound according to the invention, works as R2And R3It is formed together 1- imidazole radicals with the nitrogen-atoms being connect with them, They can be by 1 R5Optionally replace；R5For methyl, ethyl；The preparation method of compound F-2 such as route F, other substituent groups are such as Defined in claim.
Specific embodiment:
Embodiment is intended to illustrate and be not intended to limit the scope of the invention.The nuclear magnetic resonance spectroscopy Bruker of compound ARX-600 measurement, mass spectrum are measured with Agilent 1100LC/MSD；Agents useful for same is that analysis is pure or chemical pure.
Embodiment 1:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (diformazan Amino) methylquinoline
Step A:3- benzyloxy -4-methoxybenzaldehyde (A-1)
150mlN is added in Anhydrous potassium carbonate (62.1g, 0.45mol), 30min is stirred in dinethylformamide, stirs It is lower that different 4-hydroxyl-3-methoxylbenxaldehyde (45.6g, 0.3mol) is added, be slowly added dropwise after being warming up to 90 DEG C benzyl chloride (45.6g, 0.36mol), drop finish in 90 DEG C of the reaction was continued 60min.End of reaction is cooled to room temperature, and reaction solution is poured into ice water, and white solid is precipitated, and stirs 3h, takes out Filter, is washed with water filter cake, dry, obtains white solid 71.7g, yield 98.6%.
Step B:2- aldehyde radical -4- benzyloxy -5- methoxy nitrobenzene (A-2)
Intermediate A -2 (40.0g, 0.165mol) is slowly added portionwise in 160mL concentrated nitric acid under condition of ice bath, is added The reaction was continued at 10 DEG C -15 DEG C after material 180min.End of reaction pours into reaction solution in ice water, there is yellow mercury oxide generation, It filters and filter cake is reconciled into PH=7 with 10%NaOH into the water again, then filter and use and filtered obtained by massive laundering agent filter cake to lotion Liquid is colourless, dry 45g faint yellow solid, yield 94.9%.
Step C:2- aldehyde radical -4- benzyloxy -5- aminoanisole (A-3)
Reduced iron powder (40g, 0.71mol), concentrated hydrochloric acid (8.6ml) and water (252ml) are added in three-necked bottle, return stirring 60min.Intermediate A -3, back flow reaction 30min is added portionwise.90 DEG C are cooled to Na2CO3 solid tune PH to 9-10, addition 3g Activated carbon reflux 30min；500ml toluene stirring 20min is added, is filtered while hot, is separated toluene layer after standing filtrate, be evaporated first Benzene layer is simultaneously beaten with ethyl alcohol, and yellow solid 32g, yield 89.3% are obtained after drying.
Step D:4- thiophenyl-ethyl 3-oxobutanoate (A-9)
DMF (250ml) solution of benzenethiol (22g, 0.20mol) is added in the eggplant-shape bottle of 500ml, then by the chloro- 3- of 4- Oxobutyric (39.5g, 0.24mol) instill eggplant-shape bottle in, be added at one time after being sufficiently stirred potassium carbonate (41.5g, 0.30mol) it is stirred at room temperature.After end of reaction into reaction solution be added 500ml water, with 2*500ml ethyl acetate extract, then with satisfy With saline solution (300*2) lotion ethyl acetate layer, boils off ethyl acetate and obtain red oil 41.1g, yield 86.2%.
Step E:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl-3-quinolin Ethyl formate (A-4)
Again respectively by intermediate A-3 (31g, 0.11mol), intermediate A -9 (43g, 0.18mol), piperidines (1g, 0.012mol) It is added in the 500ml eggplant-shape bottle containing 217ml isopropanol, back flow reaction 12-15h.End of reaction filters to obtain filter cake, dries 39.6g, yield 71.5% (with the calculating of intermediate IV).
Step F:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl-3-quinolin hydrazides (A-5)
Intermediate A -4 (39g, 0.085mol) is added in the 1L eggplant-shape bottle containing 390mlDMF, 80% hydration is added Hydrazine 195ml reacts 27 hours in 60 DEG C.Reaction solution is poured into 1L water and is stirred 1 hour, filtered to obtain filter cake, use second by end of reaction Dry 37.2g white solid after alcohol mashing, yield 98.4%.
Step G:6- benzyloxy -7- methoxyl group 2- (thiophenyl) methyl -3- (N`- formoxyl) hydrazide group quinoline (B-1)
Intermediate A -5 (12g, 0.027mol) is added at room temperature in the 250ml conical flask of the formic acid containing 120ml, room Temperature stirring 3h.End of reaction pours into reaction solution in 500ml ether, stirs 20min, filters, dry with ether lotion filter cake Obtain white solid 12.55g, yield 98.4%.
Step H:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles)) base quinoline (B- 2)
Intermediate B -1 (12g, 0.025mol) is added to containing 120mlPOCl3250ml eggplant-shape bottle in 40 DEG C reaction 4h.Boil off most of solvent (POCl3), remaining solution is added dropwise in ice water, adjusts PH=7 with 10%NaOH solution, Filter and use massive laundering agent filter cake, and after being beaten with ethyl alcohol in drier dry yellow solid 7.1g, yield 61.5%.
Step I:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) quinoline (B-3)
Under nitrogen protection, the dichloromethane solution of 1mol/L Boron tribromide (18.8g, 0.075mol) is added drop-wise to centre (guarantee that temperature is not higher than -15 DEG C during being added dropwise) in trifluoroacetic acid (75ml) solution of body B-2 (7.5g, 0.016mol), drop Bi Yu -15 DEG C of reaction 6h.Reaction terminates, and reaction solution is poured into 150ml ice water, adjusts PH=with 10% sodium hydroxide solution 7, the methylene chloride in water is divided exactly, filters, is washed with water agent filter cake, dry yellow solid 4.4g, yield 73.1%.
