CN101506170B

CN101506170B - 6-(heterocycle-substituted benzyl)-4-oxoquinoline compound and use of the same as HIV integrase inhibitor

Info

Publication number: CN101506170B
Application number: CN2007800311668A
Authority: CN
Inventors: 佐藤元秀; 荒卷久晃; 山下正树; 井上昌文; 川上浩; 新海久; 中村洋; 松崎裕儿; 和卷修一
Original assignee: Japan Tobacco Inc
Current assignee: Japan Tobacco Inc
Priority date: 2006-06-23
Filing date: 2007-06-22
Publication date: 2011-09-14
Anticipated expiration: 2027-06-22
Also published as: CN101506170A; ZA200900129B

Abstract

The present invention relates to a compound represented by the following formula [I] wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical composition, an anti-HIV agent and an HIV integrase inhibitor containing such compound. The compound of the present invention has an HIV integrase inhibitory activity, and is useful as an anti-HIV agent, or as an agent for the prophylaxis or treatment of AIDS. In addition, by the combined use with other anti-HIV agents such as a protease inhibitor, a reverse transcriptase inhibitor and the like, it can be a more effective anti-HIV agent. Because it shows integrase-specific high inhibitory activity, the compound can be a pharmaceutical agent safe on human body, which causes only a fewer side effects.

Description

6-(benzyl of heterocyclic substituted)-4-oxoquinoline compound and its purposes as hiv integrase inhibitor

Technical field

The present invention relates to new 4-oxoquinoline compound or its pharmacologically acceptable salt or its solvate, it is as anti-HIV medicament.In addition, the present invention relates to comprise the pharmaceutical composition of 4-oxoquinoline compound or its pharmacologically acceptable salt or its solvate and pharmaceutically acceptable carrier; Anti-HIV medicament, hiv integrase inhibitor etc., it comprises as the 4-oxoquinoline compound of activeconstituents or its pharmacologically acceptable salt or its solvate; Anti-HIV medicament, it comprises the combination of the HIV (human immunodeficiency virus)-resistant activity material of 4-oxoquinoline compound or its pharmacologically acceptable salt or its solvate and one or more other types; Deng.

Background technology

The HIV (Human Immunodeficiency Virus (I type)) that belongs to retrovirus is the virus that causes AIDS (acquired immune deficiency syndrome (AIDS)).

HIV is target with the CD4 positive cell group such as helper cell, scavenger cell and dendritic cell, and destroys these immunologically competent cells and cause immune deficiency.

Therefore, AIDS can be treated or prevent to the medicament of eradicating HIV in vivo or suppressing its growth effectively.

Have the bimolecular rna gene in the shell of HIV (shell), and it is coated with envelope protein.The RNA coding characteristic is several enzymes (proteolytic enzyme, reversed transcriptive enzyme, intergrase) of virus etc.The reversed transcriptive enzyme and the intergrase of translation are present in the shell, proteolytic enzyme be present in the shell and shell outside.

HIV contact and invasion and attack host cell cause shelling, and the mixture of RNA and intergrase etc. are discharged in the tenuigenin.Reversed transcriptive enzyme is by rna transcription DNA, and the double-stranded DNA of generation total length.DNA is introduced into host cell nuclear, and is incorporated into by intergrase among the DNA of host cell.The DNA that integrates is changed into mRNA by the polysaccharase of host cell, and hiv protease etc. form viral required range protein by this mRNA is synthetic, and finally form virion, carries out sprouting and discharging of this virion then.

It is necessary that these viral specific enzymes are considered to the HIV growth.These enzymes have attracted people's attention as the target of exploitation antiviral drug, and have developed several anti-HIV medicaments.

For example, the zidovudine of selling as reverse transcriptase inhibitors, didanosine, lamivudine etc., and the indinavir of selling as proteinase inhibitor, nelfinavir etc.

In addition, adopted the multiple combined drug therapy (being also referred to as HAART (highly active antiretroviral therapy) usually) that uses these medicaments simultaneously.For example, use clinically " two kinds of reverse transcriptase inhibitors (zidovudine and didanosine; or tenofovir and emtricitabine) " and three kinds of medicaments of " non-nucleosides transcripting enzyme inhibitor (efavirenz) " or the combination of ritonavir " proteinase inhibitor (rltonavir, fosamprenavir or Reyataz R) with " unite use.This multiple combined drug therapy is becoming the main flow of AIDS therapy.

Yet some in known these medicaments can cause such as liver failure, nervus centralis entanglement side effects such as (as dizzy).In addition, the resistance that obtains medicament also is a problem.Worse, known HIV emergence shows multi-drug resistant in multiple combined drug therapy.

In this case, need develop new medicament further, particularly develop the anti-HIV medicament based on new mechanism, wherein expectation exploitation has the anti-HIV medicament of integrase inhibiting activities, because the intergrase of retrovirus the is HIV necessary enzyme of growing.

Yet, still find no the integrase inhibitor of effect so far.

Compound with integrase inhibiting activities is described below.

(patent is of the same clan: US2005/239819) described following compound [A] etc., it has integrase inhibiting activities (referring to patent documentation 1) as anti-HIV medicament to WO2004/046115.

Compound [A]

Wherein encircle the C of Cy for randomly replacing _3-10Carbocylic radical or the heterocyclic radical that randomly replaces; R ¹Be the C that randomly replaces _1-10Alkyl, the C that randomly replaces _3-10Carbocylic radical etc.; R ²Be hydrogen atom etc.; R ³¹Be hydrogen atom etc.; X is C-R ³²Or nitrogen-atoms; With Y be C-R ³³Or nitrogen-atoms (R wherein ³²And R ³³Be hydrogen atom etc. independently).

WO2004/046115 has also described following compound [B] etc., and it has integrase inhibiting activities as anti-HIV medicament.

Compound [B]

WO2005/087759 has described following compound [C] etc., and it has retrovirus integrase and suppress active (referring to patent documentation 2) as anti-HIV medicament.

Compound [C]

R wherein ₁Be H, C _1-6The C of alkyl or replacement _1-6Alkyl; Z is-C (O) OR ₂Or-C (O) CH ₂C (O) X; X be 5 or 6-unit aromatic ring or heterocycle or-C (O) OR ₂R ₂Be H or C _1-6Alkyl; R ₃, R ₄, R ₅And R ₆H, halogen, C respectively do for oneself _1-6Alkoxyl group ,-N (R ₈) (R ₉) ,-C (O) CH ₃,-C (O) CH ₂C (O) X ,-S (O) _n-R ₁₀Wherein n be 0,1 or 2, the heteroaryl of aryl, heteroaryl or the replacement of the Heterocyclylalkyl of the cycloalkyl of assorted alkyl, cycloalkyl, replacement, Heterocyclylalkyl, replacement, aryl, replacement; R ₈And R ₉H or C respectively do for oneself _1-2Alkyl; And R ₁₀Be C _1-6Alkyl etc., condition are if Z is-C (O) OR ₂, R so ₃, R ₄, R ₅And R ₆In at least one is-C (O) CH ₂C (O) X.

In addition, (patent is of the same clan: US2006/019906) described following compound [D] etc., it has integrase inhibiting activities (referring to patent documentation 3) as anti-HIV medicament to WO2005/113509.

Compound [D]

Wherein encircling Cy is to be selected from following group:

R is a hydrogen atom etc.; R ¹For

R wherein ¹¹For-(C _mH _2m)-OR ¹²,-(C _mH _2m)-SR ¹²,-(C _mH _2m)-SO ₂R ¹²(R wherein ¹²Be C _1-4Alkyl and m are 1 to 4 integer), saturated heterocyclic radical, sec.-propyl or the tertiary butyl etc.; R ³²Be hydrogen atom, ethyl, methoxyl group etc.; R ³³Be hydrogen atom etc.; And R ⁷Be hydrogen atom or hydroxyl.

Yet the 6-position that these publications are not disclosed in 4-Oxoquinoline ring has the compound of the benzyl that is replaced by heterocyclic radical, perhaps even do not have its a hint description.

In addition, (patent is of the same clan: US2006/084665) described following compound [E] etc., it has integrase inhibiting activities (referring to patent documentation 4) as anti-HIV medicament to WO2006/033422.

Compound [E]

Wherein encircle the C of Cy for randomly replacing _3-10Carbocylic radical or the heterocyclic radical that randomly replaces; R ¹The C that replaces for hydrogen atom, randomly _1-10Alkyl etc.; R ²Be hydrogen atom etc.; Z is C-R ³¹Or nitrogen-atoms, wherein R ³¹Be hydrogen atom etc.; X is C-R ³²Or nitrogen-atoms; With Y be C-R ³³Or nitrogen-atoms, wherein R ³²And R ³³The hydrogen atom etc. of respectively doing for oneself.

Yet this publication does not comprise in the specification sheets of the present invention open 4-oxoquinoline compound, perhaps even do not have its hint property description.

Patent documentation 1:WO2004/046115 (the 133rd page, embodiment 1-88)

Patent documentation 2:WO2005/087759

Patent documentation 3:WO2005/113509

Patent documentation 4:WO2006/033422

Summary of the invention

The problem to be solved in the present invention

According to the pharmacological research and the clinical effectiveness discovery of gained so far, anti-HIV medicament can effectively prevent or treat AIDS, and particularly having the inhibiting compound of intergrase may be effective anti-HIV medicament.

Therefore, the purpose of this invention is to provide a kind of compound, particularly have the compound of integrase inhibiting activities with HIV (human immunodeficiency virus)-resistant activity.

The mode of dealing with problems

The inventor is making great efforts the compound that discovery has HIV (human immunodeficiency virus)-resistant activity, and conscientious research has been carried out in the compound aspect that particularly has integrase inhibiting activities, has finished the present invention.

Promptly be exactly to the present invention relates to have compound (being abbreviated as compound [I] sometimes in this manual), its pharmacologically acceptable salt, its solvate of following formula [I] representative of integrase inhibiting activities and uses thereof.

Compound or pharmaceutically acceptable salt thereof or its solvate of following formula [I] representative:

Wherein

The monocyclic heterocycles base of ring A for randomly being replaced, wherein said monocyclic heterocycles base by 1 to 5 substituting group that is selected from following group of A comprise except carbon atom at least one be selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom;

Group A is by halogen atom, C _1-4Alkyl ,-(CH ₂) _n-OR ^A1,-NR ^A3R ^A4,-COR ^A2With-CONR ^A3R ^A4The group of forming, wherein R ^A1, R ^A2, R ^A3And R ^A4Identical or different, hydrogen atom or C respectively do for oneself _1-4Alkyl and n are 0 or 1 to 4 integer;

R ¹Be hydrogen atom,

Randomly by 1 to 3 C that is selected from the substituting group replacement of following group of B _1-6Alkyl,

Randomly by 1 to 5 C that is selected from the substituting group replacement of above-mentioned group of A _3-10Carbocylic radical, or

The heterocyclic radical that is replaced by 1 to 5 substituting group that is selected from above-mentioned group of A randomly, wherein said heterocyclic radical comprise except carbon atom at least one be selected from the heteroatoms of nitrogen-atoms, Sauerstoffatom and sulphur atom;

Group B is the group of being made up of following:

Randomly by 1 to 5 C that is selected from the substituting group replacement of above-mentioned group of A _3-10Carbocylic radical,

The heterocyclic radical that is replaced by 1 to 5 substituting group that is selected from above-mentioned group of A randomly, wherein said heterocyclic radical be for as defined above,

Halogen atom, cyano group,

-OR ^b1、-SR ^b1、-NR ^b2R ^b3，

-CONR ^b2R ^b3、-SO ₂NR ^b2R ^b3、-COR ^b1，

-NR ^b2COR ^b1、-SO ₂R ^b1、-NR ^b2SO ₂R ^b1，

-COOR ^B1,-NR ^B2COOR ^B1With-NR ^B4CO-NR ^B2R ^B3

R wherein ^B1, R ^B2, R ^B3And R ^B4Identical or different, hydrogen atom, C respectively do for oneself _1-4Alkyl, the C that is randomly replaced by 1 to 5 substituting group that is selected from above-mentioned group of A _3-10Carbocylic radical, or the heterocyclic radical that is randomly replaced by 1 to 5 substituting group that is selected from above-mentioned group of A, wherein said heterocyclic radical is for as defined above;

R ²Be hydrogen atom, C _1-4Alkyl or-OR ¹¹, R wherein ¹¹Be hydrogen atom or C _1-4Alkyl;

R ³And R ⁴Identical or different, hydrogen atom, halogen atom, C respectively do for oneself _1-4Alkyl or-OR ¹², R wherein ¹²Be hydrogen atom or C _1-4Alkyl;

R ⁵Be halogen atom, C independently of one another _1-4Alkyl or-OR ¹³, R wherein ¹³Be hydrogen atom or C _1-4Alkyl;

M is 0,1 or 2; With

R ⁶Be hydrogen atom, perhaps R ¹And R ⁶Carbon atom with its bonding forms randomly by 1 to 5 C that is selected from the substituting group replacement of above-mentioned group of A _3-10Cycloalkyl.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein encircling A is the monocyclic heterocycles base that comprises at least one nitrogen-atoms, described monocyclic heterocycles base is randomly replaced by 1 to 5 substituting group that is selected from group A, and via nitrogen atom bonding to phenyl ring.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [2] or its solvate, wherein encircling A is to be selected from following heterocyclic radical: 1-pyrrolidyl, 2-oxo-pyrrolidine-1-base, piperidino-(1-position only), 2-oxo-piperidine-1-base, 1-piperazinyl, beautiful jade subbase, thiomorpholine subbase, 3-oxo morpholine-4-base, 1,1-dioxy isothiazolidine-2-base, 2-Yang Dai oxazolidine-3-base and 3-oxo pyrazoles alkane-1-base, wherein said heterocyclic radical are randomly replaced by 1 to 5 substituting group that is selected from above-mentioned group of A.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein R ¹Be the C that is randomly replaced by 1 to 3 substituting group that is selected from following group of B _1-6Alkyl, and R ⁶Be hydrogen atom.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein R ²Be C _1-4Alkyl or-OR ¹¹, R wherein ¹¹Be hydrogen atom or C _1-4Alkyl.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein R ²Hydrogen atom.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein R ³And R ⁴Identical or different, the halogen atom of respectively doing for oneself.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein m is 1, and R ⁵Be halogen atom.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, wherein m is 0.

The compound or pharmaceutically acceptable salt thereof of above-mentioned [1] or its solvate, it is selected from:

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2),

6-[3-chloro-2-fluoro-5-(tetramethyleneimine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3),

6-[3-chloro-2-fluoro-5-(2-Yang Dai oxazolidine-3-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 5),

6-[3-chloro-2-fluoro-5-(piperidines-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 6),

6-[3-chloro-2-fluoro-5-(2-oxo-piperidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 7),

6-[3-chloro-2-fluoro-5-((R)-3-hydroxyl pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 8),

6-[3-chloro-2-fluoro-5-((S)-3-hydroxyl pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 9),

6-[3-chloro-2-fluoro-5-(2-methyl-3-oxo pyrazoles alkane-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 10),

6-[5-(4-ethanoyl piperazine-1-yl)-3-chloro-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 11),

6-[3-chloro-5-(3,3-two fluoropyrrolidines-1-yl)-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 12),

6-[3-chloro-2-fluoro-5-((R)-3-fluoropyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 13),

6-[3-chloro-2-fluoro-5-((S)-3-fluoropyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 14),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 15),

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 16),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 17),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 18),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 19),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-the 7-ethyl-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 20),

6-[3-chloro-5-(1,1-dioxo isothiazolidine-2-yl)-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 21),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 22),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 23),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 24),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 25),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 26),

6-[3-chloro-2-fluoro-5-(thiomorpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 27),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((1R, 2S)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 28),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 29),

6-[3-chloro-2-fluoro-5-(4-hydroxy piperidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 32),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 34),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((1R, 2S)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 35),

6-[3-chloro-2-fluoro-5-(pyridine-2-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 36),

6-[3-chloro-2-fluoro-5-(thiazol-2-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 37),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 38),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 39),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 40),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 41),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-hydroxymethyl-2-methoxyl group-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 42),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((R)-1-hydroxymethyl-2-methoxyl group-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 43),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 44),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 45),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 46),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 47),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 48),

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 49),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 50),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 51),

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 52),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 53),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 54),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 55),

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 56),

6-[3-chloro-2-fluoro-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 57)

6-[3-chloro-2,4-two fluoro-5-(3-oxo morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 58) and

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 59).

A kind of pharmaceutical composition, it comprises in above-mentioned [1] to [10] each compound or pharmaceutically acceptable salt thereof or its solvate and pharmaceutically acceptable carrier.

A kind of anti-HIV medicament, it comprises as each compound or pharmaceutically acceptable salt thereof or its solvate in above-mentioned [1] to [10] of activeconstituents.

A kind of hiv integrase inhibitor, it comprises as each compound or pharmaceutically acceptable salt thereof or its solvate in above-mentioned [1] to [10] of activeconstituents.

A kind of anti-HIV medicament, it comprises in above-mentioned [1] to [10] combination of each the compound or pharmaceutically acceptable salt thereof or the HIV (human immunodeficiency virus)-resistant activity material of its solvate and one or more other types.

Each compound or pharmaceutically acceptable salt thereof or its solvate purposes in the anti-HIV medicament of preparation in above-mentioned [1] to [10]

Each compound or pharmaceutically acceptable salt thereof or its solvate purposes in the preparation hiv integrase inhibitor in above-mentioned [1] to [10].

A kind of method that is used for preventing or treating Mammals HIV transmissible disease, it comprises to each compound or pharmaceutically acceptable salt thereof or its solvate in above-mentioned [1] to [10] of described administration significant quantity.

The method of above-mentioned [17], it further comprises the HIV (human immunodeficiency virus)-resistant activity material to one or more other types of administration significant quantity.

A kind of method that is used for suppressing the Mammals hiv integrase, it comprises to each compound or pharmaceutically acceptable salt thereof or its solvate in above-mentioned [1] to [10] of described administration significant quantity.

A kind of anti-HIV composition, it comprises in above-mentioned [1] to [10] each compound or pharmaceutically acceptable salt thereof or its solvate and pharmaceutically acceptable carrier.

A kind of pharmaceutical composition that is used to suppress hiv integrase, it comprises in above-mentioned [1] to [10] each compound or pharmaceutically acceptable salt thereof or its solvate and pharmaceutically acceptable carrier

The height that compound exhibits of the present invention goes out anti-hiv integrase suppresses active.

Therefore, these compounds can be to have hiv integrase to suppress active, are used for for example preventing or treating AIDS, as efficacious agents such as integrase inhibitor, antiviral drug, anti-HIV medicaments.In addition, by their anti-HIV medicaments are used in combination such as proteinase inhibitor, reverse transcriptase inhibitors etc. with it, they can be more effective anti-HIV medicaments.And because intergrase is had the high active specificity that suppresses, they can be to be used for human body safety, side effect medicament seldom.

Implement best mode of the present invention

Employed in this manual each substituting group, each symbol and each several part are defined as follows.

Described " halogen atom " is fluorine atom, chlorine atom, bromine atoms or iodine atom, preferred fluorine atom, chlorine atom or bromine atoms.

Described " C _1-4Alkyl " for having the straight or branched alkyl of 1 to 4 carbon atom, can mention methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl especially.

Described " C _1-6Alkyl " for having the straight or branched alkyl of 1 to 6 carbon atom; can mention methyl especially; ethyl; propyl group; sec.-propyl; butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, the 1-methyl butyl, the 1-ethyl propyl, the 2-ethyl propyl, 2, the 2-dimethyl propyl, 1, the 2-dimethyl propyl, tert-pentyl, hexyl, isohexyl, the 1-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, the 1-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group etc.

Described " C _3-10Cycloalkyl " for having 3 to 10 carbon atoms, the cycloalkyl of preferred 3 to 6 carbon atoms can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl and ring decyl especially.

Described " C _3-10Carbocyclic ring " for to have the saturated or unsaturated cyclic hydrocarbon radical of 3 to 10 carbon atoms, refer to aryl, cycloalkyl, cycloalkenyl group or its condensed ring.

For described " aryl ", can mention phenyl, naphthyl, pentalene base (pentalenyl), Azulene base (azulenyl) etc. especially, preferred phenyl and naphthyl, preferred especially phenyl.

For described " cycloalkyl ", can mention cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, adamantyl, norcamphane base etc. especially, preferred cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Described " cycloalkenyl group " comprises at least one, 1 or 2 two key preferably, can mention cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl (2 especially, 4-cyclohexadiene-1-base, 2,5-cyclohexadiene-1-base etc.), cycloheptenyl, cyclooctene base etc.

For the condensed ring of these " aryl ", " cycloalkyl " or " cycloalkenyl group ", can mention indenyl, indanyl, 1 especially, 4-dihydro naphthyl, 1,2,3,4-tetralyl (1,2,3,4-tetrahydrochysene-2-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl etc.), perhydro naphthyl etc.The condensed ring of phenyl and another ring preferably, more preferably indenyl, indanyl, 1,4-dihydro naphthyl, 1,2,3,4-tetralyl etc., preferred especially indanyl.

Described " randomly by 1 to 5 C that is selected from the substituting group replacement of group A _3-10Carbocylic radical " be above-mentioned definition " randomly by 1 to 5, preferred 1 to 3 C that the substituting group that is selected from following group of A replaces _3-10Carbocylic radical ", it comprises unsubstituted " C _3-10Carbocylic radical ".

Described " group A " is " halogen atom ", " C of above-mentioned definition by above-mentioned definition _1-4Alkyl " ,-(CH ₂) _n-OR ^A1,-NR ^A3R ^A4,-COR ^A2With-CONR ^A3R ^A4The group of forming, wherein R ^A1, R ^A2, R ^A3And R ^A4Identical or different, " the C of respectively do for oneself hydrogen atom or above-mentioned definition _1-4Alkyl " and n be 0 or 1 to 4 integer.

For described " (CH ₂) _n-OR ^A1", can mention hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, tert.-butoxy, hydroxymethyl, methoxymethyl, 2-(methoxyl group) ethyl etc. especially.

For described " NR ^A3R ^A4", can mention amino, methylamino-, ethylamino, third amino, sec.-propyl amino, tertiary butyl amino, dimethylamino, diethylamino, N-ethyl-N-methylamino-, N-methyl-N-propyl group amino, N-sec.-propyl-N-methylamino etc. especially.

For described " COR ^A2", can mention formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, 2 especially, 2-dimethyl propylene acyl group etc.

For described " CONR ^A3R ^A4", can mention formamyl, methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, sec.-propyl formamyl, tert-butyl formamyl, formyl-dimethylamino, diethylamino formyl radical, N-ethyl-N-methylamino formyl radical etc. especially.