Step J:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (diformazan ammonia Base) methylquinoline (embodiment 1)
Be separately added into 25ml eggplant-shape bottle 0.25g37% formalin, 0.35g33% dimethylamine solution, 1d dense salt Acid and 7ml methanol are added intermediate B -3 (0.4g, 1.1mmol) after stirring half an hour at room temperature and react 2 hours.Reaction It finishes, filters, with methanol lotion filter cake, dry faint yellow solid.
MS(ES+)m/z 423.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.81(s,1H), 7.45-7.38 (m, 2H), 7.34 (s, 1H), 7.28 (t, J=7.7Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 4.90 (s, 2H),4.07(s,2H),4.00(s,3H),2.32(s,6H).
According to the method for embodiment 1, it is reacted and is implemented by Mannich with intermediate B -3 as raw material using different amine Example 2-6 compound.
Embodiment 2:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (diethyl Amino) methylquinoline
MS(ES+)m/z 451.2(M+H)+.
Embodiment 3:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
MS(ES+)m/z 449.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.81(s,1H), 7.45-7.37 (m, 2H), 7.34 (s, 1H), 7.28 (t, J=7.7Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 4.90 (s, 2H),4.32(s,2H),3.99(s,3H),2.73(s,4H),1.78(s,4H).
Embodiment 4:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperazine Piperidinyl) methylquinoline
MS(ES+)m/z 463.1(M+H)+.1H NMR(600MHz,DMSO-d6)δ9.47(s,1H),8.79(s,1H), 7.41 (d, J=7.5Hz, 2H), 7.34 (s, 1H), 7.28 (t, J=7.7Hz, 2H), 7.17 (t, J=7.4Hz, 1H), 4.89 (s,2H),4.17(s,2H),3.99(s,3H),2.63(s,4H),1.56(s,4H),1.45(s,2H).
Embodiment 5:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- Quinoline base) methylquinoline
MS(ES+)m/z 465.1(M+H)+.1H NMR(600MHz,CDCl3)δ8.65(s,1H),8.53(s,1H),7.40 (d, J=7.3Hz, 2H), 7.35 (s, 1H), 7.21 (t, J=7.6Hz, 2H), 7.15 (t, J=7.3Hz, 1H), 4.93 (s, 2H),4.18(s,2H),4.06(s,3H),3.81(s,4H),2.72(s,4H).
Embodiment 6:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- first Base -1- piperazinyl) methylquinoline
MS(ES+)m/z 478.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.54(s,1H),7.40 (d, J=7.3Hz, 2H), 7.34 (s, 1H), 7.21 (t, J=7.4Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 4.93 (s, 2H),4.18(s,2H),4.05(s,3H),3.35–2.45(m,8H),2.37(s,3H).
Embodiment 7:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) - 5- (dimethylamino) methylquinoline
Step K:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl -3- (N`- acetyl group) hydrazide group quinoline (A-6)
Intermediate A -5 (12g, 0.027mol) is suspended in the ethyl acetate of 480ml, saturation NaHCO is added3Solution 48ml is warming up to 45 DEG C, and the ethyl acetate solution of chloroacetic chloride (2.5g, 0.032mol) is then added dropwise into above-mentioned reaction solution Reaction solution is moved on platform after being added dropwise and stirs 10min and stand 10min by 24ml.It filters and uses 120ml ethyl acetate respectively With 120ml rinsing agent filter cake, dry white solid 12.5g, yield 95.2%.
Step L:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) Intermediate A -6 (12g, 0.025mol) is added to containing 120mlPOCl by quinoline (A-7)3250ml eggplant-shape bottle in 60 DEG C reaction 3h.Boil off most of solvent (POCl3), remaining solution is added dropwise in ice water, adjusts PH=7 with 10%NaOH solution, Filter and use massive laundering agent filter cake, and after being beaten with ethyl alcohol in drier dry yellow solid 7.3g, yield 63.2%.
Step M:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) quinoline Quinoline (A-8) is added drop-wise to centre under nitrogen protection, by the dichloromethane solution of 1mol/L Boron tribromide (17.5g, 0.070mol) (guarantee that temperature is not higher than -15 DEG C during being added dropwise) in trifluoroacetic acid (70ml) solution of body A-8 (7.0g, 0.015mol), drop Bi Yu -15 DEG C of reaction 6h.Reaction terminates, and reaction solution is poured into 140ml ice water, adjusts PH=with 10% sodium hydroxide solution 7, the methylene chloride in water is divided exactly, filters, is washed with water agent filter cake, dry yellow solid 4.0g, yield 70.7%.
Step N:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (dimethylamino) methylquinoline (embodiment 7)
Be separately added into 25ml eggplant-shape bottle 0.17g37% formalin, 0.27g33% dimethylamine solution, 1d dense salt Acid and 3ml methanol are added intermediate A -8 (0.3g, 0.79mmol) after stirring half an hour at room temperature and react 2.5 hours. End of reaction filters, with methanol lotion filter cake, dry faint yellow solid.
MS(ES+)m/z 437.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),7.61(s,1H), 7.44-7.34 (m, 2H), 7.28 (t, J=7.5Hz, 2H), 7.19 (t, J=7.3Hz, 1H), 4.92 (s, 2H), 4.78 (d, J= 5.0Hz, 2H), 4.08 (s, 3H), 2.80 (d, J=4.5Hz, 6H), 2.63 (s, 3H)
According to the method for embodiment 7, is reacted and implemented by Mannich with intermediate A -8 as raw material using different amine Example 8-12 compound.
Embodiment 8:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) - 5- (lignocaine) methylquinoline
MS(ES+)m/z 465.2(M+H)+.1H NMR(400MHz,DMSO-d6) δ 8.73 (s, 1H), 7.41 (d, J= 7.4Hz, 2H), 7.32 (s, 1H), 7.28 (t, J=7.6Hz, 2H), 7.21-7.14 (m, 1H), 4.88 (s, 2H), 4.26 (s, 2H), 3.98 (s, 3H), 2.79-2.62 (m, 4H), 2.60 (s, 3H), 1.11 (t, J=7.1Hz, 6H)
Embodiment 9:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) - 5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 463.0(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.44–7.37(m, 2H), 7.34 (s, 1H), 7.28 (t, J=7.6Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 4.88 (s, 2H), 4.33 (s, 2H), 3.99(s,3H),2.75(s,4H),2.60(s,3H),1.80(s,4H).
Embodiment 10:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 477.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.65(s,1H), 7.42-7.35 (m, 2H), 7.27 (t, J=7.5Hz, 2H), 7.19 (t, J=7.3Hz, 1H), 4.94 (s, 2H), 4.73 (d, J= 4.4Hz, 2H), 4.08 (s, 3H), 3.41 (d, J=11.5Hz, 2H), 3.05 (d, J=10.9Hz, 2H), 2.62 (s, 3H), 1.76 (s, 4H), 1.64 (d, J=12.9Hz, 1H), 1.39 (d, J=12.3Hz, 1H)
Embodiment 11:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 479.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.59(s,1H),7.45–7.38(m, 2H), 7.35 (s, 1H), 7.22 (t, J=7.5Hz, 2H), 7.15 (t, J=7.3Hz, 1H), 4.92 (s, 2H), 4.18 (s, 2H), 4.05(s,3H),3.82(s,4H),2.73(s,4H),2.62(s,3H).
Embodiment 12:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 492.2(M+H)+514.2(M+Na)+.1H NMR(400MHz,DMSO-d6)δ9.01(s,1H), 7.55 (s, 1H), 7.40 (d, J=7.6Hz, 2H), 7.28 (t, J=7.6Hz, 2H), 7.18 (t, J=7.3Hz, 1H), 4.89 (s,2H),4.05(s,2H),3.99(s,3H),3.21(m,8H),2.78(s,3H),2.62(s,3H).
Embodiment 13:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (dimethylamino) methylquinoline
Step O:6- benzyloxy -7- methoxyl group -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) Intermediate A -6 (8.6g, 0.018mol), lawesson reagent (8.6g, 0.021mol) are added quinoline (C-1) contains 104ml tetrahydro In the 250ml eggplant-shape bottle of furans, back flow reaction 2h.End of reaction boils off most of solvent, then is dissolved with methylene chloride, respectively Organic layer is washed with saturated sodium bicarbonate and saturated common salt, organic layer is evaporated and is beaten with ethyl alcohol, dry white solid 7g is produced Rate 81.7%.
Step P:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) quinoline Quinoline (C-2) intermediate C-1 (5.5g, 0.011mol) is added in the mixed liquor (66ml, 2:1) of concentrated hydrochloric acid and glacial acetic acid, heating To 80 DEG C of reaction 1h.Reaction solution is slowly added in ice water, is filtered, filter cake is added to the water and adjusts PH=with saturated sodium bicarbonate 7, it filters, is washed with water agent filter cake, dry white solid 4.23g, yield 94.4%.
Step Q:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (dimethylamino) methylquinoline (embodiment 13)
Be separately added into 25ml eggplant-shape bottle 37% formalin of 0.12g, 33% dimethylamine solution of 0.17g, 1d it is dense Hydrochloric acid and 4ml methanol are added intermediate C-2 (0.2g, 0.51mmol) after stirring half an hour at room temperature and react 5 hours. End of reaction filters, with methanol lotion filter cake, dry white solid.
MS(ES+)m/z 453.3(M+H)+.1H NMR(400MHz,CDCl3)δ8.26(s,1H),7.39–7.33(m, 3H), 7.22 (t, J=7.4Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 5.30 (s, 1H), 4.78 (s, 2H), 4.07 (s, 2H), 4.04(s,3H),2.84(s,3H),2.44(s,6H).
According to the method for embodiment 13, obtains difference by raw material and -6 cyclization of intermediate A, debenzylation of different acyl chlorides and take The intermediate C-2 of Dai Ji, intermediate C-2 react to obtain embodiment 14-24 compound from different amine by Mannich.
Embodiment 14:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 481.3(M+H)+.1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.39–7.33(m, 3H), 7.22 (t, J=7.5Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 4.79 (s, 2H), 4.23 (s, 2H), 4.04 (s, 3H), 2.84 (s, 3H), 2.79 (q, J=7.1Hz, 4H), 1.23 (t, J=7.2Hz, 6H)
Embodiment 15:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 479.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.38–7.30(m, 3H), 7.26 (t, J=7.6Hz, 2H), 7.16 (t, J=7.3Hz, 1H), 4.81 (s, 2H), 4.22 (s, 2H), 3.98 (s, 3H), 2.81(s,3H),2.63(s,4H),1.75(s,4H).
Embodiment 16:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 493.1(M+H)+515.0(M+Na)+；1H NMR(400MHz,CDCl3)δ8.28(s,1H), 7.40-7.30 (m, 3H), 7.21 (t, J=7.4Hz, 2H), 7.14 (t, J=7.1Hz, 1H), 5.30 (s, 1H), 4.78 (s, 2H),4.12(s,2H),4.04(s,3H),2.84(s,3H),2.68(s,4H),1.73(s,4H),1.54(s,2H).
Embodiment 17:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 495.0(M+H)+516.9(M+Na)+；1H NMR(400MHz,CDCl3)δ8.47(s,1H), 7.41-7.31 (m, 3H), 7.21 (t, J=7.4Hz, 2H), 7.15 (t, J=7.3Hz, 1H), 4.83 (s, 2H), 4.30 (s, 2H),4.07(s,3H),3.91(s,4H),2.95–2.79(m,7H).
Embodiment 18:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
1H NMR(400MHz,DMSO-d6) δ 8.56 (s, 1H), 7.39-7.30 (m, 3H), 7.26 (t, J=7.6Hz, 2H), 7.16 (t, J=7.3Hz, 1H), 4.83 (s, 2H), 4.05 (s, 2H), 3.99 (s, 3H), 2.82 (s, 3H), 2.62-2.22 (m, 8H),2.15(s,3H).