For the described " C that is replaced by 1 to 5 substituting group that is selected from group A randomly _3-10Carbocylic radical "; can mention phenyl especially; naphthyl; the 2-fluorophenyl; the 2-chloro-phenyl-; the 2-bromophenyl; the 3-fluorophenyl; the 3-chloro-phenyl-; the 3-bromophenyl; the 4-fluorophenyl; the 2-aminomethyl phenyl; the 3-aminomethyl phenyl; the 4-aminomethyl phenyl; the 2-ethylphenyl; the 3-ethylphenyl; the 2-isopropyl phenyl; the 3-isopropyl phenyl; the 2-hydroxy phenyl; the 3-hydroxy phenyl; the 4-hydroxy phenyl; the 2-p-methoxy-phenyl; the 3-p-methoxy-phenyl; the 2-ethoxyl phenenyl; the 3-ethoxyl phenenyl; 2-propoxy-phenyl; 3-propoxy-phenyl; the 2-aminophenyl; the 3-aminophenyl; 2-(methylamino) phenyl; 3-(methylamino) phenyl; 2-(dimethylamino) phenyl; 3-(dimethylamino) phenyl; 2-(diethylamino) phenyl; 2-(N-ethyl-N-methylamino) phenyl; 2-(N-sec.-propyl-N-methylamino) phenyl; the 2-acetylphenyl; the 3-acetylphenyl; 2-(formamyl) phenyl; 3-(formamyl) phenyl; 2-(methylamino formyl radical) phenyl; 3-(methylamino formyl radical) phenyl; 2-(formyl-dimethylamino) phenyl; 3-(formyl-dimethylamino) phenyl; 2; the 3-difluorophenyl; 2; the 3-dichlorophenyl; 3; the 4-dichlorophenyl; 2; the 3-dibromo phenyl; 2; the 4-difluorophenyl; 2; the 4-dichlorophenyl; 2; the 5-dichlorophenyl; 2; the 6-dichlorophenyl; 2-chloro-3-fluorophenyl; 2-chloro-4-fluorophenyl; 2-chloro-5-fluorophenyl; 2-chloro-6-fluorophenyl; 3-chloro-2-fluorophenyl; 5-chloro-2-fluorophenyl; 5-bromo-2-chloro-phenyl-; 2-chloro-3-aminomethyl phenyl; 2-chloro-5-aminomethyl phenyl; 3-chloro-2-aminomethyl phenyl; 2-chloro-3-hydroxy phenyl; 2-chloro-5-hydroxy phenyl; 2-chloro-3-p-methoxy-phenyl; 2-chloro-5-p-methoxy-phenyl; 3-chloro-2-p-methoxy-phenyl; 2-chloro-3-aminophenyl; 2-chloro-5-aminophenyl; 2-chloro-3-(methylamino) phenyl; 2-chloro-5-(methylamino) phenyl; 2-chloro-3-(dimethylamino) phenyl; 2-chloro-5-(dimethylamino) phenyl; 2; 3; the 4-trifluorophenyl; 2-chloro-3; the 4-difluorophenyl; 2-chloro-3; the 5-difluorophenyl; 2-chloro-3; the 6-difluorophenyl; 2-chloro-4; the 5-difluorophenyl; 2-chloro-4; the 6-difluorophenyl; 3-chloro-2; the 4-difluorophenyl; 3-chloro-2; the 5-difluorophenyl; 3-chloro-2; the 6-difluorophenyl; 2; 3-two chloro-4-fluorophenyls; 2-chloro-3; 5; the 6-trifluorophenyl; 3-chloro-2; 4; the 5-trifluorophenyl; 3-chloro-2; 4; the 6-trifluorophenyl; 2; 3-two chloro-4; 5; the 6-trifluorophenyl; 3; 5-two chloro-3; 4; the 6-trifluorophenyl; 2; 6-two chloro-3; 4, the 5-trifluorophenyl; perfluorophenyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; 2-hydroxyl cyclopropyl; 2-hydroxyl cyclobutyl; 3-hydroxyl cyclobutyl; 2-hydroxycyclopent base; 3-hydroxycyclopent base; the 2-hydroxy-cyclohexyl; the 3-hydroxy-cyclohexyl; the 4-hydroxy-cyclohexyl; the 4-indanyl; 1H-indenes-4-base etc.

Described " heterocyclic radical " is to comprise except that carbon atom at least one, preferred 1 to 4 C that is selected from heteroatomic saturated or unsaturated (comprising that part is undersaturated and undersaturated fully) monocycle 4 to 6-units (preferred 5-unit or 6-unit) heterocyclic radical, these heterocyclic condensed ring or these heterocycles of nitrogen-atoms, Sauerstoffatom and sulphur atom and is selected from benzene, pentamethylene and hexanaphthene _3-10The isocyclic condensed ring.

For described " saturated monocyclic heterocycles base ", can mention azetidinyl, pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, 1, the 3-dioxolanyl, 1,3-oxygen thia cyclopentyl (oxathiolanyl) oxazolidinyl isoxazole alkyl, thiazolidyl, the isothiazole alkyl, piperidyl, piperazinyl, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranyl alkyl dioxin, morpholinyl, 3-oxo morpholinyl, thio-morpholinyl, 2-aza-oxo-cyclobutane base, 2-oxo-pyrrolidine base, 3-oxo pyrazoles alkyl, 2-Yang Dai oxazolidinyl, 1,1-dioxo isothiazole alkyl, 2-oxo-piperidine base, 4-oxo-piperidine base, 2,6-dioxopiperidine base etc.

For described " undersaturated monocyclic heterocycles base ", can mention pyrryl, furyl, thienyl, imidazolyl, 1,2-dihydro-2-oxo-imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, 1,2, the 4-triazolyl, 1,2, the 3-triazolyl, tetrazyl, 1,3,4-oxadiazole base, 1,2,4-oxadiazole base, 1,3, the 4-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, furazan base (furazanyl), pyridyl, pyrimidyl, 3,4-dihydro-4-oxo-pyrimidine base, pyridazinyl, pyrazinyl, 1,3, the 5-triazinyl, imidazolinyl, pyrazolinyl oxazolinyl (2-oxazolinyl, the 3-oxazolinyl, the 4-oxazolinyl) isoxazoline-3-yl, thiazoline, the isothiazoline base, pyranyl, 2-oxo pyranyl, 2-oxo-2,5-dihydrofuran base, 1,1-dioxo-1H-isothiazolyl etc.

For described " condensed heterocycle base ", can mention indyl (2-indyl for example, the 3-indyl, the 4-indyl, 7-indyl etc.), pseudoindoyl, 1,3-dihydro-1,3-dioxo pseudoindoyl, benzofuryl (2-benzofuryl for example, the 4-benzofuryl, 7-benzofuryl etc.), indazolyl, isobenzofuran-base, benzothienyl (2-benzothienyl for example, the 4-benzothienyl, 7-benzothienyl etc.) benzoxazolyl (2-benzoxazolyl for example, the 4-benzoxazolyl, 7-benzoxazolyl etc.), benzimidazolyl-(2-benzimidazolyl-for example, the 4-benzimidazolyl-, 7-benzimidazolyl-etc.), benzothiazolyl (2-[4-morpholinodithio base for example, 4 benzothiazolyls, 7-benzothiazolyl etc.), the indolizine base, quinolyl, isoquinolyl, 1,2-dihydro-2-oxoquinoline base, quinazolyl, quinoxalinyl, the cinnolines base, phthalazinyl, quinolizinyl, purine radicals, the pterin base, indolinyl, iso-dihydro-indole-group, 5,6,7, the 8-tetrahydric quinoline group, 1,2,3, the 4-tetrahydric quinoline group, 2-oxo-1,2,3, the 4-tetrahydric quinoline group, benzo [1,3] dioxolyl, 3,4-methylene radical dioxo pyridyl, 4,5-ethylene oxo-pyrimidine base, benzopyranyl, chromanyl, isochroman base etc.The condensed ring of preferred monocycle 5-unit or 6-unit's heterocycle and phenyl ring.

Described " the randomly heterocyclic radical that is replaced by 1 to 5 substituting group that is selected from group A " comprises unsubstituted " heterocyclic radical " for " randomly by 1 to 5, preferred 1 to 3 heterocyclic radical that the substituting group that is selected from the group A of above-mentioned definition replaces " of above-mentioned definition.

For described " heterocyclic radical ", preferably comprise 1 or 2 heteroatomic monocyclic heterocycles base, perhaps it condenses into the heterocyclic radical of ring with phenyl ring.

For described " randomly by 1 to 5 heterocyclic radical that is selected from the substituting group replacement of group A ", can mention the 1-pyrrolidyl especially, the 2-pyrrolidyl, the 3-pyrrolidyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the morpholine subbase, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, 4,5-dichloro thio phenyl-3-base, 2-oxo-2,5 dihydrofuran-3-base, 1,1-dioxo-1H-isothiazole-5-base, 4-methylthiazol-5-base, the 1-imidazolyl, the 2-imidazolyl, the 3-imidazolyl, the 4-imidazolyl, the 1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, the 2-oxazolyl, the 3-isoxazolyl, the 2-thiazolyl, the 3-isothiazolyl, the 2-pyridyl, 3-fluorine pyridine-2-base, 3-chloropyridine-2-base, 3-chloro-4-fluorine pyridine-2-base, 3,5-dichloropyridine-2-base, the 3-pyridyl, 2-fluorine pyridin-3-yl, 2-chloropyridine-3-base, 2-chloro-4-fluorine pyridin-3-yl, 2-chloro-5-fluorine pyridin-3-yl, 2,5-dichloropyridine-3-base, 2-chloro-6-fluorine pyridin-3-yl, 2,6-dichloropyridine-3-base, the 4-pyridyl, 2-fluorine pyridin-4-yl, 2-chloropyridine-4-base, 2-chloro-3-fluorine pyridin-4-yl, 2,3-difluoro pyridine-4-base, 2,3-dichloropyridine-4-base, 2,5-dichloropyridine-4-base, 2-chloro-6-fluorine pyridin-4-yl, 2,6-dichloropyridine-4-base, 2-chloro-3,6-difluoro pyridine-4-base, 2-chloro-3,5-difluoro pyridine-4-base, 2,3,6-trifluoromethyl pyridine-4-base, 2,3,5,6-ptfe pyridine-4-base, the 2-indyl, the 3-indyl, the 4-indyl, the 7-indyl, the 2-benzofuryl, the 4-benzofuryl, 7 benzofuryls, the 2-benzothienyl, the 4-benzothienyl, 7 benzothienyls, the 2-benzimidazolyl-, the 4-benzimidazolyl-, the 2-benzoxazolyl, the 4-benzoxazolyl, 7-benzoxazolyl 2-[4-morpholinodithio base, the 4-benzothiazolyl, the 7-benzothiazolyl, 2-benzo [1,3] dioxolyl, 4-benzo [1,3] dioxolyl, 5-benzo [1,3] dioxolyl, tetrahydropyrans-2-base etc.

Described " randomly by 1 to 3 C that is selected from the substituting group replacement of group B _1-6Alkyl " for above-mentioned definition " the C that is replaced by the substituting group of 1 to 3 group B that is selected from following definitions randomly _1-6Alkyl ", comprise unsubstituted " C _1-6Alkyl ".

Described " organizing B " is by the following group of forming: " randomly by 1 to 5 heterocyclic radical that is selected from the substituting group replacement of group A " of " randomly by 1 to 5 C3-10 carbocylic radical that is selected from the substituting group replacement of group A " of above-mentioned definition, above-mentioned definition, " halogen atom " of above-mentioned definition, cyano group

-OR ^b1、-SR ^b1、-NR ^b2R ^b3，

-CONR ^b2R ^b3、-SO ₂NR ^b2R ^b3、-COR ^b1，

-NR ^b2COR ^b1、-SO ₂R ^b1、-NR ^b2SO ₂R ^b1，

-COOR ^B1,-NR ^B2COOR ^B1With-NR ^B4CO-NR ^B2R ^B3

R ^B1, R ^B2, R ^B3And R ^B4Identical or different, " the C of respectively do for oneself hydrogen atom, above-mentioned definition _1-4Alkyl ", " C that is replaced by 1 to 5 substituting group that is selected from group A randomly of above-mentioned definition _3-10Carbocylic radical " or " the randomly heterocyclic radical that is replaced by 1 to 5 substituting group that is selected from group A " of above-mentioned definition.

For described " OR ^B1", can mention hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, phenoxy group, pyridine-2-base oxygen base, tetrahydropyrans-2-ylmethyl etc. especially.

For " SR ^B1", can mention thiohydroxy, methyl sulfane base, ethyl sulfane base, propylthio alkyl, sec.-propyl sulfane base, tert-butyl sulfane base etc. especially.

For described " NR ^B2R ^B3", can mention amino, methylamino, ethylamino, propyl group amino, sec.-propyl amino, tertiary butyl amino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propyl group amino, N-sec.-propyl-N-methylamino, phenyl amino, pyridine-2-base amino, N-methyl-N-phenyl amino etc. especially.

For described " CONR ^B2R ^B3", can mention formamyl, methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, sec.-propyl formamyl, tertiary butyl formamyl, formyl-dimethylamino, diethylamino formyl radical, N-ethyl-N-methylamino formyl radical, phenyl amino formyl radical etc. especially.

For described " SO ₂NR ^B2R ^B3", can mention sulfamyl, methyl sulfamyl, ethyl sulfamyl, propyl group sulfamyl, sec.-propyl sulfamyl, tertiary butyl sulfamyl, dimethylamino alkylsulfonyl, diethyl amino alkylsulfonyl, N-ethyl-N-methyl sulfamyl, phenyl sulfamoyl base etc. especially.

For described " COR ^B1"; can mention formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, 2 especially; 2-dimethyl propylene acyl group, benzoyl, tetramethyleneimine-1-base carbonyl, 2-fluoropyrrolidine-1-base carbonyl, 2-oxo-pyrrolidine-1-base carbonyl, piperidino-(1-position only) carbonyl, 4-oxo-piperidine-1-base carbonyl, lupetidine-1-base carbonyl, piperazine-1-base carbonyl, morpholine subbase carbonyl etc.

For " NR ^B2COR ^B1"; can mention formyl radical amino, acetylamino, propionyl amino, butyryl radicals amino, isobutyryl amino, 2 especially; 2-dimethyl propylene acyl amino, N-ethanoyl-N-methylamino, benzoyl-amido, tetramethyleneimine-1-base carbonylamino, 2-fluoropyrrolidine-1-base carbonylamino, 2-oxo-pyrrolidine-1-base carbonylamino, piperidino-(1-position only) carbonylamino, 4-oxo-piperidine-1-base carbonylamino, lupetidine-1-base carbonylamino, piperazine-1-base carbonylamino, morpholine subbase carbonylamino etc.

For " SO ₂R ^B1", can mention methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl, tertiary butyl alkylsulfonyl etc. especially.

For described " NR ^B2SO ₂R ^B1", can mention methyl sulphonyl amino, ethylsulfonyl amino, sulfonyl propyl base amino, sec.-propyl sulfuryl amino, tertiary butyl sulfuryl amino, N-methyl-N-(methyl sulphonyl) amino etc. especially.

For described " COOR ^B1", can mention carboxyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, tert-butoxycarbonyl etc. especially.

For " NR ^B2COOR ^B1", can mention methoxycarbonyl amino, ethoxy carbonyl amino, propoxycarbonyl amino, isopropoxy carbonyl amino, tert-butoxycarbonyl amino, N-(tert-butoxycarbonyl)-N-methylamino etc. especially.

For described " NR ^B4CO-NR ^B2R ^B3", can mention urea groups, 3-methyl urea groups, 3-ethyl urea groups, 1 especially, 3-dimethyl urea groups etc.

For the described " C that is replaced by 1 to 3 substituting group that is selected from following group of B randomly _1-6Alkyl "; can mention methyl especially; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; the tertiary butyl; amyl group; isopentyl; the 1-methyl butyl; the 1-ethyl propyl; the 2-ethyl propyl; 2; the 2-dimethyl propyl; 1; the 2-dimethyl propyl; tert-pentyl; hexyl; isohexyl; the 1-methyl amyl; 1; the 1-dimethylbutyl; 1; the 2-dimethylbutyl; 1; the 3-dimethylbutyl; the 1-ethyl-butyl; 1-ethyl-1-methyl-propyl; 1-ethyl-2-methyl-propyl; 1; 1; 2-trimethylammonium propyl group; 1; 2; 2-trimethylammonium propyl group; methyl fluoride; trifluoromethyl; the 1-chloroethyl; the 2-fluoro ethyl; the 2-chloroethyl; the 3-fluoropropyl; the 2-chloropropyl; 2; 2; the 2-trifluoroethyl; hydroxymethyl; methoxymethyl; ethoxyl methyl; the propoxy-methyl; the isopropoxy methyl; butoxymethyl; the isobutoxy methyl; the sec-butoxy methyl; the tert.-butoxy methyl; phenoxymethyl; pyridine-2-base oxo methyl; the 1-hydroxyethyl; the 2-hydroxyethyl; the 1-methoxy ethyl; the 2-methoxy ethyl; the 1-ethoxyethyl group; the 2-ethoxyethyl group; 1-methoxyl group-1-methylethyl; 2-propoxy-ethyl; 2-isopropoxy ethyl; the 2-butoxyethyl group; 2-isobutoxy ethyl; 2-sec-butoxy ethyl; 2-tert.-butoxy ethyl; 2-phenoxy group ethyl; 2-(pyridine-2-base oxygen base) ethyl; the 2-hydroxypropyl; 2-hydroxyl-1-methylethyl; 2-hydroxyl-1; the 1-dimethyl ethyl; 1-(hydroxymethyl) propyl group; the 3-hydroxypropyl; the 2-hydroxybutyl; the 4-hydroxybutyl; 2-hydroxyl amyl group; 5-hydroxyl amyl group; 2; 3-dihydroxyl-propyl group; 2; 3-dihydroxyl butyl; 2-hydroxyl-1-(hydroxymethyl) ethyl; 2-hydroxy-2-methyl propyl group; 1-(hydroxymethyl) butyl; 1-(hydroxymethyl)-2-methyl-propyl; 1-(hydroxymethyl)-2; the 2-dimethyl propyl; 1-(hydroxymethyl)-2-methyl butyl; 2-hydroxyl-1-phenylethyl; 2-hydroxyl-2-phenylethyl; 1-(hydroxymethyl)-2-phenylethyl; 1-(hydroxymethyl)-3-methyl butyl; 3-hydroxyl-1-methyl-propyl; 1; 1-dimethyl-3-hydroxypropyl; 1; 2-dimethyl-3-hydroxypropyl; 1-sec.-propyl-3-hydroxypropyl; 1-ethyl-3-hydroxypropyl; 2-hydroxyl-1-sec.-propyl propyl group; 1-ethyl-1-(hydroxymethyl) propyl group; 1; 1-dimethyl-2-hydroxypropyl; 1; 2-dimethyl-2-hydroxypropyl; 1-ethyl-2-hydroxypropyl; 4-hydroxyl-1-methyl butyl; 1-(hydroxymethyl) amyl group; amino methyl; (methylamino) methyl; (ethylamino) methyl; (dimethylamino) methyl; (N-ethyl-N-methylamino) methyl; the 1-amino-ethyl; the 2-amino-ethyl; 1-(methylamino) ethyl; 2-(methylamino) ethyl; 1-(ethylamino) ethyl; 2-(ethylamino) ethyl; 2-(dimethylamino) ethyl; methyl sulfane ylmethyl; 2-(methyl sulfane base) ethyl; the carboxyl methyl; the 2-carboxy ethyl; 2-carboxyl propyl group; 3-carboxyl propyl group; the carbamyl ylmethyl; 2-(formamyl) ethyl; methylamino formyl radical methyl; the formyl-dimethylamino methyl; 2-(phenyl amino formyl radical) ethyl; the 2-oxopropyl; the sulfonyloxy methyl ylmethyl; 2-(methyl sulphonyl) ethyl; the sulfamyl methyl; methyl sulfamyl methyl; dimethylamino alkylsulfonyl methyl; tertiary butyl sulfamyl methyl; 2-(acetylamino) ethyl; 2-(methyl sulphonyl amino) ethyl; 2-(ethoxy carbonyl amino) ethyl; benzyl; phenylethyl; the 3-phenyl propyl; the 4-phenyl butyl; 3; the 4-dichloro benzyl; 2-hydroxyl-2-phenylethyl; cyclopentyl-methyl; cyclohexyl methyl; 2-cyclohexyl ethyl; 1-cyclohexyl-2-hydroxyethyl; 1-cyclohexyl methyl-2-hydroxyethyl; phenyl amino formyl radical methyl; 2-(pyridine-2-yl) ethyl; 2-(imidazoles-1-yl) ethyl; 2-(benzo benzene sulphur-2-yl) ethyl; 2-beautiful jade subbase ethyl; 2-(4-methylthiazol quinoline-5-yl) ethyl; the 1-carboxy ethyl; 1-(formamyl) ethyl; 1-carboxyl-2-methyl-propyl; 1-(formamyl)-2-methyl-propyl; 2-hydroxyl-1-(hydroxymethyl) propyl group; 1-(hydroxymethyl)-2-mercaptoethyl; 1-(hydroxymethyl)-3-(methyl sulfane base) propyl group; 2-carboxyl-1-(hydroxymethyl) ethyl; 2-formamyl-1-(hydroxymethyl) ethyl; 2-(indol-3-yl)-1-(hydroxymethyl) ethyl; 2-(imidazol-4 yl)-1-(hydroxymethyl) ethyl; 2-(4-hydroxy phenyl)-1-(hydroxymethyl) ethyl; 3-formamyl-1-(hydroxymethyl) propyl group; 5-amino-1-(hydroxymethyl) amyl group; 2-(tetrahydropyrans-2-base oxygen base) ethyl; the acetylamino methyl; the methyl sulphonyl amino methyl; the methoxycarbonyl amino methyl; the sulfamyl methyl; (tert-butoxycarbonyl amino) methyl; (2,2-dimethyl propylene acyl amino) methyl; (N-tert-butoxycarbonyl-N-methylamino) methyl; the propionyl amino methyl; the butyryl radicals amino methyl; the isobutyryl amino methyl; the benzoyl-amido methyl; the ethoxy carbonyl amino methyl; (morpholine subbase carbonylamino) methyl; (3-methyl urea groups) methyl; (3-ethyl urea groups) methyl etc.

For R ¹, preferably can mention methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, methoxymethyl, ethoxyl methyl, 1-methoxy ethyl, 2-methoxy ethyl, 1-ethoxyethyl group, 1-methoxyl group-1-methylethyl etc.

Described " randomly by 1 to 5 C that is selected from the substituting group replacement of group A _3-10Cycloalkyl ", it is by R ₁And R ₆Form with the carbon atom of its bonding, for above-mentioned definition randomly by 1 to 5, preferred 1 to 3 " C that the substituting group that is selected from " the group A " of above-mentioned definition replaces _3-10Cycloalkyl ", and comprise unsubstituted " C _3-10Cycloalkyl ".

For the described " C that is replaced by 1 to 5 substituting group that is selected from group A randomly _3-10Cycloalkyl ", can mention cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl etc. especially.

" the monocyclic heterocycles base " of described " the randomly monocyclic heterocycles base that is replaced by 1 to 5 substituting group that is selected from group A " is for comprising except carbon atom at least one, preferred 1 to 4 saturated or unsaturated (comprising that part is undersaturated and undersaturated fully) monocycle 4-to 6-unit (preferably 5-unit or 6-unit) heterocyclic radical that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom.

For described " monocyclic heterocycles base ", can mention following heterocyclic radical especially.

Described " the randomly monocyclic heterocycles base that is replaced by 1 to 5 substituting group that is selected from group A " for above-mentioned definition randomly by 1 to 5, preferred 1 to 3 " monocyclic heterocycles heterocyclic radical " that the substituting group that is selected from " group A " of above-mentioned definition replaces comprises unsubstituted " monocyclic heterocycles base ".

Described " randomly by 1 to 5 monocyclic heterocycles base that is selected from the substituting group replacement of group A " for ring A; can mention the 1-pyrrolidyl especially; 2-oxo-pyrrolidine-1-base; 3-hydroxyl pyrrolidine-1-base; 3-fluoropyrrolidine-1-base; 3; 3-two fluoropyrrolidines-1-base; piperidino-(1-position only); 2-oxo-piperidine-1-base; 4-hydroxy piperidine-1-base; the 1-piperazinyl; 4-methylpiperazine-1-base; 4-ethanoyl piperazine-1-base; the morpholine subbase; 3-oxo morpholine-4-base; the thiomorpholine subbase; 1; 1-dioxo isothiazolidine-2-base; 2-Yang Dai oxazolidine-3-base; 3-oxo pyrazoles alkane-1-base; 2-methyl-3-oxo pyrazoles alkane-1-base; the 2-pyridyl; the 2-thiazolyl; 1; 2; 4-oxadiazole-3-base; the 5-methyl isophthalic acid; 2,4-oxadiazole-3-base etc.

Ring A is preferably the monocyclic heterocycles base that comprises at least one nitrogen-atoms, and described monocyclic heterocycles base is randomly replaced by 1 to 5 substituting group that is selected from group A, and via nitrogen atom bonding in formula [1] by the phenyl ring of following formula representative

For ring A, it is preferred being selected from following heterocyclic radical: the 1-pyrrolidyl, 2-oxo-pyrrolidine-1-base, piperidino-(1-position only), 2-oxo-piperidine-1-base, 1-piperazinyl, morpholine subbase, 3-oxo morpholine-4-base, thiomorpholine subbase, 1,1-dioxo isothiazolidine-2-base, 2-Yang Dai oxazolidine-3-base and 3-oxo pyrazoles alkane-1-base, wherein said heterocyclic radical are randomly replaced by 1 to 5 substituting group that is selected from group A.For ring A, it is further preferred being selected from following heterocyclic radical: 2-oxo-pyrrolidine-1-base, 2-oxo-piperidine-1-base, beautiful jade subbase and 3-oxo morpholine-4-base, wherein said heterocyclic radical are randomly replaced by 1 to 5 substituting group that is selected from group A.

For ring A, one of the most preferred embodiment is 2-oxo-pyrrolidine-1-base, another the most preferred embodiment is that right beautiful jade subbase.

Another embodiment preferred for ring A, can mention and be selected from following heterocyclic radical: the 1-pyrrolidyl, 2-oxo-pyrrolidine-1-base, piperidino-(1-position only), 2-oxo-piperidine-1-base, 1-piperazinyl, morpholine subbase, 3-oxo morpholine-4-base, thiomorpholine subbase, 1,1-dioxo isothiazolidine-2-base, 2-Yang Dai oxazolidine-3-base, 3-oxo pyrazoles alkane-1-base, 2-pyridyl, 2-thiazolyl and 1,2,4-oxadiazole-3-base, wherein said heterocyclic radical are randomly replaced by 1 to 5 substituting group that is selected from group A.

For the group A that is used to encircle A, halogen atom, C _1-4Alkyl ,-OR ^A1With-COR ^A2Be preferred, R wherein ^A1And R ^A2Identical or different, hydrogen atom or C respectively do for oneself _1-4Alkyl.

Preferably, R ¹Be the C that is randomly replaced by 1 to 3 substituting group that is selected from group B _1-6Alkyl, R ⁶Be hydrogen atom.More preferably, R ¹For randomly by 1 to 3-OR ^B1The C that replaces _1-6Alkyl, wherein R ^B1Be hydrogen atom or C _1-4Alkyl, and R ⁶Be hydrogen atom.

R ²Be preferably C _1-4Alkyl or-OR ¹¹, R wherein ¹¹Be hydrogen atom or C _1-4Alkyl.For R ²Another embodiment preferred, can mention hydrogen atom.

Preferably, R ³And R ⁴Identical or different, the halogen atom of respectively doing for oneself, more preferably, R ³Be fluorine atom and R ⁴Be the chlorine atom.

M is preferably 0 or 1, and more preferably 1.When m is 1, R then ⁵Be preferably halogen atom, more preferably fluorine atom.

Group for the following formula representative

Preferably can mention

Deng.Work as R ¹When being not hydrogen atom, R then ¹Be preferably the group of configuration with following formula representative

For the compound or pharmaceutically acceptable salt thereof of formula [I] representative, following compound is preferred.

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (reference example 30),

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (reference example 31),

6-[3-chloro-2-fluoro-5-(4-methylpiperazine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (reference example 33),

6-[3-chloro-2,4-two fluoro-5-(3-oxo morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 58),

Described " pharmacologically acceptable salt " can be any salt, as long as it is the compound formation non-toxic salt of representing with above-mentioned formula [I].The example comprises with the salt of mineral acid, with organic acid salt, with the salt of mineral alkali, with the salt of organic bases, with amino acid whose salt etc.

For with the salt of mineral acid, for example can mention salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrogen bromide etc.

For with organic acid salt, for example can mention salt with oxalic acid, propanedioic acid, toxilic acid, citric acid, fumaric acid, lactic acid, oxysuccinic acid, succsinic acid, tartrate, acetate, trifluoroacetic acid, glyconic acid, xitix, methylsulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids etc.

For with the salt of mineral alkali, can mention for example sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt etc.

For with the salt of organic bases, for example can mention and methylamine, diethylamine, Trimethylamine 99, triethylamine, thanomin, diethanolamine, trolamine, quadrol, three (hydroxymethyl) methylamine, dicyclohexyl amine, N, the salt of N '-dibenzyl-ethylenediamin, guanidine, pyridine, picoline, choline, cinchonine, morpholine, meglumine etc.

For with amino acid whose salt, for example can mention salt with Methionin, arginine, Aspartic Acid, L-glutamic acid etc.

Every kind of salt can obtain by compound and mineral alkali, organic bases, mineral acid, organic acid or amino acid reaction by formula [I] representative according to known method itself.

In the present invention, the pharmacologically acceptable salt particular certain cancers or the sylvite of the compound of formula [I] representative.

The compound or pharmaceutically acceptable salt thereof of molecule that described " solvate " is wherein solvent and the representative of its coordinate formula [I], it also comprises hydrate (being also referred to as aquo compound).Described solvate is preferably the acceptable solvent thing, such as 2/3 ethylate of the monohydrate of the monohydrate of the compound of formula [I] representative, 1/2 hydrate, dihydrate, sodium salt, a methylate, an ethylate, a second nitrile compound, dihydrochloride etc.

The solvate of the compound or pharmaceutically acceptable salt thereof of formula [I] representative can obtain according to known method itself.

In addition, the compound of above-mentioned formula [I] representative has various isomer.For example, when having asymmetric carbon atoms, can there be enantiomer and diastereomer, as steric isomer based on it.Therefore, all these isomer and composition thereof all comprise within the scope of the invention.For compound of the present invention, from various isomer, by product, metabolite or prodrug, separate and purifying be preferred, it is preferred having what be no less than 90% purity, it is preferred having what be no less than 95% purity.

The compound of formula [I] representative can be crystal or amorphous forms.

In addition, the compound of formula [I] representative can be with isotropic substance (for example ³H, ¹⁴C, ³⁵S etc.) mark.

In the present invention, the prodrug of the compound of formula [I] representative also can be useful medicament.

Described " prodrug " is meant the derivative of compound of the present invention, and it has can chemistry or the group that decomposes of metabolism, and is returned to the primary compound after in being administered to body, to show its inherent effect, to comprise complex compound and the salt that does not contain covalent linkage.

Described prodrug is used for for example improving the absorption and the target target site of oral administration.

As the site of wanting modification, reactive functional group can mention such as hydroxyl, carboxyl, amino, thiol group etc. at compound camber of the present invention.

The examples of groups of hydroxyl modification comprises ethanoyl, propionyl, isobutyryl, valeryl, benzoyl, 4-methyl benzoyl, dimethylamino formyl radical, sulfo group etc.Carboxy-modified examples of groups comprises ethyl, oxy acid methyl neopentyl, 1-(acetoxyl group) ethyl, 1-(oxyethyl group carbonyl oxygen base) ethyl, 1-(cyclohexyloxy carbonyl oxygen) ethyl, carboxyl methyl, (5-methyl-2-oxo-1,3-dioxo 1-4-yl) methyl, phenyl, o-tolyl etc.Amino modified examples of groups comprises hexyl carbamyl, 3-methylthio group-1-(kharophen) propyl group carbonyl, 1-sulfo group-1-(3-oxyethyl group-4-hydroxy phenyl) methyl, (5-methyl-2-oxo-1,3-dioxo-4-yl) methyl etc.

Compound of the present invention can be used as anti-HIV medicament or composition, integrase inhibitor, antiviral agent etc. and delivers medicine to Mammals (people, mouse, rat, hamster, rabbit, cat, dog, ox, sheep, monkey etc.).

When compound of the present invention is used as pharmaceutical composition or pharmaceutical preparation, its common and pharmaceutically acceptable carrier, vehicle, thinner, extender, disintegrating agent, stablizer, sanitas, buffer reagent, emulsifying agent, seasonings, tinting material, sweeting agent, thickening material, corrigent, solubilizing agent and other additive mix, described other additive itself is known, such as water, vegetables oil, alcohol (for example ethanol or benzylalcohol etc.), polyoxyethylene glycol, triacetin, gelatin, carbohydrate is (as lactose, starch etc.), Magnesium Stearate, talcum, lanolin, vaseline etc., and by ordinary method formation tablet, pill, pulvis, granule, suppository, injection, eye drops, liquid, capsule, lozenge, aerosol, elixir, suspensoid, emulsion, syrup etc., and per os or non-through stomach and intestine whole body or topical.

Although dosage changes with age, body weight, symptom, result of treatment, medication etc., for the adult, it typically is each 0.01mg to 1g, its oral administration or with injection type such as being administered once every days such as intravenous injection to repeatedly.

Anti-HIV medicament need keep its effect usually for a long time, so that not only can temporarily suppress viral growth effectively, and can suppress viral regrowth effectively.This means needs long term administration, also means for the effect that keeps the long period whole night usually to use high single dose inevitably.The administration of this long-term high dosage has increased the danger that causes side effect.

Given this, one of embodiment preferred of compound of the present invention is that such compound allows the height of oral administration to absorb, and such compound can keep the Plasma Concentration to drug compound for a long time.

Except above-mentioned, embodiment preferred as compound of the present invention, can mention have good pharmacological activity compound (for example, have strong hiv integrase and suppress the compound that active compound has high HIV (human immunodeficiency virus)-resistant activity), compound with good bioavailability (for example, have the compound of high cell membrane permeability, to the stable compound of metabolic enzyme, compound with low conjugated protein ability), the compound (for example, demonstrating low P450 (CYP)-active compound of inhibition etc.) of high safety.

In compound of the present invention, (particularly, hiv integrase suppresses active IC to have high pharmacological activity ₅₀Be lower than 0.1 μ M, preferably be lower than 0.01 μ M) and the compound of high oral absorption be preferred, its Plasma Concentration keeps for a long time after administration.

Use above-claimed cpd, expection can reduce the dosage and/or the frequency of the human compound of the present invention of administration.Preferred administration frequency is no more than one day twice, (two days one for example once a day, inferior) more preferably once a day.

The situation that new 4-Oxoquinoline of the present invention can be used for improving the viremia that is caused by HIV and/or keep its improvement, treatment virus infection be HIV transmissible disease and/or keep the situation of its improvement particularly.

As the index of " treatment ", " improvement " or " influence ", can adopt in the body minimizing of blood inner virus level particularly or HIV rna level.

" prevention AIDS " is meant the individuality that for example medicament is delivered medicine to the test HIV positive but do not develop the AIDS morbid state as yet; Medicament delivered medicine to show the AIDS morbid state of improvement after the treatment but still carry needs the HIV that eradicates, the individuality of worrying the AIDS recurrence; Owing to worry possible infection with medicament administration before infected by HIV; Deng.

The example that " other the anti-HIV medicament " that is used for multiple combined drug therapy reaches " other HIV (human immunodeficiency virus)-resistant activity material " comprises anti-HIV antibody or other antibody, HIV vaccine or other vaccine, immunostimulant is such as Interferon, rabbit, Interferon, rabbit agonist etc., the ribozyme of anti-HIV, the HIV antisense drug, hiv reverse transcriptase inhibitor, the hiv protease inhibitor, hiv integrase inhibitor, bind receptor (the CD4 of the host cell of virus identification, CXCR4, CCR5 etc.) and the binding inhibitors (CCR5 antagonist etc.) between this virus, archaeal dna polymerase inhibitor or DNA synthetic inhibitor, act on the medicament of HIVp24, the HIV fusion inhibitor, IL-2 agonist or antagonist, the TNF-alpha-2 antagonists, alpha-glucosidase inhibitor, purine nucleoside phosphorylase inhibitor, apoptosis agonist or inhibitor, anticholinesterase, immunomodulator etc.

The specific examples of described hiv reverse transcriptase inhibitor comprises Retrovir (R) (zidovudine), Epivir (R) (lamivudine), Zerit (R) (sanilvudine), Videx (R) (didanosine), Hivid (R) (zalcitabine), Ziagen (R) (abacavir sulfate), Viramune, (R) (nevirapine), Stocrin, (R) (efavirenz), Rescriptor (R) (delavirdine mesylate salt), Combivir (R) (zidovudine+lamivudine), Trizivir (R) (abacavir sulfate+lamivudine+zidovudine), Coactinon (R) (emivirine), Phosphonovir (R), Coviracil (R), Aovudine (3 '-fluoro-3 '-deoxythymidine), Thiovir (thiophosphoryl formic acid), Capravirin (5-[(3, the 5-dichlorophenyl) sulfo-]-4-sec.-propyl-1-(4-pyridylmethyl) imidazoles-2-methyl alcohol carboxylamine), fumaric acid tenofovir disoproxil (fumaric acid (R)-[[2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl] phosphonic acids two (isopropoxy carbonyl oxy methyl) ester), DPC-083 ((4S)-6-chloro-4-[(1E)-cyclopropyl vinyl]-3,4-dihydro-4-trifluoromethyl-2 (1H)-quinazolinone), DPC-961 ((4S)-6-chloro-4-(cyclopropyl acethlene base)-3,4-dihydro-4-(trifluoromethyl)-2 (1H)-quinazolinone), DAPD ((-)-β-D-2,6-diaminopurine dioxolane), Immunocal, MSK-055, MSA-254, MSH-143, NV-01, TMC-120, DPC-817, GS-7340, TMC-125, SPD-754, D-A4FC, capravirine, UC-781, emtricitabine, Aovudine, Phosphazid, BCH-10618, DPC-083, Etravirine, BCH-13520, MIV-210, abacavir sulfate/lamivudine, GS-7340, GW-5634, GW-695634 etc., wherein (R) is meant registered trademark (down together), and the name of other medicament is called common name.

The specific examples of described hiv protease inhibitor comprises Crixivan (R) (sulfuric acid oxyacetic acid Indinavir); Saquinavir; Invirase (R) (saquinavir mesylate); Norvir (R) (ritonavir); Viracept (R) (Viracept); rltonavir; Prozei (R) (amprenavir); Kaletra (R) (ritonavir+rltonavir); two methylsulfonic acid mozenavir ([4R-(4 α; 5 α; 6 β)]-1; 3-two [(3-aminophenyl) methyl] six hydrogen-5; 6-dihydroxyl-4; 7-two (phenyl methyl)-2H-1; 3-diaza heptan is because of-2-ketone dimethanesulfonate); tipranavir (3 '-[(1R)-1-[(6R)-5; 6-dihydro-4-hydroxyl-2-oxo-6-phenylethyl-6-propyl group-2H-pyrans-3-yl] propyl group]-5-(trifluoromethyl)-2-pyridine sulfonamide); LASINAVIR (N-[5 (S)-(tert-butoxycarbonyl amino)-4 (S)-hydroxyl-6-phenyl-2 (R)-(2; 3; 4-trimethoxy benzyl) caproyl]-L-Xie Ansuan 2-methoxy-ethylene acid amides); KNI-272 ((the R)-N-tertiary butyl-3-[(2S; 3S)-the 2-hydroxyl-3-N-[(R)-2-N-(isoquinoline 99.9-5-base oxygen base ethanoyl) amino-3-methyl sulfo-propionyl] amino-4-phenyl butyryl radicals]-5; 5-dimethyl-1; 3-thiazolidine-4-methane amide); GW-433908; TMC-126; DPC-681; ball alkene (buckminsterfullerene); MK-944A (MK944 (N-(2 (R)-hydroxyl-1 (S)-indanyl)-2 (R)-phenyl methyl-4 (S)-hydroxyl-5-[4-(2-benzo [b] furfuryl)-2 (S)-(tertiary butyl carbamyl) piperazine-1-yl] valeramide)+indinavir sulfate); JE-2147 ([2 (S)-oxo-4-phenyl methyl-3 (S)-[(2-methyl-3-oxygen base) phenylcarbonyl group amino]-1-oxa-butyl]-4-[(2-aminomethyl phenyl) methylamino-] carbonyl-4 (R)-5; 5-dimethyl-1; the 3-thiazole); BMS-232632 ((3S; 8S; 9S; 12S)-3; 12-two (1; the 1-dimethyl ethyl)-8-hydroxyl-4; 11-dioxo-9-(phenyl methyl)-6-[[4-(2-pyridyl) phenyl] methyl]-2; 5; 6; 10; 13-pentaaza tetradecane dicarboxylic acid dimethyl ester); DMP-850 ((4R; 5S; 6S; 7R)-1-(3-amino-1H-indazole-5-ylmethyl)-4; 7-dibenzyl-3-butyl-5; 6-dihydroxyl perhydro-1,3-diaza heptan is because of-2-ketone); DMP-851; RO-0334649; Nar-DG-35; R-944; VX-385; TMC-114; tipranavir; fosamprenavir sodium; fosamprenavir calcium; Darunavir; GW-0385; R-944; RO-033-4649; AG-1859 etc.

The illustrative examples of described hiv integrase inhibitor is S-1360; L-870810 etc.; the example of described archaeal dna polymerase inhibitor or DNA synthetic inhibitor is Foscavir (R); ACH-126443 (L-2 '; 3 '-two dehydrogenations-dideoxy-5-fluorine cytidine); Entecavir ((1S; 3S; 4S)-and 9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl] guanine); poon element (calanolide) A ([10R-(10 α; 11 β; 12 α)]-11; 12-dihydro-12-hydroxyl-6; 6; 10; 11-tetramethyl--4-propyl group-2H; 6H; 10H-benzo [1; 2-b:3; 4-b ': 5; 6-b "] three pyran-2-ones); the plain B of poon; NSC-674447 (1; 1 '-Cellmic C 121); Iscador (mistletoe (viscum alubm) extract); Rubutecan etc.; the illustrative examples of described HIV antisense drug is HGTV-43; GEM-92 etc.; the illustrative examples of described anti-HIV antibody or other antibody is NM-01; PRO-367; KD-247; Cytolin (R); TNX-355 (CD4 antibody); AGT-1; PRO-140 (CCR5 antibody); anti--CTLA-4MAb etc.; the illustrative examples of described HIV vaccine or other vaccine is ALVAC (R); AIDSVAX (R); Remune (R); HIV gp41 vaccine; HIV gp120 vaccine; HIV gp140 vaccine; HIV gp160 vaccine; HIV p17 vaccine; the HIVp24 vaccine; HIV p55 vaccine; AlphaVax Vector System; canarypox gp160 vaccine; AntiTat; MVA-F6 Nef vaccine; HIV rev vaccine; the C4-V3 polypeptide; p2249f; VIR-201; HGP-30W; TBC-3B; PARTICLE-3B etc.; Antiferon (interferon-' alpha ' vaccine) etc.; the illustrative examples of described Interferon, rabbit or Interferon, rabbit agonist is Sumiferon (R); MultiFeron (R); interferon; Reticulose; humanleukocyteinterferon-etc.; the illustrative examples of described CCR5 antagonist is SCH-351125 etc.; the illustrative examples of the medicament of the described HIV of acting on p24 is GPG-NH2 (glycyl-prolyl-G-NH2) etc.; the illustrative examples of described HIV fusion inhibitor is FP-21399 (1; 4-two [3-[(2; the 4-dichlorophenyl) carbonylamino]-2-oxo-5; 8-disodium alkylsulfonyl] naphthyl-2; 5-Dimethoxyphenyl-1; the 4-dihydrazone); T-1249; SyntheticPolymeric Construction No3; pentafuside; FP-21399; PRO-542; Enfuvirtide etc.; the illustrative examples of described IL-2 agonist or antagonist is an interleukin II; Imunace (R); Multikine (R); Ontak (R); Ontak (R) etc.; the illustrative examples of described TNF-alpha-2 antagonists is Thalomid (R) (Thalidomide); Remicade (R) (infliximab); sulfogel polysaccharide etc.; the illustrative examples of described alpha-glucosidase inhibitor is Bucast (R) etc.; the illustrative examples of described purine nucleoside phosphorylase inhibitor is a peldesine (2-amino-4-oxo-3H; the 5H-7-[(3-pyridyl) methyl] pyrrolo-[3; 2-d] pyrimidine) etc.; the illustrative examples of described apoptosis agonist or inhibitor is Arkin Z (R); Panavir (R); Coenzyme Q10 99.0 (2-ten (3-methyl-2-crotonylidene)-5; 6-dimethoxy-3-methyl-para benzoquinone) etc.; the illustrative examples of described acetylcholinesterase depressant is Cognex (R) etc., and the illustrative examples of described immunomodulator is Imunox (R); Prokine (R); the Met--enkephalin (6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin); WF-10 (the tetrachlorodecaoxide solution that 10-doubly dilutes); Perthon; PRO-542; SCH-D; UK-427857; AMD-070; AK-602 etc.

In addition, other exemplary example is Neurotropin (R), Lidakol (R), Ancer20 (R), Ampligen (R), Anticort (R), Inactivin (R), PRO-2000, Rev M10 gene, the specific cytotoxic T cell of HIV (CTL immunotherapy, ACTG rules 080 therapy, CD4-ζ gene therapy), SCA is conjugated protein, the RBC-CD4 mixture, the motexafin gadolinium, GEM-92, CNI-1493, (±)-FTC, Ushercell, D2S, BufferGel (R), VivaGel (R), the Glyminox vaginal jellies, Sodium Lauryl Sulphate BP/USP, 2F5,2F5/2G12, VRX-496, Ad5gag2, BG-777, IGIV-C, BILR-255 etc.

" other anti-HIV medicament " and " other HIV (human immunodeficiency virus)-resistant activity material " as the multiple combined drug therapy that uses with compound of the present invention are preferably reverse transcriptase inhibitors and proteinase inhibitor.Two or three in addition more kinds of medicament can be used in combination, one of wherein be used in combination medicament and be preferred embodiment with different mechanisms of action.In addition, the preferred selection do not have the medicament that doubles side effect.

The specific examples of described medicament combination comprises following combination: efavirenz, tynofovir, emtricitabine, Indinavir, nelfinavir, Reyataz R (atazanavir), ritonavir+Indinavir, ritonavir+rltonavir, ritonavir+Saquinavir, didanosine+lamivudine, zidovudine+didanosine, stavudine+didanosine, zidovudine+lamivudine, stavudine+lamivudine and tynofovir+emtricitabine and compound of the present invention [I] (Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adultsand Adolescents.August 13,2001).Particularly preferably be and efavirenz, Indinavir, nelfinavir, tynofovir, emtricitabine, being used in combination of two kinds of medicaments of zidovudine and lamivudine, and with zidovudine+lamivudine, tynofovir+lamivudine, tynofovir+zidovudine, tynofovir+efavirenz, tynofovir+nelfinavir, tynofovir+Indinavir, tynofovir+emtricitabine, emtricitabine+lamivudine, emtricitabine+zidovudine, emtricitabine+efavirenz, emtricitabine+nelfinavir, emtricitabine+Indinavir, nelfinavir+lamivudine, nelfinavir+zidovudine, nelfinavir+efavirenz, nelfinavir+Indinavir, efavirenz+lamivudine, being used in combination of three kinds of medicaments of efavirenz+zidovudine or efavirenz+Indinavir.

Under the situation of combination medicine-feeding, the medicament administration simultaneously that compound of the present invention can will use in (medicinal composition hereinafter referred to as) with combination or by the certain time interval administration.Under the situation of combination medicine-feeding, can administration comprise the pharmaceutical composition of compound of the present invention and medicinal composition.Alternatively, administration comprises the pharmaceutical composition of compound of the present invention and comprises the pharmaceutical composition of medicinal composition respectively.Compound of the present invention and described medicinal composition medicine-feeding way can be identical or different.

Under the situation of combination medicine-feeding, compound of the present invention can by the single dose administration of 0.01mg to 1g once a day or one day several times, perhaps can be by minimum minimum dose administration.Described medicinal composition can be by the dosed administration that is generally used for preventing or treating the HIV transmissible disease, for example the single dose of 0.01mg to 0.3g.Alternatively, can be by the minimum dose administration.

Provide some examples of the preparation method of embodiment of the present invention compound used therefor below.Yet the preparation method of The compounds of this invention is not limited to these examples.

Even not explanation in the preparation method also can effectively prepare such as introducing following method: protecting group is incorporated in the functional group, then goes protection in subsequent step when needed; Make functional group carry out each step, and in proper step, this groups converted is become required functional group as precursor; Exchange the order of corresponding preparation method and step; Deng.

Processing in each step all can be used ordinary method and carried out, and wherein separates and purifying is as required by selecting or make up ordinary method, waits such as crystallization, recrystallization, distillation, distribution, silica gel chromatography, preparation HPLC and carries out.

The preparation method 1

Hal wherein ¹Be halogen atom, preferred bromine atoms or iodine atom, Hal ²Be halogen atom, preferred fluorine atom or chlorine atom, R ^C1And R ^C2Identical or different, C respectively does for oneself _1-4Alkyl is such as methyl, ethyl etc., R ^7AFor carboxyl-protecting group such as C _1-4Alkyl (for example, methyl, ethyl etc.), benzyl etc., R ^P1For hydroxyl-protecting group such as ethanoyl, methoxycarbonyl, methoxymethyl, methoxy ethoxy methyl, trimethyl silyl, t-butyldimethylsilyl, tert-butyl diphenylmethyl silylation etc., other symbol is for as defined above.