Embodiment 19:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 515.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.07–8.03(m, 2H), 7.66-7.58 (m, 3H), 7.41-7.35 (m, 3H), 7.25 (t, J=7.7Hz, 2H), 7.14 (t, J=7.3Hz, 1H), 4.88(s,2H),4.20(s,2H),4.01(s,3H),2.42(s,6H).
Embodiment 20:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 543.1(M+H)+.
Embodiment 21:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 541.1(M+H)+562.9(M+Na)+.1H NMR(400MHz,DMSO-d6)δ8.63(s,1H), 8.07-7.97 (m, 2H), 7.65-7.56 (m, 3H), 7.42-7.34 (m, 3H), 7.25 (t, J=7.6Hz, 2H), 7.14 (t, J =7.3Hz, 1H), 4.88 (s, 2H), 4.42 (s, 2H), 4.00 (s, 3H), 2.86 (s, 4H), 1.82 (s, 4H)
Embodiment 22:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 555.2(M+H)+.1H NMR(600MHz,DMSO-d6)δ8.63(s,1H),8.09–7.99(m, 2H), 7.62 (d, J=3.7Hz, 3H), 7.44-7.32 (m, 3H), 7.24 (t, J=7.6Hz, 2H), 7.14 (t, J=7.3Hz, 1H),4.88(s,2H),4.19(s,2H),3.99(s,3H),2.64(s,4H),1.57(s,4H),1.45(s,2H).
Embodiment 23:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 557.2(M+H)+.
Embodiment 24:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 570.2(M+H)+.
Embodiment 25:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) methylquinoline
Step R:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (two Methylamino) methylquinoline (embodiment 25)
Intermediate D-1 (0.1g, 0.24mmol) is added in the 25ml eggplant-shape bottle containing 2ml glacial acetic acid, is warming up to 40 DEG C React 2.5h.Reaction solution is added in 10ml ice water, with 10ml methylene chloride lotion water layer, with saturated sodium bicarbonate by water layer PH is adjusted to neutrality, then with the methylene chloride aqueous layer extracted of 3*15ml and merges organic layer, with saturated common salt rinsing agent organic layer, It is evaporated to obtain yellow solid.
MS(ES+)m/z 439.2(M+H)+.
According to the method for embodiment 25, embodiment 26-48 chemical combination is obtained through oxidation using different compound D-1 as raw material Object.
Embodiment 26:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 467.2(M+H)+.
Embodiment 27:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 465.2(M+H)+.
Embodiment 28:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 479.2(M+H)+.1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.56(s,1H),7.73 (dd, J=6.6,2.9Hz, 2H), 7.55-7.44 (m, 3H), 7.40 (s, 1H), 5.19 (d, J=12.5Hz, 1H), 4.92 (d, J =12.5Hz, 1H), 4.22 (s, 2H), 4.04 (s, 3H), 2.75 (s, 4H), 1.85-1.71 (m, 4H), 1.56 (s, 2H)
Embodiment 29:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 481.1(M+H)+.
Embodiment 30:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 494.1(M+H)+.
((5- methyl-1,3,4- dislike two to 2- to embodiment 31:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 453.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.81–7.74(m, 2H), 7.54-7.46 (m, 3H), 7.42 (s, 1H), 5.23 (d, J=12.4Hz, 1H), 4.85 (d, J=12.4Hz, 1H), 4.23 (s,2H),4.03(s,3H),2.69(s,3H),2.55(s,6H).
((5- methyl-1,3,4- dislike two to 2- to embodiment 32:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 481.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.23(s,1H),7.74–7.63(m, 2H), 7.52-7.43 (m, 3H), 7.37 (s, 1H), 5.03 (d, J=12.7Hz, 1H), 4.78 (d, J=12.7Hz, 1H), 4.22 (s, 2H), 4.03 (s, 3H), 2.87 (s, 3H), 2.79 (q, J=7.1Hz, 4H), 1.23 (t, J=7.2Hz, 6H)
((5- methyl-1,3,4- dislike two to 2- to embodiment 33:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 479.1(M+H)+.
((5- methyl-1,3,4- dislike two to 2- to embodiment 34:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 493.1(M+H)+.
((5- methyl-1,3,4- dislike two to 2- to embodiment 35:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 495.3(M+H)+.
((5- methyl-1,3,4- dislike two to 2- to embodiment 36:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 508.2(M+H)+.
Embodiment 37:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 469.0(M+H)+491.1(M+Na)+；1H NMR(400MHz,CDCl3)δ8.27(s,1H), 7.74-7.67 (m, 2H), 7.52-7.44 (m, 3H), 7.39 (s, 1H), 5.05 (d, J=12.7Hz, 1H), 4.77 (d, J= 12.7Hz,1H),4.13(s,2H),4.03(s,3H),2.87(s,3H),2.51(s,6H).
Embodiment 38:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 497.0(M+H)+.
Embodiment 39:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 495.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.74–7.67(m, 2H), 7.52-7.44 (m, 3H), 7.38 (s, 1H), 5.05 (d, J=12.7Hz, 1H), 4.76 (d, J=12.7Hz, 1H), 4.32 (s,2H),4.02(s,3H),2.87(s,7H),1.96(s,4H).
Embodiment 40:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 509.3(M+H)+.
Embodiment 41:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 511.1(M+H)+.
Embodiment 42:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 524.3(M+H)+.
Embodiment 43:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 531.2(M+H)+.1H NMR(400MHz,CDCl3)δ8.23(s,1H),8.02–7.93(m, 2H), 7.66-7.58 (m, 2H), 7.50-7.43 (m, 3H), 7.42-7.36 (m, 3H), 7.35 (s, 1H), 5.05 (d, J= 12.7Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.05 (s, 2H), 3.99 (s, 3H), 2.41 (s, 6H)
Embodiment 44:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 559.1(M+H)+.