Step 1

Can obtain compound [3] from compound [2] by conventional halogenation.

For example, can be by in solvent ratio such as trifluoromethayl sulfonic acid, acetate, the vitriol oil, dimethyl formamide etc., be cooled under the heating, using compound [2] and halogenating agent, obtaining compound [3] such as reactions such as bromine, N-bromosuccinimide, N-iodosuccinimides.

Step 2

Can obtain acyl halide from compound [3] according to conventional methods, for example, by at solvent ratio such as hydrocarbon flux (for example toluene, dimethylbenzene etc.); Halon solvent (for example methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.); Ester solvent (for example ethyl acetate etc.)) etc. in, be cooled under the heating, compound [3] and halogenating agent are such as reactions such as oxalyl chloride, thionyl chloride.

For example, when thionyl chloride is used as halogenating agent, can add the dimethyl formamide of catalytic amount.

Can be by under extremely heating in room temperature; alkali such as triethylamine, diisopropylethylamine, salt of wormwood, pyridine etc. in the presence of, in solvent acyl halide and compound [4] reaction, and room temperature to the heating under; compound and compound [5] reaction with obtaining obtain compound [6].Compound [6] can be E form, Z-shaped formula or its mixture.

As solvent, can mention that hydrocarbon flux is such as benzene, toluene, hexane, dimethylbenzene etc.; Halon solvent ratio such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is such as 1,4-diox, ether, 1,2, glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent is such as acetonitrile etc.; Ester solvent is such as ethyl acetate etc.; Its mixed solvent etc.

Alternatively, also can be by acyl halide and diethyl malonate that in two steps, replaces compound [4] and dimethylformamide dimethyl acetal reaction, compound and compound [5] reaction with obtaining obtain compound [6].

Step 3

Can be by in solvent, alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert.-butoxide, sodium hydride, potassium hydride KH etc. in the presence of, cyclisation compound [6] obtains compound [7].

As one of preferred manufacturing procedure, can be by in solvent, 1,8-diazabicylo [5.4.0]-7-undecylene exists down, and cyclisation compound [6] under room temperature extremely heats obtains compound [7].

As solvent, can mention that hydrocarbon flux is such as benzene, toluene, hexane, dimethylbenzene etc.; Halon solvent ratio such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is such as 1,4-diox, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent is such as dimethyl formamide, methyl-sulphoxide, acetonitrile etc.; Its mixed solvent etc.

Step 4

Can pass through alkoxylated compounds [7] according to conventional methods to introduce R ², obtain compound [8].

For example, work as R ²For-OR ¹¹' (R wherein ¹¹' be C _1-4Alkyl) time, can in solvent ratio such as methyl alcohol, ethanol, propyl alcohol, butanols etc., make compound [7] and metal alkoxide reaction, obtain compound [8] by under heating.

Select corresponding solvent and the metal alkoxide of alkoxyl group with expectation.Work as R ²During for methoxyl group, reaction can be carried out with sodium methylate or potassium methylate in methanol solvate.Work as R ²During for oxyethyl group, reaction can be carried out with sodium ethylate or potassium ethylate in alcohol solvent.

Also can be without this step, the fluorine atom by using compound [2] wherein or compound [3] is by R ²The compound that replaces obtains compound [8].

Step 5

Can obtain compound [9] by introducing protecting group according to conventional methods to the hydroxyl of compound [8].

Alternatively; also can obtain compound [9] according to conventional methods as follows: introduce protecting group by hydroxyl to compound [6]; make the compound that obtains carry out cyclisation, make the compound that obtains carry out alkoxylate according to the method identical with step 4 according to the method identical with step 3.

For example, work as R ^P1During for the tert-butyl dimetylsilyl, compound [8] can at room temperature in the presence of imidazoles, react with the chlorination t-butyldimethylsilyl in dimethyl formamide or toluene solvant.

Work as R ^P1During for methoxycarbonyl, compound [8] can in the presence of pyridine, react with methyl-chloroformate in chloroform solvent being cooled under the room temperature.

In preparation method of the present invention, also can using wherein, the fluorine atom of compound [2] is replaced compound [2] to obtain wherein R by the compound of hydrogen atom or methoxyl group replacement ²Compound [3], compound [6], compound [7], compound [8] and compound [9] for hydrogen atom or methoxyl group.

The preparation method 2

Wherein Hal is that halogen atom is such as chlorine atom, bromine atoms etc. ,-B (OR ^C3) (OR ^C4) be-B (OH) ₂,-B (OCH ₃) ₂,-B (OCH (CH ₃) ₂) ₂, 4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane (dioxaborolan)-2-bases, 5,5-dimethyl-1,3,2-dioxaborinan-2-base etc., other symbol is for as defined above.

Step 1

Can in the presence of alkali and catalyzer,, obtain compound [10] by under argon gas or nitrogen atmosphere and heating by compound [9] and tetramethyl ethylene ketone borine, boric acid ester or the reaction of two boron esters.

As described two boron esters, can mention two (neopentylglycolato), two boron, two (tetramethyl ethylene ketone base (pinacolato)), two boron etc.

As described catalyzer, can mention that palladium catalyst is such as Pd (PPh ₃) ₄, PdCl ₂(dppb), PdCl ₂(dppf), PdCl ₂(dppf) CH ₂Cl ₂, PdCl ₂(PPh ₃) ₂, Pd (OAc) ₂, PdCl ₂, palladium black, palladium carbon etc.

As described alkali, can mention quadrol, yellow soda ash, hydrated barta, potassiumphosphate, cesium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert.-butoxide, triethylamine, potassium acetate etc. usually.

As part, can add triphenylphosphine, three (2-toluyl) phosphine, 2-(dicyclohexyl phosphino-) xenyl etc.

Alternatively, compound [9] can be in the presence of n-Butyl Lithium with boric acid ester such as reactions such as boric acid three isobutyl esters, trimethyl borates.

As described solvent, can mention methyl-sulphoxide, 1,4-diox, tetrahydrofuran (THF), toluene, 1,2-glycol dimethyl ether, water etc.

Step 2

Can carry out the Suzuki reaction by compound [10] and compound [11], obtain compound [12].

For example, can be under heating, at solvent ratio such as dimethyl formamide, acetonitrile, alcoholic solvent (methyl alcohol for example, ethanol etc.), 1, the 2-glycol dimethyl ether, tetrahydrofuran (THF), toluene, water, in its mixed solvent etc., (for example four (trityl group phosphines) close palladium such as palladium catalyst at catalyzer, dichloro two (trityl group phosphine) closes palladium (II), acid chloride-triphenylphosphine etc.), nickel catalyzator is nickelous chloride for example, chlorination 1, two (diphenyl phosphine) propane nickel (II) of 3-etc.) and alkali such as yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, potassiumphosphate, triethylamine, sodium hydrogen phosphate, cesium carbonates etc. exist down, make compound [10] and compound [11] reaction, obtain compound [12].

This reaction can be by enhancings such as adding lithium chlorides.

Step 3

Can be according to conventional methods hydroxyl protecting group by elimination of compound [12] obtain compound [I-1].

For example, work as R ^P1During for ethanoyl or methoxycarbonyl, can be by handling such as heating compound [12] with concentrated hydrochloric acid; Heating compound in strong aqua [12] etc. goes protection.

For example, work as R ^P1During for t-butyldimethylsilyl, can go protection by the following method: at room temperature in tetrahydrofuran (THF), handle compound [12] with tetrabutylammonium; In tetrahydrofuran (THF), use sodium-hydroxide treatment compound [12]; To heating, handle compound [12] etc. in room temperature with acetate-water-tetrahydrofuran (THF).

Work as R ^P1During for ethanoyl or methoxycarbonyl, can make compound [12] and alkali such as reactions such as sodium hydroxide, potassium hydroxide, obtain compound [I-2] by under heating.

Step 4

Can by in room temperature to heating, in solvent, alkaline condition such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. or compound [I-1] is hydrolyzed at acidic conditions under such as hydrochloric acid, sulfuric acid etc., obtain compound [I-2].

As described solvent, can mention that alcoholic solvent is such as methyl alcohol, ethanol, n-propyl alcohol, Virahol etc.; Hydrocarbon flux is such as benzene, toluene, hexane, dimethylbenzene etc.; Ether solvents is such as 1,4-diox, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Water; Its mixed solvent etc.

Step 5

Can obtain compound [46] by the following method: under heating, in solvent, make glycol dibromide and reaction, the compound that obtains and trimethylchlorosilane are reacted, and the aqueous solution that adds compound [11] in this reaction mixture reacts.

As described solvent, can mention ether solvents such as 1,4-diox, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Hydrocarbon flux is such as benzene, toluene, hexane, dimethylbenzene etc.; Deng.

Step 6

Can be by being cooled under the heating, in solvent, catalyzer and when needing part such as triphenylphosphine, three (2-furyl) phosphine etc. in the presence of, make compound [46] and compound [9] reaction, obtain compound [12].

As described catalyzer, can mention that palladium catalyst closes palladium, three (dibenzalacetone) such as two (dibenzalacetones) and closes two palladiums, dichloro two (triphenylphosphine) and close palladium, dichloro two (benzonitrile) and close that palladium, dichloro quadrol close palladium, acid chloride, four (triphenylphosphine) closes palladium etc.; Nickel catalyzator etc.

The preparation method 3

The preparation embodiment of compound [11]

Hal wherein ³Be halogen atom, preferred bromine atoms or iodine atom, R ^P2For hydroxyl-protecting group such as ethanoyl, methoxycarbonyl, methoxymethyl, methoxy ethoxy methyl, trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl etc., ring A ' is for containing the ring A of NH as the ring integral part, such as tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine, isothiazolidine, oxazolidine, pyrazolidine etc.; Other symbol is for as defined above, and condition is a substituent R ⁵Can not be bonded to the * position.

Step 1

According to the method identical, can obtain compound [14] by halogenated compound [13] according to conventional methods with preparation method 1 step 1.

Step 2

Can obtain compound [15] by reducing compound [14] according to conventional methods.

For example, can be in solvent ratio such as tetrahydrofuran (THF) etc., reductive agent such as lithium aluminum hydride, sodium boorohyride, borine-tetrahydrofuran (THF) mixture etc. in the presence of, make compound [14] reaction under the heating being cooled to, obtain compound [15].

This reduction also can be by via carrying out via the method for mixing acid acid anhydrides or via the method for acyl halide.

Step 3

According to the method identical, can obtain compound [16] by introducing protecting group according to conventional methods to the hydroxyl of compound [15] with preparation method 1 step 5.

Step 4

Can obtain compound [18] by making compound [16] and compound [17] reaction.

For example, can being cooled under the heating, in solvent, in the presence of catalyzer and alkali, make compound [16] and compound [17] reaction, obtain compound [18] by under argon gas or nitrogen atmosphere.

As described catalyzer, can mention that palladium catalyst is such as Pd ₂(dba) ₃● CHCl ₃, four (triphenylphosphines) close palladium, dichloro two (triphenylphosphine) close palladium (II), acid chloride, etc.; Copper catalyst is such as copper, cupric chloride (I), cupric bromide (I), cupric iodide (I) etc.; Deng.

As described alkali, can mention yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, potassiumphosphate, triethylamine, Potassium monofluoride, cesium fluoride, sodium hydrogen phosphate, cesium carbonate etc.

When using palladium catalyst, can add triphenylphosphine, 2,2 '-two (diphenyl phosphine)-1,1 '-naphthyl naphthalenes etc. are as part.As described solvent, can mention dimethyl formamide, acetonitrile, alcoholic solvent (for example methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.), 1,4-diox, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), toluene, water, its mixed solvent etc.

When using copper catalyst, can make spent glycol (CH ₃) ₂N-(CH ₂) ₂-OH; Diamines is such as (CH ₃) ₂N-(CH ₂) ₂-NH ₂, (CH ₃) ₂N-(CH ₂) ₂-N (CH ₃) ₂, CH ₃NH-(CH ₂) ₂-NHCH ₃Deng as part.As described solvent, can mention dimethyl formamide, acetonitrile, alcoholic solvent (for example methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.), toluene, dimethylbenzene etc.

Step 5

According to the method identical with preparation method 2 step 3, can be according to conventional methods hydroxyl-protecting group by elimination of compound [18] obtain compound [19].

Step 6

Can be according to conventional methods hydroxyl by halogenated compound [19] obtain compound [20].

For example, can in solvent, make compound [19] and halogenating agent, obtain compound [20] by being cooled under the room temperature such as reactions such as thionyl chloride, phosphorus trichloride, phosphorus tribromide, carbon tetrabromide-triphenylphosphine, N-bromosuccinimides.

As described solvent, can mention halon solvent ratio such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is such as 1,4-diox, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Deng.

The preparation method 4

The preparation embodiment of compound [11]

Wherein each symbol is for as defined above.

Step 1

According to the method identical, can make compound [16] and compound [21] carry out the Suzuki reaction and obtain compound [22] with preparation method 2 step 2.

Step 2

According to the method identical with preparation method 2 step 3, can be according to conventional methods hydroxyl-protecting group by elimination of compound [22] obtain compound [23].

Step 3

According to the method identical with preparation method 3 step 6, can be according to conventional methods hydroxyl by halogenated compound [23] obtain compound [24].

The preparation method 5

R wherein ²Preparation embodiment for the compound [9] of ethyl

R wherein ^C5For carboxyl-protecting group such as C _1-4Alkyl (for example, methyl, ethyl etc.) etc., R ^P3For protecting group such as trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl etc., other symbol is for as defined above.

Step 1

Can obtain compound [26] by introducing protecting group according to conventional methods to the carboxyl of compound [25].

For example, can be by in solvent ratio such as dimethyl formamide, tetrahydrofuran (THF), toluene etc., alkali such as yellow soda ash, salt of wormwood, sodium hydride, potassium hydride KH etc. in the presence of, make compound [25] and alkylating agent such as reactions such as methyl iodides, obtain compound [26].

Step 2

Can be by under extremely heating in room temperature, at solvent ratio such as dimethyl formamide, acetonitrile, 1,4-diox, 1, in 2-glycol dimethyl ether, tetrahydrofuran (THF), toluene, the water etc., catalyzer such as palladium catalyst (for example four (triphenylphosphines) close palladium, dichloro two (triphenylphosphine) closes palladium (II), acid chloride-triphenylphosphine etc.), copper catalyst (for example cupric iodide (I) etc.) or its mixture and alkali such as salt of wormwood, saleratus, sodium bicarbonate, potassiumphosphate, triethylamine etc. in the presence of, make compound [26] and compound [27] reaction, obtain compound [28].

Step 3

Can pass through the protecting group R of elimination of compound [28] according to conventional methods ^P3Obtain compound [29].

For example, work as R ^P3During for trimethyl silyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, can obtain compound [29] by the following method: be cooled under the room temperature, in tetrahydrofuran (THF), handling compound [28] with tetrabutylammonium; In tetrahydrofuran (THF), use sodium-hydroxide treatment compound [28]; To heating, handle compound [28] etc. in room temperature with acetate-water-tetrahydrofuran (THF).

Step 4

Can obtain compound [30] such as catalytic reduction under nitrogen atmosphere etc. by reducing compound [29] according to conventional methods.

For example, can be by at room temperature, under nitrogen atmosphere, in solvent ratio such as tetrahydrofuran (THF), methyl alcohol, ethyl acetate, its mixed solvent etc., in the presence of catalyzer exists such as palladium-carbon etc., compound [29] is reacted obtain compound [30].

Step 5

According to the method identical, can obtain compound [31] by halogenated compound [30] according to conventional methods with preparation method 1 step 1.

Step 6

According to the method identical with preparation method 2 step 4, can be according to conventional methods carboxyl-protecting group by elimination of compound [31] obtain compound [32].

Step 7

According to the method identical with preparation method 1 step 2, can make the reaction of compound [32] and compound [4], and make compound and compound [5] reaction that obtains, obtain compound [33].

Step 8

According to the method identical, can obtain compound [34] by cyclisation compound [33] with preparation method 1 step 3.

Step 9

According to the method identical, can obtain compound [35] by introducing protecting group to the hydroxyl of compound [34] with preparation method 1 step 5.

The preparation method 6

R wherein ^P4For amino-protecting group such as benzoyl, the tertiary butyl, tertiary butyl carbonyl, tert-butoxycarbonyl etc., other symbol is for as defined above, condition is a substituent R ⁵Can not be bonded to the * position.

Step 1

Can obtain compound [36] by nitrated compound [13] according to conventional methods.

For example, can obtain compound [36] with nitrating agent (for example mixing acid of nitric acid, nitrosonitric acid, concentrated nitric acid and the vitriol oil etc.) nitrated compound [13] by being cooled under the room temperature.

Step 2

According to the method identical, can obtain compound [37] by reducing compound [36] according to conventional methods with preparation method 3 step 2.

Step 3

Can obtain compound [38] according to following ordinary method: such as passing through under neutrality or alkaline condition with zinc or iron; With iron and acid; With tin or chlorination (II) and concentrated hydrochloric acid; Use Sodium Sulphide; Under alkaline condition,, under nitrogen atmosphere, make compound [37] carry out catalytic reduction etc. with reducing compounds such as hydrosulphite [37].

For example, can by in room temperature to heating, in solvent ratio such as ethanol, tetrahydrofuran (THF), water, its mixed solvent etc., make compound [37] and reduced iron and ammonium chloride reaction.Obtain compound [38].Alternatively, can make at room temperature and react, obtain compound [38] by under cooling, to compound [37] in, adding acetate and zinc powder.Alternatively, can be by at room temperature, under nitrogen atmosphere, in solvent ratio such as tetrahydrofuran (THF), methyl alcohol, ethyl acetate, its mixed solvent etc., in the presence of catalyzer exists such as palladium-carbon etc., compound [37] is reacted, obtain compound [38].

Step 4

Can obtain compound [39] by introducing protecting group according to conventional methods to the amino of compound [38].

For example, work as R ^P4During for tert-butoxycarbonyl, can make compound [38] and di-t-butyl reaction of sodium bicarbonate in solvent ratio such as tetrahydrofuran (THF) etc., obtain compound [39] by under extremely heating in room temperature.

Step 5

According to the method identical with preparation method 3 step 6, can be according to conventional methods hydroxyl by halogenated compound [39] obtain compound [40].

The preparation method 7

Wherein Q be-CO-,-COO-or-SO ₂-, p is 2 to 4 integer, other symbol is for as defined above.

Step 1

According to the method identical with preparation method 2 step 2, can make compound [10] and compound [40] carry out the Suzuki reaction, obtain compound [41].

Step 2

Can be according to conventional methods amino-protecting group by elimination of compound [41] obtain compound [42].

For example, work as R ^P4During for tert-butoxycarbonyl, can go protection by the following method:, be used in the compound [41] of the solution-treated of hydrochloric acid in ethyl acetate in ethyl acetate such as at room temperature; At room temperature, be used in salt acid treatment compound [41] in the tetrahydrofuran (THF); At room temperature, be used in hydrochloric acid 1, the solution-treated in the 4-diox is 1, the compound in the 4-diox [41]; Handle the solution of compound [41] in chloroform with trifluoroacetic acid, etc.

Step 3

Can be by being cooled under the heating, in solvent ratio such as dimethyl formamide, acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, toluene etc., alkali such as triethylamine, yellow soda ash, pyridine, 4-(dimethylamino) pyridine etc. in the presence of, make compound [42] and compound [43] reaction, obtain compound [44].

Step 4

Can be by being cooled under the heating, in solvent ratio such as dimethyl formamide, acetonitrile, tetrahydrofuran (THF), toluene etc., alkali such as yellow soda ash, salt of wormwood, triethylamine, potassium tert.-butoxide, sodium hydride, potassium hydride KH etc. in the presence of, make compound [44] carry out cyclisation, obtain compound [45].

Step 5

According to the method identical with preparation method 2 step 3, can be according to conventional methods hydroxyl-protecting group by elimination of compound [45] obtain compound [I-3].

Step 6

According to the method identical with preparation method 2 step 4, can be according to conventional methods carboxyl-protecting group by elimination of compound [I-3] obtain compound [I-4].

Embodiment

Now, elaborate 4-oxoquinoline compound, its pharmacologically acceptable salt or its solvate of formula of the present invention [I] representative and preparation method thereof for example, it should not be construed as restrictive.

Embodiment 1

Step 1

With 3-chloro-2-fluorobenzoic acid (25.00g 143.21mmol) is dissolved in the vitriol oil (100ml), and 5 ℃ or more drip under the low temperature N-iodosuccinimide (32.20g, 143.21mmol).After adding is finished, under uniform temp, stirred this mixture 3 hours, and at room temperature stirred 13 hours.This reaction mixture impouring is added sodium sulfate, and (14.90g in frozen water 143.19mmol) (about 500ml), after stirring, filters the solid of collecting precipitation, and washes with water.Under 65 ℃, the solid that drying under reduced pressure obtains 8 hours obtains being filbert (pale-brown) solid target compound (41.02g, productive rate 95%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：8.06(1H，dd，J＝6.1，2.2Hz)，8.22(1H，dd，J＝6.4，2.2Hz)

MS(ESI)：M-299

Step 2

(2.00g 6.66mmol) is dissolved in the tetrahydrofuran (THF) (10ml) compound that will obtain in step 1.Under nitrogen gas stream, drip borine-tetrahydrofuran (THF) mixture down at tetrahydrofuran (THF) (20.00ml, 20.00mmol) the 1.0M solution at 0 ℃.After being added dropwise to complete, heat this mixture to room temperature, stirred 2 hours, and reflux 2 hours.Under ice-cooled, in this reaction mixture, drip 2N hydrochloric acid (11ml), after stirring, with this mixture of ethyl acetate extraction.Water, saturated sodium bicarbonate aqueous solution, water and saturated brine wash organic layer, and use dried over sodium sulfate successively.After filtration, concentrated filtrate under reduced pressure is by silica gel chromatography (hexane: ethyl acetate=6: 1 to 5: the 1) resistates that obtains of purifying, the solid target compound that obtains being white in color (1.70g, productive rate 89%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.83-1.84(1H，m)，4.74-4.76(2H，m)，7.65-7.70(2H，m)

Step 3

The compound that will in step 2, obtain (1.70g 5.93mmol) is dissolved in the dimethyl formamide (17ml), add imidazoles (606mg, 8.90mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (1.07g 7.10mmol), and at room temperature stirred this mixture 3 hours.Water is joined in this reaction mixture, and with this mixture of ethyl acetate extraction.Water and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate by the resistates that silica gel chromatography (independent hexane) purifying obtains, obtains being the target compound (2.31g, productive rate 97%) of colorless oil.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.12(6H，s)，0.95(9H，s)，4.74(2H，s)，7.60-7.62(1H，m)，7.68-7.69(1H，m)

Step 4

With acid chloride (II) (448mg, 2.00mmol), (±)-2,2 '-two (diphenyl phosphine)-1,1 '-naphthyl naphthalene (2.49g, 4.00mmol) and cesium carbonate (9.76g, 29.96mmol) join 1, in the 4-diox (40ml), under argon gas stream, to aforementioned mixture (with 1,4-diox (40ml) washing) in drip the compound that in step 3, obtains (8.00g, 19.96mmol) and morpholine (2.62ml, 29.95mmol) solution in the trimethyl carbinol (40ml).This mixture of reflux 24 hours.After making its cooling, water is added in this reaction mixture, and with this mixture of ethyl acetate extraction.Water and saturated brine wash organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=8: the 1) resistates that obtains of purifying obtains target compound (4.29g, productive rate 60%) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.12(6H，s)，0.95(9H，s)，3.08-3.10(4H，m)，3.84-3.86(4H，m)，4.76(2H，s)，6.79(1H，dd，J＝5.9，3.1Hz)，6.95(1H，dd，J＝5.4，3.1Hz)

Step 5

(537mg 1.49mmol) is dissolved in the tetrahydrofuran (THF) (1ml) compound that will obtain in step 4, adds tetrabutylammonium fluoride at tetrahydrofuran (THF) (2.99ml, 2.99mmol) the 1.0M solution in, and at room temperature stirred this mixture 2 hours.Water and ethyl acetate are added in this reaction mixture, and separating layer is washed organic layer and is used dried over sodium sulfate with saturated brine.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=1: the 1) resistates that obtains of purifying obtains being light brown solid target compound (308mg, productive rate 84%) by silica gel chromatography.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：1.90(1H，t，J＝6.0Hz)，3.08-3.12(4H，m)，3.83-3.86(4H，m)，4.74(2H，d，J＝6.0Hz)，6.83(1H，dd，J＝6.0，3.0Hz)，6.88(1H，dd，J＝5.3，3.0Hz)

MS(ESI)：M+246

Step 6

The compound that will in step 5, obtain (1.00g 4.07mmol) is dissolved in the chloroform (10ml), and the triphenylphosphine resin of adding 3mmol/g (2.04g, 6.11mmol).And (2.03g 6.11mmol), and at room temperature stirred this mixture 40 minutes at the ice-cooled N-bromosuccinimide of adding down.Filter this reaction mixture, and concentrated filtrate under reduced pressure.By silica gel chromatography (hexane: ethyl acetate=4: the 1) resistates that obtains of purifying, the solid target compound that obtains being white in color (1.10g, productive rate 88%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：3.09-3.11(4H，m)，3.83-3.86(4H，m)，4.46(2H，d，J＝1.2Hz)，6.79(1H，dd，J＝5.4，3.1Hz)，6.86(1H，dd，J＝6.0，3.0Hz)

Step 7

With Boc-D-Ser (Bzl)-ol (Boc-O-benzyl-D-serinol) (10.00g, 35.54mmol) be dissolved in the toluene (50ml), add four-just-butyl monoammonium sulfate (1.28g, 3.56mmol), aqueous sodium hydroxide solution (50ml) and the monobromethane (7.96ml of 8N, 106.65mmol), and at room temperature stirred this mixture 20 hours.(2.65ml 35.54mmol), and at room temperature further stirred this mixture 3.5 hours to add monobromethane.Extract this reaction mixture with toluene, wash organic layer, and use dried over mgso with saturated brine.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=4: the 1) resistates that obtains of purifying obtains target compound (10.49g, productive rate 95%) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.17(3H，t，J＝7.1Hz)，1.44(9H，s)，3.49-3.57(6H，m)，3.90-3.92(1H，m)，4.53(2H，s)，4.92-4.94(1H，m)，7.27-7.37(5H，m)

Step 8

(10.49g 33.90mmol) is dissolved in the methyl alcohol (100ml) compound that will obtain in step 7, adds palladium-carbon (1.10g) of 4.5%, adds hydrogen under standard pressure, and at room temperature stirs this mixture 1.5 hours.(celite) filters this reaction mixture with diatomite, and concentrated filtrate under reduced pressure, obtains crude product (8.06g).

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：1.20(3H，t，J＝7.2Hz)，1.46(9H，s)，2.76-2.78(1H，m)，3.47-3.84(7H，m)，5.17-5.22(1H，m)

Step 9

The crude product that will obtain in step 8 (8.06g) is dissolved in 1, in the 4-diox (20ml), adds 4N hydrochloric acid-1, and (34ml 136mmol), and at room temperature stirred this mixture 3.5 hours to the 4-diox.Under reduced pressure concentrate this reaction mixture, obtain crude product (5.86g).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.21(3H，t，J＝7.0Hz)，3.53-3.61(2H，m)，3.69-3.71(3H，m)，3.89-3.94(2H，m)，8.04(3H，br?s)

MS (ESI): M+120 (free cpds)

Step 10

(25.24g 115.24mmol) is dissolved in the dimethyl formamide (300ml), adds salt of wormwood (23.89g with 4-bromo-2-fluorobenzoic acid, 172.86mmol), (9.33ml 149.81mmol), and at room temperature stirred this mixture 4 hours at ice-cooled further down adding methyl iodide.This reaction mixture is added in the water that contains acetate (15), and with this mixture of ethyl acetate extraction three times.Water (four times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (24.90g) of light yellow solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：3.93(3H，s)，7.33-7.38(2H，m)，7.82(1H，dd，J＝7.7，8.6Hz)

Step 11

The crude product that will obtain in step 10 (2.50g) is dissolved in 1, in the 4-diox (20ml), add triethylamine (20ml), trimethyl silyl acetylene (1.97ml successively, 13.95mmol), dichloro two (triphenylphosphine) closes palladium (II) (377mg, 0.537mmol) and cupric iodide (I) (61mg, 0.322mmol), and under 60 ℃ heating, further stirred this mixture 1 hour.After making its cooling, with this reaction mixture of diatomite filtration, with ether washing, and concentrated filtrate under reduced pressure.Ethyl acetate and water are added in the resistates that obtains, and separating layer is used the ethyl acetate extraction water layer.Water and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=15: the 1) resistates that obtains of purifying obtains being the target compound (3.04g, quantitative yield, 2 steps) of yellow oily by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.26(9H，s)，3.93(3H，s)，7.20-7.28(2H，m)，7.87(1H，dd，J＝7.7，7.7Hz)

Step 12

(2.46g 9.81mmol) is dissolved in the tetrahydrofuran (THF) (25ml) compound that will obtain in step 11.Under 0 ℃, add entry (353 μ l, 9.61mmol) and tetrabutylammonium fluoride at tetrahydrofuran (THF) (490 μ l, the 0.490mmol) 1.0M in, and under uniform temp, stirred this mixture 30 minutes.Water and ethyl acetate are joined in this reaction mixture, and separating layer.Water (twice) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=10: the 1) resistates that obtains of purifying obtains being filbert solid target compound (1.52g, productive rate 91%) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：3.26(1H，s)，3.94(3H，s)，7.24-7.33(2H，m)，7.90(1H，dd，J＝7.8，7.8Hz)

Step 13

The compound that will in step 12, obtain (2.23g 12.53mmol) is dissolved in the ethyl acetate (20ml), and the palladium-carbon (wet) of adding 5% (200mg) adds hydrogen under standard pressure,, and at room temperature stirred this mixture 22 hours.With this reaction mixture of diatomite filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=20: 1 to 15: the 1) resistates that obtains of purifying obtains being the target compound (1.94g, productive rate 85%) of colorless oil.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.25(3H，t，J＝7.6Hz)，2.69(2H，q，J＝7.6Hz)，3.92(3H，s)，6.95-7.04(2H，m)，7.85(1H，dd，J＝7.8，7.8Hz)

Step 14

The compound that will in step 13, obtain (1.94g 10.65mmol) is dissolved in the vitriol oil (15ml), ice-cooled drip down N-iodosuccinimide (2.40g, 10.67mmol).Under ice-cooled, stirred this mixture 20 minutes, and at room temperature stirred 2 hours.(120mg 0.532mmol), and at room temperature stirred this mixture 30 minutes to add N-iodosuccinimide.This reaction mixture impouring is comprised sodium sulfate, and (2.0g is in frozen water 15.87mmol), and after stirring, with this mixture of ethyl acetate extraction.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane is to hexane: ethyl acetate=15: the 1) resistates that obtains of purifying obtains being the target compound (3.20g, productive rate 98%) of colorless solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.23(3H，t，J＝7.5Hz)，2.73(2H，q，J＝7.5Hz)，3.92(3H，s)，7.02(1H，d，J＝11.8Hz)，8.35(1H，d，J＝7.2Hz)

Step 15

(3.20g 10.39mmol) is dissolved in tetrahydrofuran (THF) (10ml) and the methyl alcohol (10ml) compound that will obtain in step 14, and (5.20ml 20.77mmol), and at room temperature stirred this mixture 14 hours to add the 4N aqueous sodium hydroxide solution.Under reduced pressure concentrate this reaction mixture, 6N hydrochloric acid and ethyl acetate are added in this resistates, and separating layer.Use the ethyl acetate extraction water layer.Water and saturated brine wash organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, solid crude product (3.03g) obtains being white in color.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.25(3H，t，J＝7.5Hz)，2.76(2H，q，J＝7.5Hz)，7.06(1H，d，J＝11.8Hz)，8.44(1H，d，J＝7.2Hz)

Step 16

The crude product that will obtain in step 15 (2.84g) is dissolved in the toluene (30ml), add thionyl chloride (1.06ml, 14.49mmol) and dimethyl formamide (catalytic amount), and under 100 ℃ heating this mixture of stirring 2 hours.After making its cooling, under reduced pressure concentrate this reaction mixture, make itself and toluene carry out component distillation twice.The resistates that obtains is dissolved in the toluene (15ml), this drips of solution is added to 3-(dimethylamino) ethyl propenoate (1.45g, 10.14mmol) and diisopropylethylamine (2.19ml, 12.56mmol) in the middle solution of toluene (15ml), under 90 ℃ heating, stirred this mixture 14 hours.After making its cooling, water is added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (twice) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 1 to 1: the 2) resistates that obtains of purifying obtains being tawny buttery target compound (2.85g, 70%, 2 step of productive rate).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.96(3H，t，J＝7.1Hz)，1.20(3H，t，J＝7.5Hz)，2.71(2H，q，J＝7.5Hz)，2.88(3H，br?s)，3.29(3H，br?s)，4.00(2H，q，J＝7.1Hz)，6.90(1H，d，J＝11.4Hz)，7.76(1H，s)，8.02(1H，br?s)

Step 17

With triethylamine (349 μ l, 2.51mmol) and the crude product that in step 9, obtains (312mg) be dissolved in the chloroform, (700mg 1.67mmol), and at room temperature stirred this mixture 1.5 hours to be added in the compound that obtains in the step 16.Under reduced pressure concentrate this reaction mixture.The resistates that obtains is dissolved in the ethyl acetate, water (twice) and saturated brine washing successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (898mg) of light yellow oily.

Step 18

The crude product that will obtain in step 17 (898mg) is dissolved in the dimethyl formamide (8ml), and (692mg 5.01mmol), and stirred this mixture 21 hours under 80 ℃ heating to add salt of wormwood.After making its cooling, water and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, solid crude product (758mg) obtains being white in color.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.17(3H，t，J＝6.9Hz)，1.31(3H，t，J＝7.5Hz)，1.40(3H，t，J＝7.2Hz)，2.84-3.01(2H，m)，3.50-3.62(2H，m)，3.97-4.08(2H，m)，4.11-4.18(1H，m)，4.26-4.41(3H，m)，4.81-4.88(1H，m)，5.62(1H，t，J＝6.9Hz)，7.37(1H，s)，7.98(1H，s)，8.61(1H，s)

Step 19

The crude product that will obtain in step 18 (758mg) is dissolved in the dimethyl formamide (8ml), add imidazoles (171mg, 2.51mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (302mg 2.00mmol), and at room temperature stirred this mixture 1 hour.Water and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=2: the 3) resistates that obtains of purifying obtains being the target compound (820mg, 84%, 3 step of productive rate) of colorless oil by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.02(3H，s)，-0.01(3H，s)，0.82(9H，s)，1.20(3H，t，J＝7.0Hz)，1.28(3H，t，J＝7.5Hz)，1.40(3H，t，J＝7.2Hz)，2.85(2H，q，J＝7.5Hz)，3.54(2H，q，J＝7.0Hz)，3.89(2H，d，J＝5.3Hz)，4.04(2H，d，J＝4.9Hz)，4.34-4.42(2H，m)，4.75-4.81(1H，m)，7.38(1H，s)，8.74(1H，s)，8.95(1H，s)

Step 20

Compound (the 100mg that will in step 19, obtain, 0.170mmol) be dissolved in 1, in the 4-diox (1ml), add acid chloride (II) (2mg successively, 0.0085mmol), 2-(dicyclohexyl is seen) xenyl (12mg, 0.034mmol), triethylamine (95 μ l, 0.68mmol) and tetramethyl ethylene ketone borine (pinacolborane) at tetrahydrofuran (THF) (511 μ l, 0.511mmol) in 1M solution, and under 80 ℃ heating, stirred this mixture 1 hour.After making its cooling, saturated aqueous ammonium chloride solution and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=1: the 2) resistates that obtains of purifying obtains being the target compound (70mg, productive rate 70%) of colorless oil by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.02(6H，s)，0.83(9H，s)，1.20(3H，t，J＝7.1Hz)，1.24(3H，t，J＝7.4Hz)，1.35(12H，s)，1.40(3H，t，J＝7.2Hz)，3.03(2H，dq，J＝1.6，7.4Hz)，3.54(2H，q，J＝7.1Hz)，3.90(2H，d，J＝5.6Hz)，4.00-4.08(2H，m)，4.37(2H，dq，J＝2.0，7.2Hz)，4.79-4.85(1H，m)，7.28(1H，s)，8.70(1H，s)，8.95(1H，s)

Step 21

Compound (the 70mg that will in step 20, obtain, 0.119mmol and the compound (44mg that in step 6, obtains, 0.143mmol) be dissolved in 1, in the 2-glycol dimethyl ether (1.5ml), add four (triphenylphosphines) and close palladium (0) (7mg, 0.006mmol) and the 2M aqueous sodium carbonate (240 μ l 0.480mmol), and stirred this mixture 50 minutes under 80 ℃ heating.After making its cooling, water and ethyl acetate are added in this reaction mixture, and separating layer.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=1: the 3) resistates that obtains of purifying obtains being the target compound (66mg, the not product of purifying (crudely purified)) of colorless oil by preparation thin-layer chromatography (PTLC).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.03(3H，s)，-0.02(3H，s)，0.82(9H，s)，1.21(3H，t，J＝7.0Hz)，1.23(3H，t，J＝7.6Hz)，1.40(3H，t，J＝7.0Hz)，2.73(2H，q，J＝7.6Hz)，2.96(4H，t，J＝4.9Hz)，3.56(2H，q，J＝7.0Hz)，3.76(4H，t，J＝4.9Hz)，3.91(2H，d，J＝5.3Hz)，4.05(2H，d，J＝4.9Hz)，4.09(2H，s)，4.35-4.42(2H，m)，4.80-4.87(1H，m)，6.40-6.42(1H，m)，6.74-6.76(1H，m)，7.36(1H，s)，8.31(1H，s)，8.74(1H，s)

Step 22

The compound that will obtain in step 21 (66mg) is dissolved in the tetrahydrofuran (THF) (1ml), adds tetrabutylammonium fluoride at tetrahydrofuran (THF) (144 μ l, 0.144mmol) the 1.0M solution in, and at room temperature stirred this mixture 40 minutes.Water and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying methyl alcohol=15: 1) obtains being the target compound (53mg, 77%, 2 step of productive rate) of colorless oil by PTLC.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.21(3H，t，J＝7.2Hz)，1.22(3H，t，J＝7.5Hz)，1.41(3H，t，J＝7.1Hz)，2.63-2.81(2H，m)，2.88(4H，t，J＝4.7Hz)，3.56-3.63(2H，m)，3.72(4H，t，J＝4.7Hz)，3.98-4.02(1H，m)，4.06-4.18(4H，m)，4.28-4.43(3H，m)，4.54-4.69(1H，m)，4.86-4.92(1H，m)，6.15-6.18(1H，m)，6.71-6.73(1H，m)，7.37(1H，s)，7.66(1H，s)，8.68(1H，s)

Step 23

(53mg 0.092mmol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (1ml) and water (0.2ml) compound that will obtain in step 22, and (8mg 0.2mmol), and at room temperature stirred this mixture 3 hours to add lithium hydroxide monohydrate.With this reaction mixture of Citric acid acidified aqueous solution.Filter the solid of collecting precipitation, wash with water, and drying under reduced pressure, the solid target compound that obtains being white in color (46mg, productive rate 91%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.03(3H，t，J＝7.0Hz)，1.26(3H，t，J＝7.5Hz)，2.91(2H，q，J＝7.5Hz)，3.08(4H，t，J＝4.9Hz)，3.46(2H，q，J＝7.0Hz)，3.71(4H，t，J＝4.9Hz)，3.85-4.01(4H，m)，4.20(2H，s)，5.27(1H，t，J＝5.4Hz)，5.33-5.41(1H，m)，6.91-6.93(1H，m)，7.03-7.05(1H，m)，7.96(1H，s)，8.02(1H，s)，8.90(1H，s)，15.21(1H，s)

MS(ESI)：M+547

Embodiment 2

Step 1

(5.00g 28.64mmol) is dissolved in the vitriol oil (15ml), and (1.50ml 31.50mmol), and at room temperature stirred this mixture 19 hours at the ice-cooled nitric acid of dropping down with 3-chloro-2-fluorobenzoic acid.In this reaction mixture impouring frozen water (about 200ml), after stirring, filter the solid of collecting precipitation, and wash with water.The solid that obtains is dissolved in the ethyl acetate, washes with water, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains being light orange solid target compound (4.81g, productive rate 76%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：8.54(1H，dd，J＝5.7，2.9Hz)，8.74(1H，dd，J＝5.8，2.8Hz)，14.25(1H，br?s)

Step 2

(500mg 2.28mmol) is dissolved in the tetrahydrofuran (THF) (5ml), under argon gas stream the compound that will obtain in step 1, at the ice-cooled triethylamine (0.317ml that drips down, 2.28mmol) and isobutyl chlorocarbonate (0.296ml 2.28mmol), and stirred this mixture 25 minutes under uniform temp.Filter this reaction mixture, and wash with tetrahydrofuran (THF) (5ml).Use ice-cooled filtrate, add sodium boorohyride (129mg, 3.42mmol) and water (1.5ml), and under uniform temp this mixture of stirring 25 minutes.Saturated aqueous ammonium chloride solution and saturated brine are added in this reaction mixture, and separating layer is washed organic layer with saturated brine, and uses dried over mgso.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=4: the 1) resistates that obtains of purifying obtains being the target compound (357mg, productive rate 76%) of filbert oily by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：2.06(1H，t，J＝6.4Hz)，4.88(2H，d，J＝6.0Hz)，8.27(1H，dd，J＝6.2，2.9Hz)，8.36(1H，dd，J＝5.5，2.9Hz)

Step 3

In the mixture of ethanol (10ml) and water (5ml), add reduced iron (486mg, 8.70mmol) and ammonium chloride (465mg, 8.70mmol).Under 80 ℃, and the compound that dropping obtains in step 2 (357mg, the 1.74mmol) solution in tetrahydrofuran (THF) (10ml), and under the heating of uniform temp, stirred this mixture 20 minutes.After making its cooling,, and wash with ethyl acetate with this reaction mixture of diatomite filtration.Water, saturated sodium bicarbonate aqueous solution and saturated brine wash filtrate successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (287mg) of yellow solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：4.44(2H，d，J＝5.8Hz)，5.20(2H，br?s)，5.23(1H，t，J＝5.8Hz)，6.53(1H，dd，J＝6.0，2.8Hz)，6.61(1H，dd，J＝5.6，2.8Hz)

Step 4

The crude product that will obtain in step 3 (287mg) is dissolved in the tetrahydrofuran (THF) (3ml), add two-tertiary butyl sodium bicarbonate (418mg, 1.91mmol), and this mixture of reflux 6 hours.Under reduced pressure concentrate this reaction mixture, by silica gel chromatography (hexane: ethyl acetate=4: the 1) resistates that obtains of purifying, the solid target compound that obtains being white in color (320mg, 67%, 2 step of productive rate).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.53(9H，s)，1.89(1H，t，J＝6.3Hz)，4.75(2H，d，J＝6.3Hz)，6.46(1H，s)，7.26-7.28(4H，m)，7.51(1H，dd，J＝6.3，2.6Hz)

Step 5

Compound (the 608mg that will in step 4, obtain, 2.21mmol) be dissolved in the chloroform (12ml), under ice-cooled, add 3mmol/g triphenylphosphine resin (1.11g successively, 3.32mmol) and N-bromosuccinimide (471mg, 2.65mmol), and at room temperature stirred this mixture 1.5 hours.(26 μ l) adds in this reaction mixture with ethanol, filters this mixture, and washs with chloroform.Under reduced pressure concentrate this filtrate.The resistates that obtains is dissolved in the ethyl acetate, water and saturated brine washing successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=4: the 1) resistates that obtains of purifying obtains being the target compound (369mg, productive rate 49%) of light yellow solid by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.52(9H，s)，4.46(2H，d，J＝1.2Hz)，6.45(1H，br?s)，7.31(1H，dd，J＝5.8，3.0Hz)，7.46(1H，dd，J＝6.1，2.4Hz)

Step 6

With 2,4 difluorobenzene formic acid (600.00g 3.80mol) is dissolved in the vitriol oil (2400ml), and 5 ℃ or more drip under the low temperature N-iodosuccinimide (854.40g, 3.60mol).After adding is finished, under uniform temp, stirred this mixture 3 hours.In this reaction mixture impouring frozen water (about 10L), add 10% aqueous sodium persulfate solution (40ml), and stirred this mixture 30 minutes.Filter the solid of collecting precipitation, it is suspended in the water (about 3L), the repetitive scrubbing slurries become 3 or higher up to pH.The wet crystal (1677g) that recrystallization obtains from 50% EtOH/ water (3000ml), the solid target compound that obtains being white in color (824.70g, productive rate 76%).

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：6.94(1H，dd，J＝10.3，10.3Hz)，8.46(1H，d，J＝7.5Hz)

Step 7

The compound that will in step 6, obtain (650.57g 2.29mol) is dissolved in the toluene (1300ml), add thionyl chloride (184ml, 2.52mol) and dimethyl formamide (catalytic amount), and at 90 ℃ of these mixtures of stirring 2 hours down.After making its cooling, under reduced pressure concentrate this reaction mixture, make itself and toluene (330ml) carry out component distillation twice.The resistates that obtains is dissolved in the toluene (690ml), this drips of solution is added to 3-(dimethylamino) ethyl propenoate (361.52g, 2.525mol) and diisopropylethylamine (480ml 2.75mol) in the solution in toluene (690ml), stirred this mixture 3 hours under 90 ℃ heating.After making its cooling, (260.00g 2.52mol) adds in this reaction mixture, and at room temperature stirs this mixture 1 hour with (S)-(+)-valerian ammonia alcohol.Water (2600ml) is added in this reaction mixture, separating layer, and with toluene (680ml) aqueous layer extracted.Water (2000ml time) washing organic layer twice, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate obtains being brown buttery crude product (1180g).

Step 8

The crude product that will obtain in step 7 (1180g) is dissolved in the dimethyl formamide (2500ml), and (292.00g 1.06mol), and at room temperature stirred this mixture 22 hours to add potassium carbonate powder.This reaction mixture is added in the frozen water (about 10L), and stirred this mixture 30 minutes.Filter the solid of collecting precipitation, and water (2000ml) washing.The solid that drying under reduced pressure obtains is suspended in it in ethyl acetate (5000ml), and carries out slurries-washing (slurry-washing).After filtration, drying under reduced pressure filtrate obtains being the target compound (774.63g, productive rate 82%) of white-yellowish solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.6Hz)，1.10(3H，d，J＝6.6Hz)，1.28(3H，t，J＝7.0Hz)，2.27(1H，br)，3.77(1H，br)，3.86(1H，br)，4.23(2H，q，J＝7.0Hz)，4.56(1H，br)，5.12(1H，t，J＝4.9Hz)，8.09(1H，d，J＝11.1Hz)，8.62(1H，d，J＝7.5Hz)，8.68(1H，s)

Step 9

(25.00g 55.90mmol) is dissolved in the methyl alcohol (250ml) compound that will obtain in step 8, adds methanolizing sodium at methyl alcohol (12.5ml, the solution of 28% in 61.49mol), and this mixture of reflux 3 hours.After making its cooling, under reduced pressure concentrate this reaction mixture.The resistates that obtains is dissolved in the dimethyl formamide (125ml), add salt of wormwood (7.72g, 55.90mmol) and methyl iodide (3.48ml 55.90mmol), and at room temperature stirred this mixture 2 hours.This reaction mixture impouring is comprised in the frozen water (12ml) of 6N hydrochloric acid, and with twice of ethyl acetate extraction.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate obtains yellow amorphous crude product (24.94g).