Embodiment 45:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 557.2(M+H)+.1H NMR(400MHz,CDCl3)δ8.22(s,1H),8.02–7.91(m, 2H), 7.67-7.58 (m, 2H), 7.50-7.43 (m, 3H), 7.42-7.36 (m, 3H), 7.33 (s, 1H), 5.05 (d, J= 12.7Hz, 1H), 4.79 (d, J=12.7Hz, 1H), 4.24 (s, 2H), 3.98 (s, 3H), 2.75 (s, 4H), 1.87 (s, 4H)
Embodiment 46:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 571.2(M+H)+.
Embodiment 47:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 573.2(M+H)+.
Embodiment 48:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 586.3(M+H)+.
Embodiment 49:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) methylquinoline
Step S: intermediate D-1 (0.1g, 0.24mmol) is added containing methanol and chloroform mixed liquor (6ml, 1:1) In 25ml eggplant-shape bottle, then hydrogen peroxide (0.14g, 1.2mmol) solution of Disodium tungstate (Na2WO4) dihydrate (catalytic amount) is added dropwise, 20 DEG C are stirred Mix 2h；Sodium hydrogensulfite (0.1g, 0.96mmol) aqueous solution is added in reaction solution, and methanol and chloroform are evaporated, then to reactant 8ml water is added in system, filters, is washed with water agent filter cake, dry solid.
MS(ES+)m/z 455.3(M+H)+.
According to the method for embodiment 49, embodiment 50-72 chemical combination is obtained through oxidation using different compound D-1 as raw material Object.
Embodiment 50:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 483.2(M+H)+.
Embodiment 51:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 481.3(M+H)+.
Embodiment 52:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 495.1(M+H)+.
Embodiment 53:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 497.3(M+H)+.
Embodiment 54:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 510.2(M+H)+.
Embodiment 55:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 469.2(M+H)+.
Embodiment 56:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 497.3(M+H)+.
Embodiment 57:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 495.2(M+H)+.
Embodiment 58:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 509.1(M+H)+.
Embodiment 59:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 511.2(M+H)+.
Embodiment 60:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 524.3(M+H)+.
Embodiment 61:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 485.2(M+H)+.
Embodiment 62:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 513.2(M+H)+.
Embodiment 63:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 511.2(M+H)+.
Embodiment 64:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 525.2(M+H)+.
Embodiment 65:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 527.3(M+H)+.
Embodiment 66:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 540.2(M+H)+.
Embodiment 67:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (dimethylamino) methylquinoline
MS(ES+)m/z 547.1(M+H)+.
Embodiment 68:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (lignocaine) methylquinoline
MS(ES+)m/z 575.3(M+H)+.
Embodiment 69:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- pyrrolidinyl) methylquinoline
MS(ES+)m/z 573.1(M+H)+.
Embodiment 70:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- piperidyl) methylquinoline
MS(ES+)m/z 587.2(M+H)+.
Embodiment 71:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (4- morpholinyl) methylquinoline
MS(ES+)m/z 589.3(M+H)+.
Embodiment 72:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base)-5- (4- methyl-1-piperazinyl) methylquinoline
MS(ES+)m/z 602.1(M+H)+.
Embodiment 73:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- Imidazole radicals) methylquinoline
Step T: intermediate F-1 (0.1g, 0.24mmol), dioxane (2ml), miaow are separately added into 25ml eggplant-shape bottle Azoles (0.08g, 1.2mmol), concentrated hydrochloric acid (0.01ml) are warming up to 65 DEG C of reaction 5h.End of reaction,
It is cooled to room temperature, filters, successively use dioxane, rinsing agent filter cake, dry white solid.
MS(ES+)m/z 446.1(M+H)+468.0(M+Na)+.1H NMR(400MHz,DMSO-d6)δ9.49(s,1H), 8.92 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 7.39 (d, J=7.5Hz, 2H), 7.27 (t, J=7.6Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 5.65 (s, 2H), 4.89 (s, 2H), 4.06 (s, 3H)
According to the method for embodiment 73, exchange to obtain embodiment 74-96 chemical combination through amine as raw material using different compound F-1 Object.
Embodiment 74:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (2- Methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 460.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.75(s,1H), 7.46 (s, 1H), 7.40 (d, J=7.5Hz, 2H), 7.27 (t, J=7.6Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 6.67 (s,1H),6.63(s,1H),5.49(s,2H),4.90(s,2H),4.06(s,3H),2.47(s,3H).
Embodiment 75:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 460.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.72(s,1H), 7.45 (s, 1H), 7.38 (d, J=7.4Hz, 2H), 7.27 (t, J=7.6Hz, 2H), 7.17 (t, J=7.3Hz, 1H), 7.06 (s,1H),6.82(s,1H),5.63(s,2H),4.87(s,2H),4.06(s,3H),2.61(s,3H).
Embodiment 76:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 474.1(M+H)+.
Embodiment 77:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 476.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.93(s,1H), 7.47 (s, 1H), 7.36 (d, J=7.4Hz, 2H), 7.25 (t, J=7.6Hz, 2H), 7.17 (d, J=7.3Hz, 1H), 7.14 (s,1H),6.93(s,1H),5.67(s,2H),4.80(s,2H),4.06(s,3H),2.82(s,3H).
Embodiment 78:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 490.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.47(s,1H), 7.33 (d, J=7.6Hz, 2H), 7.25 (t, J=7.6Hz, 2H), 7.16 (t, J=7.3Hz, 1H), 6.81 (d, J=1.0Hz, 1H), 6.77 (d, J=1.0Hz, 1H), 5.54 (s, 2H), 4.83 (s, 2H), 4.06 (s, 3H), 2.81 (s, 3H), 2.46 (s, 3H).
Embodiment 79:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 538.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.10–8.02(m, 2H), 7.78 (s, 1H), 7.65-7.60 (m, 3H), 7.48 (s, 1H), 7.35 (d, J=7.4Hz, 2H), 7.23 (t, J= 7.7Hz,2H),7.16–7.08(m,2H),6.83(s,1H),5.66(s,2H),4.87(s,2H),4.07(s,3H).