Step 10

The crude product that will obtain in step 9 (24.94g) is dissolved in the dimethyl formamide (125ml), add imidazoles (4.95g, 72.66mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (10.10g 67.07mmol), and at room temperature stirred this mixture 15 hours.Water is joined in this reaction mixture, and with twice in this mixture of ethyl acetate extraction.Wash organic layer four times with saturated brine, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 1 to 1: the 2) resistates that obtains of purifying obtains being the target compound (21.86g, 70%, 2 step of productive rate) of light yellow solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.07(3H，s)，-0.04(3H，s)，0.78(9H，s)，0.84(3H，d，J＝6.8Hz)，1.19(3H，d，J＝6.8Hz)，2.38-2.49(1H，m)，3.91(3H，s)，3.99-4.16(6H，m)，6.76(1H，s)，8.66(1H，s)，8.95(1H，s)

Step 11

Compound (the 3.50g that will in step 10, obtain, 6.26mmol) be suspended in the methyl-sulphoxide (25ml), under argon gas stream, add two (tetramethyl ethylene ketone bases), two boron (1.75g, 6.89mmol), potassium acetate (1.84g, 18.78mmol) and [1,1 '-two (diphenyl phosphine) ferrocene] dichloro closes palladium (II) methylene dichloride (1: 1) mixture (153mg 0.188mmol), and stirred this mixture 1.5 hours under 80 ℃ heating.After making its cooling, water and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water (three times) and saturated brine wash organic layer successively, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains the amorphous crude product of brown (3.45g).

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.07(3H，s)，-0.05(3H，s)，0.78(9H，s)，0.82(3H，d，J＝6.4Hz)，1.18(3H，d，J＝6.4Hz)，1.35(12H，s)，2.36-2.51(1H，m)，3.88(3H，s)，3.93(3H，s)，4.03-4.23(3H，m)，6.73(1H，s)，8.64(1H，s)，8.85(1H，s)

Step 12

Crude product that will in step 11, obtain (1.07g) and the compound (433mg that in step 5, obtains, 1.28mmol) be dissolved in 1, in the 2-glycol dimethyl ether, add four (triphenylphosphines) and close palladium (0) (44mg, 0.038mmol) and 2M aqueous sodium carbonate (2.60ml, 5.12mmol), and under 80 ℃ heating, stirred this mixture 30 minutes.After making its cooling, saturated aqueous ammonium chloride solution and ethyl acetate are added in this reaction mixture, and separating layer.Water and saturated brine wash organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=1: the 1) resistates that obtains of purifying obtains yellow amorphous target compound (1.21g, productive rate 71%) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.00(6H，s)，0.77(9H，s)，0.85(3H，d，J＝6.7Hz)，1.19(3H，d，J＝6.5Hz)，1.47(9H，s)，2.40-2.50(1H，m)，3.90(3H，s)，3.91(3H，s)，3.95(1H，dd，J＝11.0，2.7Hz)，4.02(2H，s)，4.03-4.06(1H，m)，4.16-4.21(1H，m)，6.29(1H，s)，6.72(1H，dd，J＝5.4，2.7Hz)，6.78(1H，s)，7.53-7.58(1H，m)，8.29(1H，s)，8.65(1H，s)

Step 13

(200mg 0.289mmol) is dissolved in the chloroform (1ml) compound that will obtain in step 12, adds trifluoroacetic acid (1ml), and at room temperature stirs this mixture 30 minutes.Under reduced pressure concentrate this reaction mixture, and the resistates that obtains is dissolved in the ethyl acetate.In this solution, add saturated sodium bicarbonate aqueous solution, and separating layer.Use the ethyl acetate extraction water layer, wash organic layer, and use dried over mgso with saturated brine.After filtration, under reduced pressure concentrated filtrate obtains yellow amorphous crude product (167mg).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.00(6H，s)，0.77(9H，s)，0.85(3H，d，J＝6.5Hz)，1.19(3H，d，J＝6.5Hz)，2.42-2.48(1H，m)，3.90(3H，s)，3.91(3H，s)，3.93-3.96(1H，m)，3.98(2H，s)，4.03-4.07(1H，m)，4.15-4.21(1H，m)，6.24(1H，dd，J＝5.4，2.9Hz)，6.54(1H，dd，J＝5.7，2.9Hz)，6.78(1H，s)，8.31(1H，s)，8.65(1H，s)

Step 14

The compound that will obtain in step 13 (167mg) is dissolved in the chloroform (1.7ml), and (46 μ l 0.564mmol) with 4-chlorobutanoylchloride (38 μ l 0.338mmol), and at room temperature stirred this mixture 15 hours to add pyridine.Under reduced pressure concentrate this reaction mixture, and the resistates that obtains is dissolved in the ethyl acetate.In this solution, add saturated sodium bicarbonate aqueous solution, and separating layer.Use the ethyl acetate extraction water layer, water, saturated sodium bicarbonate aqueous solution and saturated brine wash organic layer, and use dried over mgso successively.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying methyl alcohol=95: 5) obtains being light yellow gummy target compound (164mg, 82%, 2 step of productive rate) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.00(6H，s)，0.77(9H，s)，0.85(3H，d，J＝6.7Hz)，1.20(3H，d，J＝6.5Hz)，2.11-2.18(1H，m)，2.49(2H，t，J＝7.1Hz)，3.61(2H，t，J＝6.1Hz)，3.89(3H，s)，3.92(3H，s)，3.93-3.96(1H，m)，4.03(2H，s)，4.04-4.08(1H，m)，4.16-4.22(1H，m)，6.79(1H，s)，6.95(1H，dd，J＝5.3，2.6Hz)，7.36(1H，br?s)，7.73(1H，dd，J＝6.5，2.8Hz)，8.28(1H，s)，8.67(1H，s)

Step 15

(164mg 0.236mmol) is dissolved in the dimethyl formamide (1.7ml) compound that will obtain in step 14, and (14mg 0.354mmol), and stirred this mixture 2 hours under uniform temp to add sodium hydride down at 0 ℃.Aqueous ammonium chloride solution and ethyl acetate are added in this reaction mixture, and separating layer.Use the ethyl acetate extraction water layer, water (three times) and saturated brine wash organic layer successively, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains being the gummy crude product of brown (152mg).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.00(6H，s)，0.77(9H，s)，0.85(3H，d，J＝6.7Hz)，1.19(3H，d，J＝6.5Hz)，2.08-2.15(2H，m)，2.40-2.50(1H，m)，2.55(2H，t，J＝8.1Hz)，3.74(2H，t，J＝7.1Hz)，3.90(3H，s)，3.91-3.96(1H，m)，3.94(3H，s)，4.03-4.07(1H，m)，4.07(2H，s)，4.15-4.21(1H，m)，6.78(1H，s)，7.25-7.28(1H，m)，7.59(1H，dd，J＝6.0，2.8Hz)，8.28(1H，s)，8.65(1H，s)

Step 16

The crude product that will obtain in step 15 (152mg) is dissolved in the tetrahydrofuran (THF) (3ml), adds tetrabutylammonium fluoride at tetrahydrofuran (THF) (700 μ l, 0.699mmol) the 1.0M solution in, and at room temperature stirred this mixture 1 hour.Water and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Water and saturated brine wash organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying methyl alcohol=9: 1) obtains being the target compound (98mg, 76%, 2 step of productive rate) of light yellow oily by PTLC.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.76(3H，d，J＝6.5Hz)，1.23(3H，d，J＝6.5Hz)，2.08-2.15(2H，m)，2.43-2.51(1H，m)，2.55(2H，t，J＝8.1Hz)，3.56-3.61(1H，m)，3.69-3.74(3H，m)，3.85(3H，s)，4.03(3H，s)，4.12-4.27(3H，m)，4.79-4.90(1H，m)，6.92(1H，s)，7.38(1H，dd，J＝5.7，2.7Hz)，7.43(1H，dd，J＝6.0，2.8Hz)，7.58(1H，br?s)，8.57(1H，br?s)

Step 17

(98mg 0.18mmol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (1ml) and water (0.5ml) compound that will obtain in step 16, and (15mg 0.36mmol), and at room temperature stirred this mixture 3 hours to add lithium hydroxide monohydrate.With this reaction mixture of hcl acidifying of 1N, and use ethyl acetate extraction.Wash organic layer twice with water, use dried over mgso.After filtration, concentrated filtrate under reduced pressure, the resistates that recrystallization obtains from acetone-hexane obtains being the target compound (61mg, productive rate 64%) of light yellow solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.6Hz)，1.16(3H，d，J＝6.4Hz)，1.99-2.07(2H，m)，2.31-2.41(1H，m)，2.46-2.50(2H，m)，3.75-3.82(3H，m)，3.95-4.01(1H，m)，4.05(3H，s)，4.11(2H，s)，4.87(1H，br?s)，5.19(1H，t，J＝5.2Hz)，7.46(1H，s)，7.62(1H，dd，J＝6.0，2.6Hz)，7.82(1H，dd，J＝6.4，2.6Hz)，8.03(1H，s)，8.88(1H，s)，15.42(1H，s)

MS(ESI)：M+531

Embodiment 5

Step 1

To the compound (67mg that in the step 6 of embodiment 1, obtains, 0.22mmol), the compound (182mg that in the step 11 of embodiment 2, obtains, 0.33mmol), four (triphenylphosphines) close palladium (0) (7.5mg, 0.0065mmol) 1, aqueous sodium carbonate (the 434 μ l that add 2M in the solution of 2-glycol dimethyl ether (2.1ml), 0.87mmol), and under 80 ℃ heating, stirred this mixture 20 minutes.After reaction is finished, ethyl acetate and water are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure by the resistates that PTLC (chloroform: acetone=6: 1, launch twice) purifying obtains, obtains being the unpurified product (68mg) of filbert amorphous solid.

Step 2

At room temperature, (154 μ l, 0.15mmol) the 1.0M solution in is 1.5 hours at tetrahydrofuran (THF) with tetrabutylammonium fluoride to be stirred in the unpurified product (68mg) that obtains in the step 1 in tetrahydrofuran (THF) (0.7ml).Ethyl acetate and salt solution are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Wash the blended organic layer four times with saturated brine, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate is handled the resistates that obtains with ethyl acetate, filters the solid of collecting precipitation and filters the solid target compound that obtains being white in color (30mg, 25%, 2 step of productive rate).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.76(3H，d，J＝6.7Hz)，1.24(3H，d，J＝6.5Hz)，2.42-2.52(1H，m)，2.92-2.98(4H，m)，3.57(1H，d，J＝15.0Hz)，3.73-3.78(4H，m)，3.87(3H，s)，3.97(3H，s)，4.07(1H，d，J＝15.0Hz)，4.13-4.30(3H，m)，4.80-4.89(1H，m)，6.42-6.46(1H，m)，6.72(1H，dd，J＝5.9，2.9Hz)，6.84(1H，s)，7.61(1H，s)，8.56(1H，s)

Step 3

At room temperature, in the mixed solvent of tetrahydrofuran (THF) (300 μ l) and water (150 μ l), be stirred in the compound that obtains in the step 2 (30mg, 0.055mmol) and lithium hydroxide monohydrate (3.5mg, 0.082mmol) 4 hours.In this reaction mixture, add 5% aqueous potassium hydrogen sulfate, and with twice in this mixture of ethyl acetate extraction.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate is handled the resistates that obtains with the mixed solvent of hexane-ethyl acetate, filters the solid and the drying under reduced pressure of collecting precipitation, the solid target compound that obtains being white in color (28mg, productive rate 96%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.8Hz)，2.31-2.43(1H，m)，3.04-3.10(4H，m)，3.68-3.73(4H，m)，3.75-3.82(1H，m)，3.94-4.03(1H，m)，4.04(2H，s)，4.06(3H，s)，4.83-4.92(1H，m)，5.17-5.23(1H，m)，6.90-6.95(1H，m)，6.98-7.03(1H，m)，7.46(1H，s)，7.95(1H，s)，8.87(1H，s)，15.44(1H，br?s)

MS(ESI)：M+533

Embodiment 16

Step 1

With 3-chloro-2,4 difluorobenzene formic acid (25g 130mmol) is dissolved in the vitriol oil (250ml), and under the cooling in ice bath, dripped through 10 minutes N-iodosuccinimide (30.6g, 136mmol).After adding is finished, under uniform temp, stirred this mixture 30 minutes, and at room temperature stirred 3.5 hours.This reaction mixture impouring is comprised sodium sulfate, and (14.2g in frozen water 136mmol) (about 1000ml), after stirring, filters the solid of collecting precipitation, and washes with water.The solid that drying under reduced pressure obtains, the solid target compound that obtains being white in color (40.4g, productive rate 98%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：8.21-8.27(1H，m)

Step 2

(40.4g 127mmol) is dissolved in the tetrahydrofuran (THF) (200ml) compound that will obtain in step 1, and under argon atmospher, under 0 ℃, drips borine tetrahydrofuran (THF) mixture through 20 minutes at tetrahydrofuran (THF) (190ml, 190mmol) the 1.0M solution in.After being added dropwise to complete, at room temperature stirred this mixture 20 minutes, under 50 ℃ heating, stirred 1 hour then.After making its cooling, ice-cooled down, through 5 minutes with borine tetrahydrofuran (THF) mixture at tetrahydrofuran (THF) (100ml, 1.0M drips of solution 100mmol) adds in this reaction mixture, after being added dropwise to complete, at room temperature stirred this mixture 15 minutes, under 50 ℃ heating, stirred 1 hour then.After reaction is finished, at the ice-cooled hydrochloric acid (300ml) that drips 1N down.Ethyl acetate and saturated brine are added in this mixture, separating layer, and use the ethyl acetate extraction water layer.Wash the blended organic layer, and use dried over sodium sulfate with saturated brine, saturated sodium bicarbonate aqueous solution and saturated brine successively.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (40.0g) of light yellow solid.

Step 3

The crude product that will obtain in step 2 (40.0g) is dissolved in the dimethyl formamide (200ml), and the adding imidazoles (11.2g, 165mmol).Under the cooling, (23.0g 152mmol), and at room temperature stirred this mixture 1.3 hours to add TERT-BUTYL DIMETHYL CHLORO SILANE in ice bath.Further add imidazoles (1.3g, 7.9mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (1.91g 12.5mmol), and at room temperature stirred this mixture 0.7 hour.Water and ethyl acetate are added in this reaction mixture, separating layer, and further use the ethyl acetate extraction water layer.Wash the blended organic layer four times with saturated brine, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, by the resistates that silica gel chromatography (independent hexane) purifying obtains, the solid target compound that obtains being white in color (50.6g, 95%, 2 step of productive rate).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.12(6H，s)，0.95(9H，s)，4.70-4.74(2H，m)，7.74-7.79(1H，m)

Step 4

With 1,4-diox (200ml) joins three (dibenzalacetones) and closes two palladiums (0) chloroforms (1: 1) mixture (12.5g, 12.1mmol), (±)-2,2 '-two (diphenylphosphine)-1,1 '-dinaphthalene (15.3g, 26.6mmol) cesium carbonate (66.9g, 205mmol) in, and at room temperature, under argon atmospher, stirred this mixture 50 minutes.(14.8ml 169mmol) joins in this mixture, and (50.6g, 121mmol be 1, the solution in the 4-diox (300ml), and this mixture of reflux 20 hours to be added in the compound that obtains in the step 3 with morpholine.After making its cooling, (400ml) adds in this reaction mixture with hexane, and stirs this mixture.Leach the insoluble substance that obtains with diatomite, and wash this insoluble substance with ethyl acetate.Water and saturated brine (twice) wash blended filtrate successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and, obtain being the target compound (22.8g, productive rate 50%) of light yellow oily by the resistates that silica gel chromatography (hexane: ethyl acetate=50: 1 to 30: 1, further 20: 1) purifying obtains.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.12(6H，s)，0.95(9H，s)，3.02-3.06(4H，m)，3.84-3.89(4H，m)，4.74(2H，s)，6.99-7.05(1H，m)

Step 5

(22.8g 60.2mmol) is dissolved in the tetrahydrofuran (THF) (220ml) compound that will obtain in step 4, adds tetrabutylammonium fluoride at tetrahydrofuran (THF) (90.3ml, 90.3mmol) the 1.0M solution in, and at room temperature stirred this mixture 1 hour.Salt solution and ethyl acetate are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.Wash the blended organic layer with salt solution and saturated brine successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=2: 1 to 1: the 2) resistates that obtains of purifying obtains being the target compound (15.2g, productive rate 96%) of light yellow solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.79-1.84(1H，m)，3.03-3.09(4H，m)，3.84-3.89(4H，m)，4.74(2H，d，J＝6.0Hz)，6.92-6.99(1H，m)

Step 6

The compound that will in step 5, obtain (2g 7.6mmol) is dissolved in the chloroform (20ml), ice-cooled add down triphenylphosphine (2.39g, 9.10mmol) and carbon tetrabromide (3.02g 9.10mmol), and at room temperature stirred this mixture 20 minutes.Add triphenylphosphine (0.597g, 2.28mmol) and carbon tetrabromide (0.754g 2.27mmol), and at room temperature stirred this mixture 5 minutes.After reaction is finished, under reduced pressure concentrate this mixture, and by silica gel chromatography (hexane: ethyl acetate=50: 1 to 2: the 1) resistates that obtains of purifying, the solid target compound that obtains being white in color (2.20g, productive rate 89%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：3.02-3.08(4H，m)，3.83-3.89(4H，m)，4.46(2H，s)，6.82-6.88(1H，m)

Step 7

To the compound (55mg that in step 6, obtains, 0.17mmol) and the compound (141mg that in the step 11 of embodiment 2, obtains, 0.25mmol) 1, add four (triphenylphosphines) in the solution in the 2-glycol dimethyl ether (1.7ml) and close palladium (0) (6mg, 0.005mmol) and aqueous sodium carbonate (the 337 μ l of 2M, 0.67mmol), and under 80 ℃ heating, stirred this mixture 20 minutes.After reaction is finished, ethyl acetate and salt solution are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying acetone=5: 1) obtains being the target compound (96mg, productive rate 84%) of yellow amorphous solid by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.09(3H，s)，-0.05(3H，s)，0.76(9H，s)，0.84(3H，d，J＝6.7Hz)，1.19(3H，d，J＝6.5Hz)，2.39-2.50(1H，m)，2.93-2.98(4H，m)，3.79-3.83(4H，m)，3.89-4.08(10H，m)，4.15-4.22(1H，m)，6.60-6.66(1H，m)，6.79(1H，s)，8.27(1H，s)，8.65(1H，s)

Step 8

In tetrahydrofuran (THF) (1ml), be stirred in the compound that obtains in the step 7 (96mg, 0.14mmol) with tetrabutylammonium fluoride at tetrahydrofuran (THF) (212 μ l, 0.21mmol) the 1.0M solution in, and at room temperature stirred this mixture 1.8 hours.Ethyl acetate and salt solution are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (chloroform: acetone=10: 1 is to chloroform: the resistates that obtains of purifying methyl alcohol=10: 1) obtains being the target compound (73mg, productive rate 91%) of light yellow solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.77(3H，d，J＝6.7Hz)，1.23(3H，d，J＝6.5Hz)，2.40-2.51(1H，m)，2.88-2.93(4H，m)，3.62(1H，d，J＝14.2Hz)，3.76-3.81(4H，m)，3.87(3H，s)，3.96-4.04(4H，m)，4.15-4.28(3H，m)，4.52-4.61(1H，m)，6.49-6.56(1H，m)，6.86(1H，s)，7.66(1H，s)，8.56(1H，s)

Step 9

At room temperature, in the mixed solvent of tetrahydrofuran (THF) (740 μ l) and water (370 μ l), be stirred in the compound that obtains in the step 8 (73mg, 0.13mmol) and lithium hydroxide monohydrate (11mg, 0.26mmol) 2.3 hours.The aqueous potassium hydrogen sulfate of ethyl acetate and 5% is added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and handle the resistates that obtains with the mixed solvent of hexane-ethyl acetate.Filter the solid and the drying of collecting precipitation, obtain being hazel target compound (60mg, productive rate 84%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.8Hz)，2.31-2.45(1H，m)，2.93-3.00(4H，m)，3.70-3.75(4H，m)，3.75-3.82(1H，m)，3.95-4.02(1H，m)，4.06(3H，s)，4.07(2H，s)，4.83-4.92(1H，m)，5.17-5.23(1H，m)，7.05-7.11(1H，m)，7.46(1H，s)，8.01(1H，s)，8.88(1H，s)，15.44(1H，br?s)

MS(ESI)：M+551

Embodiment 17

Step 1

With 2-fluoro-4-methoxybenzoic acid (25.0g 147mmol) is dissolved in the vitriol oil (175ml), and ice-cooled down, dripped through 30 minutes N-iodosuccinimide (31.4g, 140mmol).After adding is finished, remove ice bath, and at room temperature stir this mixture overnight.This reaction mixture impouring is comprised sodium sulfate, and (1.9g in frozen water 15mmol), and stirred this mixture 1 hour.Filter the solid of collecting precipitation, and wash with water.The air-dry solid that obtains, and under 90 ℃, in ethanol (250ml), stirred 1 hour.After making its cooling, solid collected by filtration, the solid target compound that obtains being white in color (21.4g, productive rate 49%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.92(3H，s)，7.03(1H，d，J＝13.2Hz)，8.20(1H，d，J＝8.4Hz)，13.12(1H，br?s)

Step 2

(21.4g 72.2mmol) is suspended in the toluene (42ml) compound that will obtain in step 1, adds thionyl chloride (15.8ml, 217mmol) and dimethyl formamide (56 μ l, 0.72mmol), and under nitrogen atmosphere, under 75 ℃ heating, stirred this mixture 2.8 hours.After making its cooling, under reduced pressure concentrate this reaction mixture, make itself and toluene carry out component distillation twice, obtain resistates.

To ethyl malonic acid potassium (24.6g, 145mmol) and add in the mixture of tetrahydrofuran (THF) (125ml) triethylamine (30.2ml, 217mmol) and magnesium chloride (1.45g, 10.14mmol), and at room temperature, under argon atmospher, stir this mixture 1 hour and descend stirring 3.3 hours at 70 ℃.Under identical temperature, through 15 minutes, in this mixture, drip the solution of resistates in tetrahydrofuran (THF) (50ml) that as above obtains, then, under heating, stirred 30 minutes.After making its cooling, in this reaction mixture in ice bath, drip the hydrochloric acid (175ml) of 2N.Toluene is joined in this mixture, and separating layer.Water, sodium bicarbonate aqueous solution (twice) and water washing organic layer successively.Under reduced pressure concentrate this mixture, and carry out component distillation twice, obtain being the target compound (26.0g, productive rate 98%) of light yellow solid with toluene.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.17(3H，t，J＝7.0Hz)，3.94(3H，s)，4.00(2H，d，J＝3.3Hz)，4.11(2H，q，J＝7.0Hz)，7.09(1H，d，J＝13.7Hz)，8.20(1H，d，J＝8.4Hz)

Step 3

(26.0g 71.0mmol) is suspended in the toluene (125ml) compound that will obtain in step 2, and (11.3ml 85.1mmol), and stirred this mixture 3.8 hours under 85 ℃ heating to add dimethylformamide dimethyl acetal.After making its cooling, under reduced pressure concentrate this reaction mixture, and (hexane: ethyl acetate=1: 1 to 1: the 2) resistates that obtains of purifying obtains being the target compound (25.0g, productive rate 83%) of light yellow solid by silica gel chromatography.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.95(3H，t，J＝7.1Hz)，2.73(3H，br?s)，3.29(3H，br?s)，3.84-3.96(5H，m)，6.93(1H，d，J＝12.8Hz)，7.70(1H，s)，7.84(1H，d，J＝8.1Hz)

Step 4

At room temperature, (700mg is 1.66mmol) with uncle L--leucinol (234mg, 1.99mmol) 2.7 hours to be stirred in the compound that obtains in the step 3 in chloroform (7ml).Under reduced pressure concentrate this reaction mixture, ethyl acetate and water are added in this resistates, and separating layer.Water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate obtains white amorphous crude product (873mg).

Step 5

Under 80 ℃ heating, (689mg 4.99mmol) spends the night with salt of wormwood in dimethyl formamide (8ml) to be stirred in the crude product (873mg) that obtains in the step 4.After reaction is finished, water and ethyl acetate are added in this reaction mixture, separating layer, and wash organic layer with water twice.Use the ethyl acetate extraction water layer once more, mix all organic layers and use the salt water washing.Use the dried over sodium sulfate organic layer.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (931mg) of colorless oil.