Embodiment 80:7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 552.3(M+H)+.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.57(s,1H), 8.15-7.95 (m, 2H), 7.63 (s, 3H), 7.49 (s, 1H), 7.35 (d, J=7.7Hz, 2H), 7.23 (t, J=7.5Hz, 1H), 7.14 (t, J=7.4Hz, 1H), 6.76 (s, 1H), 6.66 (s, 1H), 5.52 (s, 2H), 4.88 (s, 2H), 4.07 (s, 3H),2.42(s,3H).
Embodiment 81:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 462.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.91(s,1H), 7.73 (s, 1H), 7.61-7.42 (m, 6H), 7.07 (s, 1H), 6.83 (s, 1H), 5.66 (s, 2H), 5.07 (d, J=12.7Hz, 1H), 4.90 (d, J=12.7Hz, 1H), 4.08 (s, 3H)
Embodiment 82:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 476.1(M+H)+.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.75(s,1H), 7.57-7.53 (m, 2H), 7.53-7.46 (m, 4H), 6.67 (d, J=1.2Hz, 1H), 6.64 (d, J=1.2Hz, 1H), 5.52 (s, 2H), 5.08 (d, J=12.7Hz, 1H), 4.91 (d, J=12.8Hz, 1H), 4.08 (s, 3H), 2.46 (s, 3H)
((5- methyl-1,3,4- dislike two to 2- to embodiment 83:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 476.3(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.73(s,1H), 7.59-7.42 (m, 6H), 7.06 (s, 1H), 6.84 (s, 1H), 5.63 (s, 2H), 5.06 (d, J=12.6Hz, 1H), 4.87 (d, J=12.6Hz, 1H), 4.07 (s, 3H), 2.63 (s, 3H)
((5- methyl-1,3,4- dislike two to 2- to embodiment 84:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- Azoles) base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 490.2(M+H)+.
Embodiment 85:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 492.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.75(s,1H), 7.61-7.40 (m, 6H), 7.07 (s, 1H), 6.84 (s, 1H), 5.67 (s, 2H), 5.00 (d, J=12.7Hz, 1H), 4.73 (d, J=12.7Hz, 1H), 4.07 (s, 3H), 2.83 (s, 3H)
Embodiment 86:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiophene two Azoles) base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 506.2(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.62–7.38(m, 6H), 6.74 (s, 1H), 6.65 (s, 1H), 5.53 (s, 2H), 5.02 (d, J=12.7Hz, 1H), 4.75 (d, J=12.7Hz, 1H),4.07(s,3H),2.81(s,3H),2.40(s,3H).
Embodiment 87:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 554.3(M+H)+.1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.07(s,2H), 7.94-7.29 (m, 10H), 7.11 (s, 1H), 6.85 (s, 1H), 5.69 (s, 2H), 5.05 (d, J=13.7Hz, 1H), 4.84 (d, J=13.2Hz, 1H), 4.08 (s, 3H)
Embodiment 88:7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiophene two Azoles) base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 568.1(M+H)+.1H NMR(400MHz,CDCl3)δ8.26(s,1H),8.12–7.85(m, 2H), 7.69-7.38 (m, 9H), 6.80 (s, 1H), 6.70 (s, 1H), 5.50 (s, 2H), 5.21 (d, J=12.8Hz, 1H), 4.93 (d, J=12.8Hz, 1H), 4.12 (s, 3H), 2.57 (s, 3H)
Embodiment 89:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 478.2(M+H)+.
Embodiment 90:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 492.1(M+H)+.
Embodiment 91:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 492.2(M+H)+.
Embodiment 92:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 506.1(M+H)+.
Embodiment 93:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 508.1(M+H)+.
Embodiment 94:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 522.2(M+H)+.
Embodiment 95:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base) -5- (1- imidazole radicals) methylquinoline
MS(ES+)m/z 570.1(M+H)+.
Embodiment 96:7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) Base)-5- (2- methyl-1-imidazole radicals) methylquinoline
MS(ES+)m/z 584.2(M+H)+.
The pharmacological research of product of the present invention
HBV activity and its cytotoxicity detection have been carried out to the quinoline derivatives of above formula I according to the invention.
(1) HepG2.2.15 human liver tumor cell's strain of stable transfection HBV full-length genome, can stably excreting in culture Complete virion (containing DNA) is in culture supernatant.Under the intervention of antiviral drugs, detection cell is secreted into culture supernatant The content of middle viral DNA can detecte the antiviral activity of example pharmaceuticals referring to the content of non-dosing control group: with real-time Fluorescence quantitative PCR method detection concentration (IC required when inhibiting HBV-DNA contents level up to 50%50)；ELISA method detection inhibits anti- The IC of original expression and secretion level50；Meanwhile using the external medication of mtt assay detection compound to HepG2.2.15 cell activity It influences, evaluates its cytotoxic effect (CC50)。
(2) each submitted sample drug does 6 diluted concentrations.Using Lamivudine as positive control drug, Lamivudine does 6 Diluted concentration.
(3) HepG2.2.15 cell (5 × 103/ hole) it is inoculated in 96 orifice plates, example pharmaceuticals are added in next day, replace within the 4th day Culture solution and example pharmaceuticals, it is to be measured in the 8th day collection culture supernatant.Instrument is purified automatically using Qiasymphony nucleic acid to carry out HBV-DNA is extracted.