Step 6

At room temperature, in dimethyl formamide (5ml), be stirred in the crude product (931mg) that obtains in the step 5, imidazoles (170mg, 2.49mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (301mg, 1.99mmol) 1 hour.Water and ethyl acetate are added in this reaction mixture, separating layer, water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure is by silica gel chromatography (hexane: ethyl acetate=2: the 3) resistates that obtains of purifying, the solid target compound that obtains being white in color (798mg, 82%, 3 step of productive rate).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.09(3H，s)，0.00(3H，s)，0.68(9H，s)，1.06(9H，s)，1.41(3H，t，J＝7.1Hz)，3.99(3H，s)，4.09-4.20(2H，m)，4.36-4.44(2H，m)，4.52(1H，dd，J＝8.7，4.5Hz)，6.86(1H，s)，8.62(1H，s)，8.94(1H，s)

Step 7

Under 80 ℃ heating, be stirred in the compound (200mg that obtains in the step 6,0.340mmol), two (tetramethyl ethylene ketone bases), two boron (95mg, 0.37mmol), potassium acetate (100mg, 1.02mmol) and [1,1 '-two (diphenylphosphine) ferrocene] dichloro closes palladium (II) methylene dichloride (1: 1) mixture (8mg, 0.01mmol) mixture in methyl-sulphoxide (2ml) is 1 hour.After making its cooling, ethyl acetate and water are added in this reaction mixture, separating layer, water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate obtains the amorphous crude product of black-brown (241mg).

Step 8

The crude product that will in step 7, obtain (241mg), the compound (126mg that in the step 6 of embodiment 1, obtains, 0.408mmol) and four (triphenylphosphines) close palladium (0) (20mg, 0.017mmol) mix with glycol dimethyl ether (4ml), aqueous sodium carbonate (the 0.7ml that adds 2M, 1.4mmol), and under 80 ℃ heating, stirred this mixture 30 minutes.After making its cooling, ethyl acetate and water are added in this reaction mixture, separating layer, water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying acetone=5: 1) obtains being brown buttery target compound (217mg, 93%, 2 step of productive rate) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.10(3H，s)，0.00(3H，s)，0.67(9H，s)，1.06(9H，s)，1.41(3H，t，J＝7.2Hz)，2.96-3.01(4H，m)，3.76-3.80(4H，m)，3.91(3H，s)，3.99(1H，d，J＝15.5Hz)，4.04(1H，d，J＝15.5Hz)，4.09-4.20(2H，m)，4.35-4.43(2H，m)，4.54(1H，dd，J＝8.8，4.4Hz)，6.51(1H，dd，J＝5.5，2.9Hz)，6.75(1H，dd，J＝5.8，2.9Hz)，6.89(1H，s)，8.28(1H，s)，8.62(1H，s)

Step 9

At room temperature, (217mg, 0.315mmol) (0.47ml, 0.47mmol) the 1.0M solution in spends the night at tetrahydrofuran (THF) with tetrabutylammonium fluoride to be stirred in the compound that obtains in the step 8 in tetrahydrofuran (THF) (2ml).Water is added in this reaction mixture, further add ethyl acetate, and separating layer.Water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and (launch for the first time by PTLC; Hexane: ethyl acetate=1: 5, launch for the second time: chloroform: the resistates that obtains of purifying methyl alcohol=20: 1) obtains being the target compound (166mg, productive rate 92%) of colorless oil.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.00(9H，s)，1.40(3H，t，J＝6.8Hz)，2.91-2.97(4H，m)，3.62(1H，d，J＝14.4Hz)，3.72-3.80(4H，m)，3.95(3H，s)，4.03(1H，d，J＝14.4Hz)，4.20-4.43(4H，m)，4.54-4.65(2H，m)，6.39-6.43(1H，m)，6.67-6.72(1H，m)，6.94(1H，s)，7.77(1H，s)，8.61(1H，s)

Step 10

At room temperature, in the mixed solvent of tetrahydrofuran (THF) (3ml) and water (0.6ml), be stirred in the compound that obtains in the step 9 (166mg, 0.289mmol) and lithium hydroxide monohydrate (24mg, 0.58mmol) 4 hours.The Citric acid aqueous solution and ethyl acetate are added in this reaction mixture, and separating layer.Water (twice) and salt water washing organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, the solid target compound that obtains being white in color (146mg, productive rate 92%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.99(9H，s)，3.08(4H，t，J＝4.8Hz)，3.71(4H，t，J＝4.8Hz)，4.03-4.11(2H，m)，4.05(2H，s)，4.08(3H，s)，5.13(1H，t，J＝4.9Hz)，5.17-5.20(1H，m)，6.90-6.92(1H，m)，7.01-7.03(1H，m)，7.54(1H，s)，7.96(1H，s)，8.79(1H，s)，15.39(1H，s)

MS(ESI)：M+547

Embodiment 25

Step 1

With 3-chloro-2,4 difluorobenzene formic acid (5.0g 26mmol) is dissolved in the vitriol oil (5.00ml), and ice-cooled down, drip nitrosonitric acid (1.43ml, 33.8mmol).After being added dropwise to complete, at room temperature stirred this mixture 1 hour.In this reaction mixture impouring frozen water, and at ice-cooled this mixture that stirs down.Filter the solid of collecting precipitation, and wash with water.Under 50 ℃, the solid that drying under reduced pressure obtains spends the night, and obtains target compound (5.54g, productive rate 90%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：8.78(1H，dd，J＝8.1，7.2Hz)

Step 2

The compound that will in step 1, obtain (5.0g 21mmol) is dissolved in the tetrahydrofuran (THF) (50ml), after ice-cooled, the adding triethylamine (3.08ml, 22.1mmol).(2.87ml 22.1mmol), and stirred this mixture 40 minutes under uniform temp to drip isobutyl chlorocarbonate.(1.19g 31.6mmol) adds in the mixture that obtains, and drips water (5ml) through 15 minutes with sodium boorohyride.Under uniform temp, stirred this mixture 30 minutes, water is added in this reaction mixture, and with this mixture of ethyl acetate extraction.After distribution, use the ethyl acetate extraction water layer.With saturated sodium bicarbonate aqueous solution and saturated brine washing blended organic layer, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains crude product (2.97g).

Step 3

In the mixture of ethanol (15ml) and water (5ml), add reduced iron (3.56g, 63.7mmol) and ammonium chloride (3.41g, 63.7mmol).Under 70 ℃, in this mixture, drip the solution of crude product (2.85g) in tetrahydrofuran (THF) (15ml) that in step 2, obtains, and under 80 ℃ heating, stirred this mixture 30 minutes.After making its cooling, use the diatomite filtration reaction mixture, ethyl acetate and saturated sodium bicarbonate aqueous solution are added in the filtrate, and separating layer.Use the ethyl acetate extraction water layer, saturated sodium bicarbonate aqueous solution and saturated brine washing blended organic layer, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (hexane: ethyl acetate=2: the 1) resistates that obtains of purifying obtains target compound (1.50g, 38%, 2 step of productive rate) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.75(1H，br?s)，3.69(2H，br?s)，4.68(2H，d，J＝3.7Hz)，6.76(1H，dd，J＝9.3，7.0Hz)

Step 4

(1.5g, 7.8mmol) (2.54g, 11.6mmol) solution in tetrahydrofuran (THF) (10ml) is 48 hours with the di-t-butyl sodium bicarbonate for the compound that reflux obtains in step 3.With the di-t-butyl sodium bicarbonate (508mg, 2.32mmol) and tetrahydrofuran (THF) (2ml) add in the reaction mixture and this mixture of reflux 30.5 hours.Add two-tertiary butyl sodium bicarbonate (2.0g, 9.2mmol), and this mixture of reflux 16.5 hours.Under reduced pressure concentrate this reaction mixture,, obtain target compound (2.4g, productive rate 95%) by silica gel chromatography (hexane: ethyl acetate=5: 1,4: 1,3: 1 to 2: the 1) resistates that purifying obtains.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.53(9H，s)，1.98(1H，t，J＝6.4Hz)，4.73(2H，d，J＝6.4Hz)，6.60(1H，br?s)，8.08(1H，t，J＝7.8Hz)

Step 5

The compound that will in step 4, obtain (2.14g 7.29mmol) is dissolved in the chloroform (20ml), add triphenylphosphine (2.06g, 7.87mmol) and carbon tetrabromide (2.66g 8.02mmol), and at room temperature stirs this mixture.Under reduced pressure concentrate this reaction mixture, by silica gel chromatography (hexane: the resistates that obtains of purifying chloroform=1: 1), and further handling with hexane.Filter the solid of collecting precipitation, and drying under reduced pressure, obtain being solid target compound (1.54g, productive rate 59%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.53(9H，s)，4.46(2H，d，J＝1.4Hz)，6.61(1H，br?s)，7.88(1H，t，J＝7.9Hz)

Step 6

Argon gas is fed the compound (497mg that in step 5, obtains, 1.39mmol), the compound (600mg that in the step 11 of embodiment 2, obtains, 1.07mmol), four (triphenylphosphines) close palladium (0) (62mg, 0.054mmol) and yellow soda ash (340mg, 3.21mmol) 1, in the solution in the mixture of 2-glycol dimethyl ether (4ml) and water (2ml) 2 minutes, and under argon atmospher, under 100 ℃ heating, stirred this solution 0.5 hour.Ethyl acetate and saturated sodium bicarbonate aqueous solution are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=2: 1 to 1: the 1) resistates that obtains of purifying obtains target compound (649mg, productive rate 85%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.08(3H，s)，-0.06(3H，s)，0.77(9H，s)，0.84(3H，d，J＝6.7Hz)，1.19(3H，d，J＝6.5Hz)，1.48(9H，s)，2.38-2.50(1H，m)，3.89(3H，s)，3.92-3.97(4H，m)，4.00-4.08(3H，m)，4.14-4.21(1H，m)，6.50(1H，br?s)，6.73(1H，s)，7.87(1H，br?s)，8.18(1H，s)，8.64(1H，s)

Step 7

At room temperature, in the mixed solvent of trifluoroacetic acid (2.5ml) and chloroform (5ml), be stirred in compound (645mg, 0.909mmol) 0.5 hour that obtains in the step 6.Under reduced pressure concentrate this reaction mixture, and ethyl acetate is added in the resistates that obtains.Use saturated sodium bicarbonate aqueous solution (twice) and saturated brine washing organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying methyl alcohol=10: 1) obtains target compound (454mg, productive rate 82%) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.08(3H，s)，-0.04(3H，s)，0.77(9H，s)，0.85(3H，d，J＝6.5Hz)，1.19(3H，d，J＝6.5Hz)，2.40-2.51(1H，m)，3.52(2H，s)，3.88-3.98(9H，m)，4.01-4.09(1H，m)，4.14-4.22(1H，m)，6.34-6.40(1H，m)，6.78(1H，s)，8.30(1H，s)，8.65(1H，s)

Step 8

To the compound that in step 7, obtains (197mg, 0.323mmol) and pyridine (53 μ l, (44 μ l 0.39mmol), and at room temperature stirred this mixture 4.3 hours 0.65mmol) to add the 4-chlorobutanoylchloride in the solution in chloroform (2ml).Under reduced pressure concentrate this reaction mixture, ethyl acetate and saturated sodium bicarbonate aqueous solution are added in the resistates that obtains, and separating layer.Wash organic layer with saturated brine, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains crude product (233mg).

Step 9

The crude product that will obtain in step 8 (233mg) is dissolved in the dimethyl formamide (2ml), and (60%, 19.4mg 0.485mmol), and stirred this mixture 15 minutes under uniform temp to add sodium hydride down at 0 ℃.Aqueous potassium hydrogen sulfate and ethyl acetate are added in this reaction mixture, and separating layer.Water and saturated brine wash organic layer successively, and use dried over mgso.After filtration, under reduced pressure concentrated filtrate obtains crude product.

Step 10

At room temperature, in tetrahydrofuran (THF) (3ml), be stirred in the crude product that obtains in the step 9 and tetrabutylammonium fluoride tetrahydrofuran (THF) (485 μ l, 0.485mmol) and acetate (55 μ l, 0.97mmol) the 1.0M solution in is 5 hours.Under reduced pressure concentrate this reaction mixture, (chloroform: the resistates that obtains of purifying methyl alcohol=15: 1) obtains target compound (178mg, 98%, 3 step of productive rate) by silica gel chromatography.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.76(3H，d，J＝6.7Hz)，1.24(3H，d，J＝6.0Hz)，2.12-2.21(2H，m)，2.43-2.53(2H，m)，3.54(1H，d，J＝14.8Hz)，3.71(2H，t，J＝7.1Hz)，3.86(3H，s)，3.99(3H，s)，4.08(1H，d，J＝14.8Hz)，4.14-4.30(3H，m)，6.87(1H，s)，6.96-7.02(1H，m)，7.58(1H，s)，8.56(1H，s)

Step 11

At room temperature, in the mixed solvent of tetrahydrofuran (THF) (2ml) and water (0.6ml), be stirred in the compound that obtains in the step 10 (175mg, 0.311mmol) and lithium hydroxide monohydrate (26.1mg, 0.622mmol) 1 hour.With the hydrochloric acid of 2N this reaction mixture that neutralizes, and with this mixture of ethyl acetate extraction.Wash organic layer with saturated brine, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and handle the resistates that obtains with the mixed solvent of hexane-ethyl acetate.Filter the solid of collecting precipitation, and drying under reduced pressure, obtain being solid target compound (92mg, productive rate 54%).

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.4Hz)，2.10(2H，tt，J＝7.4，7.4Hz)，2.42(2H，t，J＝7.4Hz)，2.31-2.44(1H，m)，3.74(2H，t，J＝7.4Hz)，3.73-3.83(1H，m)，3.95-4.06(1H，m)，4.03(3H，s)，4.10(2H，s)，4.83-4.91(1H，m)，5.19(1H，t，J＝5.0Hz)，7.45(1H，dd，J＝7.6，7.6Hz)，7.45(1H?s)，8.12(1H，s)，8.88(1H，s)，15.45(1H，s)

MS(ESI)：M+549

Embodiment 49

Step 1

Under argon atmospher, under 80 ℃ heating, be stirred in the compound (217mg that obtains in the step 6 of embodiment 17,0.369mmol), two (tetramethyl ethylene ketone bases), two boron (103mg, 0.406mmol), potassium acetate (109mg, 1.11mmol) and [1,1 '-two (diphenylphosphine) ferrocene] dichloro closes palladium (II) methylene dichloride (1: 1) mixture, and (60mg, 0.074mmol) mixture in methyl-sulphoxide (1.6ml) is 2 hours.After making its cooling, ethyl acetate and salt solution are added in this reaction mixture, and at room temperature stir this mixture.Leach the insoluble substance that obtains with diatomite.The separating filtrate layer washs organic layer four times with saturated brine, and uses dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate obtains the amorphous crude product of brown (230mg).

Step 2

The crude product that will in step 1, obtain (230mg), in the step 6 of embodiment 16, obtain compound (100mg, 0.306mmol) and tetrakis triphenylphosphine palladium (0) (10.6mg, 0.0092mmol) with 1,2-glycol dimethyl ether (2ml) mixes.(612 μ l 1.22mmol), and stirred this mixture 25 minutes under 80 ℃ heating to add the 2M aqueous sodium carbonate.After making its cooling, ethyl acetate and water are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With salt water washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 2 is to chloroform: the resistates twice that obtains of purifying acetone=5: 1) obtains the amorphous unpurified product of brown (40mg).

Step 3

At room temperature, (85 μ l, 0.085mmol) the 1.0M solution in is 5 minutes at tetrahydrofuran (THF) with tetrabutylammonium fluoride to be stirred in the unpurified product (40mg) that obtains in the step 2 in tetrahydrofuran (THF) (0.4ml).Ethyl acetate and salt solution are added in this reaction mixture, separating layer, and use the ethyl acetate extraction water layer.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying acetone=2: 1) obtains being the target compound (24mg, 13%, 3 step of productive rate) of light brown amorphous solid by PTLC.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.02(9H，s)，1.41(3H，t，J＝7.3Hz)，2.89-2.93(4H，m)，3.72(1H，d，J＝14.8Hz)，3.76-3.82(5H，m)，3.94-4.00(4H，m)，4.20-4.44(4H，m)，4.63(1H，dd，J＝9.4，3.6Hz)，6.49-6.55(1H，m)，6.95(1H，s)，

7.89(1H，s)，8.60(1H，s)

Step 4

To the compound that in step 3, obtains (24mg, 0.040mmol), (3.4mg 0.081mmol), and at room temperature stirred this mixture 2.3 hours to add lithium hydroxide monohydrate in the mixture of tetrahydrofuran (THF) (240 μ l) and water (120 μ l).5% aqueous potassium hydrogen sulfate is added in the reaction mixture, and with twice in this mixture of ethyl acetate extraction.With saturated brine washing blended organic layer twice, and use dried over sodium sulfate.After filtration, under reduced pressure concentrated filtrate is handled the resistates that obtains with the mixed solvent of hexane-ethyl acetate, filters the solid and the drying of collecting precipitation, the solid target compound that obtains being white in color (20mg, productive rate 87%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.98(9H，s)，2.93-2.98(4H，m)，3.70-3.74(4H，m)，4.00-4.14(7H，m)，5.11(1H，t，J＝4.8Hz)，5.13-5.19(1H，m)，7.02-7.08(1H，m)，7.52(1H，s)，8.01(1H，s)，8.78(1H，s)，15.37(1H，s)

MS(ESI)：M+565

Embodiment 51

Step 1

To 2-fluoro-5-iodo-benzoic acid (4.79g, 18.0mmol) and dimethyl formamide (69 μ l, (1.57ml 21.6mmol), and stirred this mixture 1 hour under 110 ℃ heating 0.90mmol) to add thionyl chloride in the suspension in toluene (20ml).Under reduced pressure concentrate this reaction mixture, make itself and toluene carry out component distillation twice.The resistates that obtains is dissolved in the toluene (15ml), under 60 ℃, through 5 minutes this solution is added 3-(dimethylamino) ethyl propenoate (2.83g, 19.8mmol) and diisopropylethylamine (4.07ml, 23.4mmol) in the solution in toluene (15ml), and under 100 ℃ heating, stirred this mixture 16 hours.Water and ethyl acetate are added in this reaction mixture, stir this mixture, separating layer.Water and saturated brine wash the organic layer that obtains successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=3: 2 to 1: the 2) resistates that obtains of purifying obtains being brown buttery target compound (6.48g, productive rate 85%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.95(3H，t，J＝7.1Hz)，2.89(3H，br?s)，3.32(3H，br?s)，3.99(2H，q，J＝7.1Hz)，6.79(1H，dd，J＝10.0，8.5Hz)，7.66(1H，ddd，J＝8.5，4.6，2.4Hz)，7.78(1H，s)，7.87(1H，dd，J＝6.6，2.4Hz)

Step 2

The compound that will obtain in step 1 (3.20g) is dissolved in the tetrahydrofuran (THF), and (977mg 8.34mmol), and at room temperature stirred this mixture 15.5 hours to add uncle L--leucinol.Under reduced pressure concentrate this reaction mixture, and ethyl acetate and water are added in the resistates.Stir this mixture, and separating layer.Water and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and carry out component distillation twice with toluene, and obtaining being brown buttery crude product (4.41g), it is the mixture of E form/Z-shaped formula.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.87-0.94(1.6H，m)，0.99-1.06(10.4H，m)，3.05-3.16(1H，m)，3.64-3.73(1H，m)，3.93-4.08(3H，m)，6.74-6.84(1H，m)，7.59-7.74(2H，m)，8.09-8.18(1H，m)

Step 3

Under 80 ℃ heating, (1.57g, 11.4mmol) suspension in dimethyl formamide (40ml) is 6 hours to be stirred in the crude product (4.41g) that obtains in the step 2 and salt of wormwood.Down water is added in the reaction mixture ice-cooled, filter the solid of collecting precipitation, and wash with water.The at room temperature air-dry solid that obtains, and under 60 ℃, drying under reduced pressure obtains being the crude product (3.23g) of brown solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.98(9H，s)，1.41(3H，t，J＝7.2Hz)，4.22-4.45(4H，m)，4.68(1H，dd，J＝8.9，2.8Hz)，5.14(1H，br?s)，7.46(1H，d，J＝9.3Hz)，7.89(1H，dd，J＝9.3，2.2Hz)，8.07(1H，d，J＝2.2Hz)，8.69(1H，s)

Step 4

To crude product that in step 3, obtains (3.23g) and imidazoles (645mg, 9.48mmol) add TERT-BUTYL DIMETHYL CHLORO SILANE (1.32g in the solution in dimethyl formamide (30ml), 8.75mmol), and under argon atmospher, at room temperature stirred this mixture 1 hour.Water and ethyl acetate are added in this reaction mixture separating layer, water (twice) and saturated brine washing organic layer successively.Use the ethyl acetate extraction water layer, the organic layer that water and saturated brine washing obtain.With dried over sodium sulfate blended organic layer.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=3: 2 to 2: the 1) resistates that obtains of purifying obtains being the target compound (3.81g, 90%, 3 step of productive rate) of light yellow amorphous solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.10(3H，s)，-0.01(3H，s)，0.66(9H，s)，1.04(9H，s)，1.41(3H，t，J＝7.2Hz)，4.06-4.19(2H，m)，4.36-4.45(2H，m)，4.60(1H，dd，J＝8.7，4.5Hz)，7.39(1H，d，J＝9.4Hz)，7.89(1H，dd，J＝9.4，2.3Hz)，8.67(1H，s)，8.88(1H，d，J＝2.3Hz)

Step 5

Under 80 ℃ heating, be stirred in the compound (300mg that obtains in the step 4,0.538mmol), two (tetramethyl ethylene ketone bases), two boron (150mg, 0.592mmol), [1,1 '-two (diphenyl phosphine) ferrocene] dichloro closes palladium (II) methylene dichloride (1: 1) mixture (22mg, 0.027mmol) and potassium acetate (158mg, 1.61mmol) solution in methyl-sulphoxide (3ml) is 20 minutes.After making its cooling, water and ethyl acetate are added in this reaction mixture, leach the insoluble substance that obtains with diatomite.The separating filtrate layer, water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure obtains being the crude product (366mg) of brown amorphous solid shape.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.10(3H，s)，-0.02(3H，s)，0.65(9H，s)，1.03(9H，s)，1.35(12H，s)，1.41(3H，t，J＝7.1Hz)，4.09-4.19(2H，m)，4.36-4.45(2H，m)，4.71(1H，dd，J＝8.2，5.0Hz)，7.59(1H，d，J＝8.8Hz)，8.01(1H，dd，J＝8.8，1.63Hz)，8.67(1H，s)，9.03(1H，d，J＝1.6Hz)

Step 6

To the crude product that in step 5, obtains (366mg), the compound (200mg that in the step 5 of embodiment 2, obtains, 0.592mmol) and four (triphenylphosphines) close palladium (0) (31mg, 0.027mmol) 1, add 2M aqueous sodium carbonate (1.1ml in the solution in the 2-glycol dimethyl ether (6ml), 2.2mmol), and under 80 ℃, stir this mixture.After reaction is finished,, and add ethyl acetate with the reaction mixture cooling.Separating layer, water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure is by silica gel chromatography (hexane: ethyl acetate=3: the 2) resistates that obtains of purifying, the target compound (301mg, 81%, 2 step of productive rate) of the amorphous solid that obtains being white in color.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.02(3H，s)，0.64(9H，s)，1.05(9H，s)，1.41(3H，t，J＝7.2Hz)，1.48(9H，s)，4.02-4.18(4H，m)，4.36-4.44(2H，m)，4.64(1H，dd，J＝8.5，4.5Hz)，6.34(1H，s)，6.84(1H，dd，J＝5.6，2.8Hz)，7.47(1H，dd，J＝8.9，2.1Hz)，7.52-7.59(2H，m)，8.41(1H，d，J＝2.1Hz)，8.69(1H，s)

Step 7

At room temperature, (301mg, 0.437mmol) solution in the mixture of trifluoroacetic acid (3ml) and chloroform (3ml) is 1 hour to be stirred in the compound that obtains in the step 6.Under reduced pressure concentrate this reaction mixture, make itself and toluene carry out component distillation.Sodium bicarbonate aqueous solution and ethyl acetate are added in the resistates that obtains, and separating layer.Water (secondary) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 3 is to chloroform: the resistates that obtains of purifying methyl alcohol=10: 1) obtains being the target compound (196mg, productive rate 76%) of amorphous solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.02(3H，s)，0.64(9H，s)，1.05(9H，s)，1.41(3H，t，J＝7.1Hz)，3.50(2H，br?s)，3.96-4.18(4H，m)，4.36-4.45(2H，m)，4.64(1H，dd，J＝8.2，4.9Hz)，6.32(1H，dd，J＝5.4，2.8Hz)，6.56(1H，dd，J＝5.6，2.8Hz)，7.48(1H，dd，J＝9.0，2.3Hz)，7.56(1H，d，J＝9.0Hz)，8.42(1H，d，J＝2.3Hz)，8.69(1H，s)

Step 8

To the compound that in step 7, obtains (100mg, 0.170mmol) and pyridine (27 μ l, (44 μ l 0.39mmol), and at room temperature stirred this mixture 20 minutes 0.34mmol) to add the 4-chlorobutanoylchloride in the solution in chloroform (1ml).Ethyl acetate is added in this reaction mixture, and water (twice) and saturated brine wash this mixture successively.Use the dried over sodium sulfate organic layer.After filtration, under reduced pressure concentrated filtrate obtains white amorphous crude product (122mg).