(4) quantitative real-time PCR detects the levels of replication of HBV-DNA in culture supernatant.Take 10 μ l supernatants for PCR Amplification, while HBV-DNA standard sample is set and does standard curve.According to corresponding HBV-DNA in the resulting culture supernatant of detection Copy number calculates the inhibiting rate that example pharmaceuticals replicate HBV-DNA, then carries out the calculating of example pharmaceuticals half inhibiting rate, obtains Its IC50。
The cytotoxicity and inhibition HBV Activity Results of compound are shown in Table 1
Table 1

Claims (29)

1. compounds of formula I and its pharmaceutically acceptable salt,
Wherein:
R1For 5-10 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the heterocycle is optional 0-3 identical or different R4Replace；
R4For C1-C6Alkyl, C3-C7Naphthenic base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl, C1-C6Alkoxy, phenyl, benzyl dissociate , carboxyl at salt, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C10Alkyl, C3-C7Naphthenic base, C1-C4Alkoxy, C2-C10Alkene Base and C2-C10Alkynyl, they can be by 0-3 identical or different R5Optionally replace；
Or R2And R3Be formed together 5-10 circle heterocyclic ring base with the nitrogen-atoms being connect with them, the heterocycle in addition to R2And R3Even Outside the nitrogen-atoms connect, the hetero atom of N, O or S are optionally selected from containing 0-4, in addition to R2And R3It is described miscellaneous outside the nitrogen-atoms connected Ring group optionally includes 0-2 carbon-carbon double bond or three key, and the heterocycle is optionally by 0-3 identical or different R5Replace；
R5For C1-C6Alkyl, C3-C7Naphthenic base, hydroxyl, halogen, C1-C6Alkoxy, trifluoromethyl, trifluoromethoxy, nitro；
N is the integer of 0-2；
Ar is 6-10 member aryl, 5-10 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and And Ar can optionally 1-3 identical or different R6Replace；
R6For C1-C6Alkyl, C3-C7Naphthenic base, C2-C6Alkenyl, C2-C6Alkynyl, hydroxyl, C1-C6Alkoxy, C1-C6Alkenyloxy group, C1- C6Alkynyloxy group, sulfydryl, C1-C6Alkane sulfydryl, C1-C6Alkene sulfydryl, phenyl, benzyl, carboxyl free, at salt, halogen, optionally by hydroxyl Base, amino or halogenated C1-C6Alkyl or C1-C6Alkoxy, nitro, cyano, amino or two (C1-C6Alkyl) replace amino.
2. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein
R1For 5-8 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0- of the heterocycle 1 R4Replace.
3. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein
R1For 5-6 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0- of the heterocycle 1 R4Replace.
4. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein R1For oxadiazoles base, thiadiazoles, institute State the optional 0-1 R of heterocycle4Replace.
5. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
R2And R3It is identical or different, it is separately selected from hydrogen, C1-C6 alkyl, C3-C5 naphthenic base, C1-C3 alkoxy, they can By 0-3 identical or different R5Optionally replace；
Or R2And R3Be formed together 5-7 circle heterocyclic ring base with the nitrogen-atoms being connect with them, the heterocycle in addition to R2And R3Even Outside the nitrogen-atoms connect, the hetero atom of N, O and S are optionally selected from containing 0-3, in addition to R2And R3It is described miscellaneous outside the nitrogen-atoms connected Ring group optionally includes 0-2 carbon-carbon double bond, and the heterocycle is optionally by 0-2 identical or different R5Replace.
6. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
R2And R3It is identical or different, it is separately selected from hydrogen, C1-C3 alkyl, C3-C5 naphthenic base, they can be by 0-2 phase Same or different R5Optionally replace；
Or R2And R3Be formed together 5-6 circle heterocyclic ring base with the nitrogen-atoms being connect with them, the heterocycle in addition to R2And R3Even Outside the nitrogen-atoms connect, the hetero atom of N, O and S are optionally selected from containing 0-3, the heterocycle is optionally by 0-1 R5Replace.
7. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
R2And R3It is identical or different, separately it is selected from methyl, ethyl；
R2And R31- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- pyrrole are formed together with the nitrogen-atoms being connect with them Alkyl, 1- imidazole radicals are coughed up, they can be by 1 R5Optionally replace.
8. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
R2And R3It is identical or different, separately it is selected from methyl, ethyl.
9. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace.
10. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein
Ar is 6-7 member aryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0-2 phase of Ar Same or different R6Replace.
11. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein Ar is 6-7 member virtue Base, and optional 0-1 identical or different R of Ar6Replace.
12. compound and its pharmaceutically acceptable salt as described in claim 1-4 any one, wherein Ar is phenyl.
13. compound as claimed in claim 5 and its pharmaceutically acceptable salt, wherein
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace.
14. compound as claimed in claim 5 and its pharmaceutically acceptable salt, wherein
Ar is phenyl.
15. compound as claimed in claim 6 and its pharmaceutically acceptable salt, wherein
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace.
16. compound as claimed in claim 6 and its pharmaceutically acceptable salt, wherein
Ar is phenyl.
17. compound as claimed in claim 7 and its pharmaceutically acceptable salt, wherein
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace.
18. compound as claimed in claim 7 and its pharmaceutically acceptable salt, wherein
Ar is phenyl.
19. compound as claimed in claim 8 and its pharmaceutically acceptable salt, wherein
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace.
20. compound as claimed in claim 8 and its pharmaceutically acceptable salt, wherein
Ar is phenyl.
21. compound according to claim 1 and its pharmaceutically acceptable salt, wherein
R1For 5-8 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0- of the heterocycle 1 R4Replace；
R4For C1-C2Alkyl, C3-C4Naphthenic base, C1-C3Alkoxy, phenyl, benzyl, carboxyl free, at salt, halogen, trifluoro Methyl；
R2And R3It is identical or different, separately it is selected from hydrogen, C1-C6Alkyl, C3-C5Naphthenic base, C1-C3Alkoxy, they can be with By 0-3 identical or different R5Optionally replace；
Or R2And R3Be formed together 5-7 circle heterocyclic ring base with the nitrogen-atoms being connect with them, the heterocycle in addition to R2And R3Even Outside the nitrogen-atoms connect, the hetero atom of N, O and S are optionally selected from containing 0-3, in addition to R2And R3It is described miscellaneous outside the nitrogen-atoms connected Ring group optionally includes 0-2 carbon-carbon double bond, and the heterocycle is optionally by 0-2 identical or different R5Replace；
R5For C1-C4Alkyl, C3-C5Naphthenic base, hydroxyl, halogen, C1-C4Alkoxy；
Ar is 6-7 member aryl, 5-8 unit's heteroaryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and Optional 0-2 identical or different R of Ar6Replace；
R6For C1-C4Alkyl, C3-C6Naphthenic base, C2-C4Alkenyl, hydroxyl, C1-C4Alkoxy, sulfydryl, phenyl, benzyl, free, At the carboxyl of salt, halogen, optionally by hydroxyl, amino or halogenated C1-C4Alkyl or two (C1-C3Alkyl) replace amino.
22. compound according to claim 21 and its pharmaceutically acceptable salt, wherein
R1For 5-6 circle heterocyclic ring base, the heterocycle contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0- of the heterocycle 1 R4Replace；
R4For C1-C2Alkyl, C3-C4Naphthenic base, phenyl, benzyl, carboxyl free, at salt.
23. compound according to claim 21 and its pharmaceutically acceptable salt, wherein
Ar is 6-7 member aryl, wherein the heteroaryl contains the 1-3 hetero atoms for being selected from N, O or S, and the optional 0-2 phase of Ar Same or different R6Replace；
R6For C1-C3Alkyl, phenyl, benzyl, halogen, amino.
24. compound according to claim 22 and its pharmaceutically acceptable salt, wherein
R2And R3It is identical or different, separately it is selected from methyl, ethyl；
Or R2And R31- piperidyl, 4- morpholinyl, 4- methyl-1-piperazinyl, 1- are formed together with the nitrogen-atoms being connect with them Pyrrolidinyl, 1- imidazole radicals, they can be by 1 R5Optionally replace；
R5For methyl, ethyl.
25. compound and its pharmaceutically acceptable salt described in 3-20 any one according to claim 1, wherein
R1For oxadiazoles base, thiadiazoles, the optional 0-1 R of heterocycle4Replace；
R4For methyl, phenyl.
26. compound according to claim 23 and its pharmaceutically acceptable salt, wherein
Ar is phenyl.
27. following compound and its pharmaceutically acceptable salt:
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) methyl quinoline Quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) methyl quinoline Quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) methyl Quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) methyl quinoline Quinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) methyl quinoline Quinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (4- methyl-1-piperazinyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (dimethylamino) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (lignocaine) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- pyrrolidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- piperidyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- morpholinyl) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- Methyl-1,3,4-oxadiazole-2) base)-5- (4- methyl-1- Piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (dimethylamino) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (lignocaine) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- pyrrolidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- piperidyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- morpholinyl) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- methyl-1,3,4- thiadiazoles) base)-5- (4- methyl-1- Piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (dimethylamino) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (lignocaine) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- pyrrolidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- piperidyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- morpholinyl) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- phenyl-1,3,4- thiadiazoles) base)-5- (4- methyl-1- Piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) first Base quinoline
7- methoxyl group-6- hydroxyl-2- (phenylsulfinyl base) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (4- methyl-1-piperazine Piperazine base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diformazan Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diethyl Amino) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- pyrrole Cough up alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- piperazine Piperidinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- Quinoline base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- first Base -1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (dimethylamino) methyl Quinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (lignocaine) methyl Quinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- pyrrolidinyl) first Base quinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- piperidyl) methyl Quinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (4- morpholinyl) methyl Quinoline
7- methoxyl group-6- hydroxyl-2- (benzenesulfonyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (4- methyl-1-piperazine Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diformazan ammonia Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (diethylamino Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- pyrroles Alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- piperidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- morpholine Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (4- methyl - 1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diformazan ammonia Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (diethylamino Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- pyrroles Alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- piperidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- morpholine Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (4- methyl - 1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diformazan ammonia Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (diethylamino Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- pyrroles Alkyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- piperidines Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- morpholine Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (4- methyl - 1- piperazinyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) methyl quinoline Quinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (2- methyl-1-imidazole radicals) Methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- imidazole radicals) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- Methyl-1,3,4-oxadiazole-2) base)-5- (2- methyl-1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- imidazole radicals) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- methyl-1,3,4- thiadiazoles) base)-5- (2- methyl-1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (thiophenyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- imidazole radicals) Methylquinoline
7- methoxyl group-6- hydroxyl-2- (thiophenyl) methyl-3- (2- (5- phenyl-1,3,4- thiadiazoles) base)-5- (2- methyl-1- Imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) first Base quinoline
7- methoxyl group-6- hydroxyl-2- (phenylsulfinyl base) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (2- methyl-1-miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- miaow Oxazolyl) methylquinoline
7- methoxyl group -6- hydroxyl -2- (phenylsulfinyl base) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (2- first Base -1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (1,3,4- oxadiazoles) base) -5- (1- imidazole radicals) methyl Quinoline
7- methoxyl group-6- hydroxyl-2- (benzenesulfonyl) methyl-3- (2- (1,3,4- oxadiazoles) base)-5- (2- methyl-1-imidazoles Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (1- imidazoles Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- Methyl-1,3,4-oxadiazole-2) base) -5- (2- methyl - 1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (1- imidazoles Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- methyl-1,3,4- thiadiazoles) base) -5- (2- methyl - 1- imidazole radicals) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (1- imidazoles Base) methylquinoline
7- methoxyl group -6- hydroxyl -2- (benzenesulfonyl) methyl -3- (2- (5- phenyl -1,3,4- thiadiazoles) base) -5- (2- methyl - 1- imidazole radicals) methylquinoline.
28. a kind of Pharmaceutical composition, compound and its pharmaceutically acceptable salt comprising any one of claim 1-27 As active constituent and pharmaceutically acceptable excipient.
29. group described in the compound and its pharmaceutically acceptable salt or claim 28 of any one of claim 1-27 Close application of the object in preparation treatment hepatitis B diseases drug.
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