Step 9

The crude product that will obtain in step 8 (122mg) is dissolved in the dimethyl formamide (1ml), and (60%, 10mg 0.25mmol), and stirred this mixture 40 minutes under uniform temp to add sodium hydride down at 0 ℃.Aqueous ammonium chloride solution is added in the reaction mixture, and with this mixture of ethyl acetate extraction.Water (three times) and saturated brine wash organic layer successively, and use dried over mgso.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 9 is to chloroform: the resistates that obtains of purifying methyl alcohol=10: 1) obtains being as white crystalline form solid target compound (98mg, productive rate 88%).

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.02(3H，s)，0.64(s，9H)，1.05(9H，s)，1.41(3H，t，J＝7.1Hz)，2.09-2.18(2H，m)，2.57(2H，t.J＝8.2Hz)，3.73-3.79(2H，m)，4.07-4.18(4H，m)，4.36-4.44(2H，m)，4.61-4.67(1H，m)，7.23-7.29(1H，m)，7.48-7.53(1H，m)，7.57(1H，d，J＝9.2Hz)，7.70(1H，dd，J＝6.3，2.8Hz)，8.40(1H，d，J＝2.2Hz)，8.68(1H，s)

Step 10

In tetrahydrofuran (THF) (1ml), be stirred in the compound that obtains in the step 9 (98mg, 0.15mmol) with tetrabutylammonium fluoride at tetrahydrofuran (THF) (224 μ l, 0.224mmol) the 1.0M solution in, and at room temperature stirred this mixture 10 minutes.Water is joined in this reaction mixture, and with this mixture of ethyl acetate extraction.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, (chloroform: the resistates that obtains of purifying methyl alcohol=15: 1), solid target compound (88mg) quantitatively obtains being white in color by PTLC.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.00(9H，s)，1.40(3H，t，J＝7.2Hz)，2.08-2.19(2H，m)，2.57(2H，t.J＝8.1Hz)，3.76(2H，t，J＝7.5Hz)，3.83(1H，d，J＝14.4Hz)，3.96(1H，d，J＝14.4Hz)，4.16-4.27(2H，m)，4.27-4.43(3H，m)，4.69-4.76(1H，m)，7.29(1H，dd，J＝5.8，2.8Hz)，7.42(1H，dd，J＝8.9，2.3Hz)，7.60-7.66(2H，m)，7.89(1H，d，J＝2.3Hz)，8.68(1H，s)

Step 11

At room temperature, in the mixed solvent of tetrahydrofuran (THF) (1.5ml) and water (0.3ml), be stirred in the compound that obtains in the step 10 (83mg, 0.15mmol) and lithium hydroxide monohydrate (13mg, 0.31mmol) 2.7 hours.The Citric acid aqueous solution is added in the reaction mixture, and with this mixture of ethyl acetate extraction.Water (three times) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and handle the resistates that obtains with the mixed solvent of hexane-ethyl acetate.Filter the solid of collecting precipitation, and drying under reduced pressure, the solid target compound that obtains being white in color (60mg, productive rate 76%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.96(9H，s)，2.05(2H，quint.，J＝7.5Hz)，2.45-2.55(2H，m)，3.82(2H，t，J＝7.1Hz)，4.00-4.12(2H，m)，4.26(2H，s)，5.06-5.13(2H，m)，7.70(1H，dd，J＝6.1，2.7Hz)，7.83(1H，dd，J＝9.2，2.2Hz)，7.87(1H，dd，J＝6.4，2.7Hz)，8.22(1H，d，J＝2.2Hz)，8.37(1H，d，J＝9.2Hz)，8.82(1H，s)，15.17(1H，br?s)

MS(ESI)：M+515

Embodiment 53

Step 1

In oil bath, under 80 ℃ heating, to zinc powder (0.793g, 12.1mmol) in the suspension of tetrahydrofuran (THF) (10ml), add glycol dibromide (0.09ml, 1.0mmol) and trimethylchlorosilane (0.27ml, 2.1mmol), and under uniform temp, stirred this mixture 10 minutes.After making its cooling, in water-bath under the cooling, be added in the compound that obtains in the step 6 of embodiment 1 (2.88g, the 9.33mmol) solution in tetrahydrofuran (THF) (20ml), and at room temperature stirred this mixture 20 minutes through 10 minutes.In this mixture, add two (triphenylphosphine) dichloro successively and close palladium (II) (252mg, 0.359mmol) and the compound (4.0g that in the step 4 of embodiment 51, obtains, 7.2mmol) solution in tetrahydrofuran (THF) (10ml), and under 80 ℃ heating, stirred this mixture 15 minutes.After reaction is finished,, and add aqueous ammonium chloride solution and ethyl acetate with the reaction mixture cooling.Leach the insoluble substance that obtains with diatomite.The separating filtrate layer, water (twice) and saturated brine wash organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=2: 3 to 1: the 2) resistates that obtains of purifying obtains being the target compound (4.71g, productive rate 99%) of ivory buff (pale yellowish-white) amorphous solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.02(3H，s)，0.64(9H，s)，1.05(9H，s)，1.41(3H，t，J＝7.1Hz)，2.99-3.05(4H，m)，3.77-3.83(4H，m)，4.02-4.18(4H，m)，4.34-4.46(2H，m)，4.64(1H，dd，J＝8.5，4.8Hz)，6.59(1H，dd，J＝5.5，3.1Hz)，6.76(1H，dd，J＝6.0，3.1Hz)，7.49(1H，dd，J＝9.1，2.1Hz)，7.57(1H，d，J＝9.1Hz)，8.42(1H，d，J＝2.1Hz)，8.68(1H，s)

Step 2

(5.51g 8.35mmol) is dissolved in the ethanol (16ml) compound that will obtain in step 1, and (8ml 32mmol), and stirred this mixture 2 hours under 80 ℃ heating to add the 4N aqueous sodium hydroxide solution.After making its cooling, 10% the Citric acid aqueous solution is added in the reaction mixture, and with this mixture of ethyl acetate extraction.Water (three times) and saturated brine washing organic layer adds sodium sulfate and activated carbon successively, and dilutes this mixture with chloroform.Under 45 ℃ heating, stirred this mixture 15 minutes.After making its cooling,, and under reduced pressure concentrate with this this mixture of diatomite filtration.Mixed solvent with hexane-ethyl acetate is handled the resistates that obtains, and filters the solid and the drying under reduced pressure of collecting precipitation, the solid target compound that obtains being white in color (3.86g, productive rate 89%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.96(9H，s)，3.07-3.12(4H，m)，3.69-3.74(4H，m)，4.00-4.12(2H，m)，4.18(2H，s)，5.05-5.13(2H，m)，6.97(1H，dd，J＝5.8，3.0Hz)，7.08(1H，dd，J＝5.7，3.0Hz)，7.88(1H，dd，J＝9.2，2.1Hz)，8.23(1H，d，J＝2.1Hz)，8.36(1H，d，J＝9.2Hz)，8.82(1H，s)，15.18(1H，br?s)

MS(ESI)：M+517

Embodiment 56

Step 1

Under argon atmospher, in oil bath, under 80 ℃ heating, to zinc powder ((0.572g, 8.76mmol) in the suspension of tetrahydrofuran (THF) (7.5ml), add glycol dibromide (65 μ l, 0.75mmol) and trimethylchlorosilane (195 μ l, 1.54mmol), and under uniform temp, stirred this mixture 5 minutes.After making its cooling, in water-bath under the cooling, be added in the compound that obtains in the step 6 of embodiment 16 (2.20g, the 6.74mmol) solution in tetrahydrofuran (THF) (15ml), and at room temperature stirred this mixture 15 minutes through 10 minutes.In this mixture, add two (triphenylphosphine) dichloro successively and close palladium (II) (182mg, 0.259mmol) and the compound (2.89g that in the step 4 of embodiment 51, obtains, 5.18mmol) solution in tetrahydrofuran (THF) (7.5ml), and under 80 ℃ heating, stirred this mixture 15 minutes.After reaction is finished,, and add aqueous ammonium chloride solution and ethyl acetate with the reaction mixture cooling.Leach the insoluble substance that obtains with diatomite.The separating filtrate layer, and use the ethyl acetate extraction water layer.Wash the blended organic layer with salt solution and saturated brine successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and, obtain being the unpurified product of target (3.39g) of light yellow amorphous solid by the resistates that silica gel chromatography (hexane: ethyl acetate=3: 4 to 3: 5 further is 1: 2) purifying obtains.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.02(3H，s)，0.63(9H，s)，1.05(9H，s)，1.41(3H，t，J＝7.2Hz)，2.94-2.99(4H，m)，3.79-3.84(4H，m)，4.02-4.18(4H，m)，4.34-4.46(2H，m)，4.65(1H，dd，J＝8.5，4.5Hz)，6.60-6.65(1H，m)，7.47(1H，dd，J＝8.9，2.1Hz)，7.58(1H，d，J＝8.9Hz)，8.40(1H，d，J＝2.1Hz)，8.69(1H，s)

Step 2

The unpurified product (3.39g) that will obtain in step 1 is dissolved in the tetrahydrofuran (THF) (34ml), adds tetrabutylammonium fluoride at tetrahydrofuran (THF) (7.5ml, 7.5mmol) the 1.0M solution in, and at room temperature stirred this mixture 5 minutes.In this reaction mixture, add salt solution, and with twice in this mixture of ethyl acetate extraction.Use salt solution (twice) and saturated brine washing blended organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and by silica gel chromatography (hexane: ethyl acetate=1: 3 is to chloroform: the resistates that obtains of purifying acetone=3: 2) obtains being the target compound (2.81g, 96%, 2 step of productive rate) of light brown amorphous solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.00(9H，s)，1.41(3H，t，J＝7.1Hz)，2.93-3.00(4H，m)，3.78-3.86(6H，m)，3.95(1H，d，J＝15.3Hz)，4.20-4.45(4H，m)，4.73(1H，dd，J＝9.4，4.1Hz)，6.54-6.60(1H，m)，7.42(1H，dd，J＝8.9，1.9Hz)，7.63(1H，d，J＝8.9Hz)，7.96(1H，d，J＝1.9Hz)，8.67(1H，s)

Step 3

(2.81g 4.99mmol) is dissolved in the mixed solvent of tetrahydrofuran (THF) (1.5ml) and water (0.3ml) compound that will obtain in step 2, and (418mg 9.98mmol), and at room temperature stirred this mixture 2 hours to add lithium hydroxide monohydrate.5% aqueous potassium hydrogen sulfate is added in the reaction mixture, and with twice in this mixture of ethyl acetate extraction.Use salt solution (twice) and saturated brine washing blended organic layer successively, and use dried over sodium sulfate.After filtration, concentrated filtrate under reduced pressure, and handle the resistates that obtains with the mixed solvent of hexane-ethyl acetate.Filter the solid of collecting precipitation, and drying under reduced pressure, the solid target compound that obtains being white in color (2.43g, productive rate 91%).

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.96(9H，s)，2.97-3.01(4H，m)，3.71-3.76(4H，m)，4.00-4.12(2H，m)，4.21(2H，s)，5.06-5.13(2H，m)，7.24(1H，dd，J＝7.7，7.7Hz)，7.83(1H，dd，J＝9.2，2.1Hz)，8.24(1H，d，J＝1.9Hz)，8.36(1H，d，J＝9.3Hz)，8.81(1H，s)，15.19(1H，br?s)

MS(ESI)：M+535

According to method same with the above-mentioned embodiment and when the needs according to other ordinary method, obtain embodiment 3,4,6-15,18-24,26-29,32,34-37,38-48,50,52,54,55 and the compound of 57-59.Among the chemical structural formula indicator gauge 1-7 of these compounds.In addition, also can prepare reference example 30,31 and 33 compounds that are presented in the table 4 according to other ordinary method according to method same as the previously described embodiments with when needing.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

The NMR of embodiment compound and MS data description are as follows.

Embodiment 3

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.73(3H，d，J＝6.5Hz)，1.17(3H，d，J＝6.5Hz)，1.94(4H，t，J＝6.6Hz)，2.33-2.42(1H，m)，3.16-3.20(4H，m)，3.76-3.83(1H，m)，3.96-4.01(1H，m)，4.03(2H，s)，4.08(3H，s)，4.90(1H，s)，5.20(1H，t，J＝5.0Hz)，6.45(1H，dd，J＝5.4，2.9Hz)，6.53(1H，dd，J＝5.7，2.9Hz)，7.47(1H，s)，7.97(1H，s)，8.89(1H，s)，15.44(1H，s)

MS(ESI)：M+517

Embodiment 4

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.4Hz)，1.15(3H，d，J＝6.6Hz)，2.33-2.37(1H，m)，3.78-3.80(1H，m)，3.96-4.04(6H，m)，4.11(2H，s)，4.42(2H，dd，J＝8.8，7.1Hz)，4.85-4.87(1H，m)，5.19-5.20(1H，m)，7.45(1H，s)，7.55(1H，dd，J＝5.7，2.9Hz)，7.68(1H，dd，J＝6.1，2.8Hz)，8.04(1H，s)，8.86(1H，s)，15.43(1H，s)

MS(ESI)：M+533

Embodiment 5

MS(ESI)：M+533

Embodiment 6

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.7Hz)，1.16(3H，d，J＝6.7Hz)，1.46-1.63(6H，m)，2.31-2.44(1H，m)，3.05-3.12(4H，m)，3.75-3.83(1H，m)，3.95-4.02(1H，m)，4.02(2H，s)，4.06(3H，s)，4.83-4.92(1H，m)，5.17-5.23(1H，m)，6.86-6.90(1H，m)，6.93-6.97(1H，m)，7.46(1H，s)，7.96(1H，s)，8.87(1H，s)，15.44(1H，br?s)

MS(ESI)：M+531

Embodiment 7

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.5Hz)，1.16(3H，d，J＝6.5Hz)，1.80-1.83(4H，m)，2.33-2.39(3H，m)，3.57(2H，t，J＝5.6Hz)，3.77-3.80(1H，m)，3.98-3.99(1H，m)，4.03(3H，s)，4.10(2H，s)，4.86-4.88(1H，m)，5.20(1H，t，J＝5.1Hz)，7.23(1H，dd，J＝6.1，2.4Hz)，7.45-7.47(2H，m)，8.09(1H，s)，8.88(1H，s)，15.46(1H，s)

MS(ESI)：M+545

Embodiment 8

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.8Hz)，1.82-1.91(1H，m)，1.96-2.07(1H，m)，2.31-2.43(1H，m)，2.98-3.03(1H，m)，3.17-3.38(3H，m)，3.75-3.83(1H，m)，3.94-4.02(1H，m)，4.02(2H，s)，4.07(3H，s)，4.33-4.40(1H，m)，4.84-4.92(1H，m)，4.96(1H，d，J＝3.7Hz)，5.17-5.23(1H，m)，6.39-6.44(1H，m)，6.48-6.52(1H，m)，7.46(1H，s)，7.96(1H，s)，8.87(1H，s)，15.44(1H，br?s)

MS(ESI)：M+533

Embodiment 9

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.8Hz)，1.82-1.91(1H，m)，1.96-2.07(1H，m)，2.30-2.43(1H，m)，2.97-3.04(1H，m)，3.17-3.38(3H，m)，3.74-3.83(1H，m)，3.94-4.02(1H，m)，4.02(2H，s)，4.07(3H，s)，4.33-4.40(1H，m)，4.84-4.92(1H，m)，4.96(1H，d，J＝3.9Hz)，5.17-5.23(1H，m)，6.40-6.44(1H，m)，6.48-6.52(1H，m)，7.46(1H，s)，7.96(1H，s)，8.87(1H，s)，15.44(1H，br?s)

MS(ESI)：M+533

Embodiment 10

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.15(3H，d，J＝6.4Hz)，2.43-2.53(3H，m)，2.89(3H，s)，3.75-3.80(3H，m)，3.96-4.03(4H，m)，4.10(2H，s)，4.85-4.87(1H，m)，5.18-5.19(1H，m)，6.87(1H，dd，J＝5.5，2.8Hz)，7.05(1H，dd，J＝6.0，3.0Hz)，7.45(1H，s)，8.09(1H，s)，8.87(1H，s)，15.44(1H，s)

MS(ESI)：M+546

Embodiment 11

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.5Hz)，1.16(3H，d，J＝6.5Hz)，2.02(3H，s)，2.31-2.46(1H，m)，3.04-3.10(2H，m)，3.11-3.16(2H，m)，3.51-3.58(4H，m)，3.75-3.83(1H，m)，3.94-4.03(1H，m)，4.04(2H，s)，4.06(3H，s)，4.84-4.92(1H，m)，5.17-5.23(1H，m)，6.92-6.97(1H，m)，7.00-7.05(1H，m)，7.46(1H，s)，7.96(1H，s)，8.88(1H，s)，15.44(1H，br?s)

MS(ESI)：M+574

Embodiment 12

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.5Hz)，1.16(3H，d，J＝6.5Hz)，2.34-2.37(1H，m)，2.49-2.52(2H，m)，3.44(2H，t，J＝7.1Hz)，3.67(2H，t，J＝13.2Hz)，3.77-3.80(1H，m)，3.99-4.04(3H，m)，4.07(3H，s)，4.87-4.89(1H，m)，5.20(1H，t，J＝5.2Hz)，6.57(1H，dd，J＝5.6，3.0Hz)，6.69(1H，dd，J＝5.7，2.9Hz)，7.46(1H，s)，7.95(1H，s)，8.88(1H，s)，15.43(1H，s)

MS(ESI)：M+553

Embodiment 13

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.4Hz)，2.18-2.35(3H，m)，3.28-3.58(4H，m)，3.75-3.81(1H，m)，3.97-4.02(3H，m)，4.07(3H，s)，4.86-4.89(1H，m)，5.20(1H，t，J＝5.1Hz)，5.33-5.51(1H，m)，6.50(1H，dd，J＝5.7，3.0Hz)，6.60(1H，dd，J＝5.8，2.8Hz)，7.46(1H，s)，7.96(1H，s)，8.87(1H，s)，15.43(1H，s)

MS(ESI)：M+535

Embodiment 14

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.4Hz)，2.20-2.31(3H，m)，3.34-3.51(4H，m)，3.76-3.82(1H，m)，3.96-4.03(3H，m)，4.07(3H，s)，4.88-4.89(1H，m)，5.20(1H，t，J＝4.7Hz)，5.34-5.52(1H，m)，6.50(1H，dd，J＝5.5，2.8Hz)，6.60(1H，dd，J＝5.8，3.2Hz)，7.46(1H，s)，7.96(1H，s)，8.87(1H，s)，15.43(1H，s)

MS(ESI)：M+535

Embodiment 15

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.18(3H，d，J＝6.0Hz)，3.07(4H，t，J＝4.7Hz)，3.21(3H，s)，3.71(4H，t，J＝4.7Hz)，3.85-4.04(8H，m)，5.18-5.23(2H，m)，6.91(1H，dd，J＝5.8，2.8Hz)，7.00(1H，dd，J＝5.7，3.0Hz)，7.44(1H，s)，7.95(1H，s)，8.94(1H，s)，15.41(1H，s)

MS(ESI)：M+549

Embodiment 16

MS(ESI)：M+551

Embodiment 17

MS(ESI)：M+547

Embodiment 18

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.98(9H，s)，1.25(3H，t，J＝7.4Hz)，2.88-2.99(2H，m)，3.08(4H，t，J＝4.8Hz)，3.71(4H，t，J＝4.8Hz)，4.03-4.13(2H，m)，4.19(2H，s)，5.14(1H，t，J＝4.9Hz)，5.18-5.21(1H，m)，6.89-6.91(1H，m)，7.03-7.06(1H，m)，7.94(1H，s)，8.18(1H，s)，8.80(1H，s)，15.22(1H，s)

MS(ESI)：M+545

Embodiment 19

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.03(3H，t，J＝7.0Hz)，3.07(4H，t，J＝4.7Hz)，3.45(2H，q，J＝6.9Hz)，3.70(4H，t，J＝4.7Hz)，3.88-4.00(9H，m)，5.25(1H，t，J＝5.3Hz)，5.34-5.39(1H，m)，6.91(1H，dd，J＝5.7，3.0Hz)，7.00(1H，dd，J＝6.0，3.0Hz)，7.45(1H，s)，7.97(1H，s)，8.85(1H，s)，15.39(1H，s)

MS(ESI)：M+549

Embodiment 20

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.25(3H，t，J＝7.5Hz)，2.90(2H，q，J＝7.5Hz)，3.07(4H，t，J＝4.8Hz)，3.26(3H，s)，3.70(4H，t，J＝4.8Hz)，3.80-3.96(4H，m)，4.18(2H，s)，5.26(1H，t，J＝5.4Hz)，5.35-5.42(1H，m)，6.90-6.92(1H，m)，7.01-7.04(1H，m)，7.95(1H，s)，8.00(1H，s)，8.86(1H，s)，15.19(1H，s)

MS(ESI)：M+533

Embodiment 21

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d，J＝6.7Hz)，1.15(3H，d，J＝6.5Hz)，2.34-2.41(3H，m)，3.50-3.54(2H，m)，3.70-3.73(2H，m)，3.74-3.81(1H，m)，3.95-4.02(1H，m)，4.04(3H，s)，4.10(2H，s)，4.87(1H，brs)，5.18-5.20(1H，m)，7.20(1H，dd，J＝5.7，2.9Hz)，7.25(1H，dd，J＝5.9，2.9Hz)，7.45(1H，s)，8.08(1H，s)，8.88(1H，s)，15.44(1H，s)

MS(ESI)：M+567

Embodiment 22

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.07(4H，t，J＝4.7Hz)，3.26(3H，s)，3.70(4H，t，J＝4.7Hz)，3.83-3.94(4H，m)，4.02-4.04(5H，m)，5.27(1H，t，J＝5.5Hz)，5.38-5.42(1H，m)，6.91(1H，dd，J＝5.7，3.0Hz)，7.00(1H，dd，J＝5.8，3.2Hz)，7.45(1H，s)，7.97(1H，s)，8.83(1H，s)，15.40(1H，s)

MS(ESI)：M+535

Embodiment 23

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.83(3H，d，J＝6.5Hz)，1.23(3H，d，J＝6.5Hz)，1.31(3H，t，J＝7.6Hz)，2.41-2.52(1H，m)，2.83(2H，q，J＝7.6Hz)，3.00(4H，t，J＝4.9Hz)，3.07(1H，br?s)，3.77(4H，t，J＝4.9Hz)，4.12-4.27(4H，m)，4.54-4.62(1H，m)，6.44-6.49(1H，m)，6.79(1H，dd，J＝2.8，6.0Hz)，7.58(1H，s)，8.24(1H，s)，8.86(1H，s)，15.25(1H，br?s)

MS(ESI)：M+531

Embodiment 24

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝7.0Hz)，1.15(3H，d，J＝7.0Hz)，1.25(3H，t，J＝7.4Hz)，2.03(2H，tt，J＝7.0，7.0Hz)，2.31-2.43(1H，m)，2.47(2H，t，J＝7.0Hz)，2.90(2H，q，J＝7.4Hz)，3.75-3.79(1H，m)，3.79(2H，t，J＝7.0Hz)，3.95-4.03(1H，m)，4.26(2H，s)，4.88-4.95(1H，m)，5.20(1H，t，J＝5.1Hz)，7.60(1H，dd，J＝2.8，6.2Hz)，7.86(1H，dd，J＝2.8，6.2Hz)，7.95(1H，s)，8.09(1H，s)，8.91(1H，s)，15.23(1H，s)

MS(ESI)：M+529

Embodiment 25

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.4Hz)，2.10(2H，tt，J＝7.4，7.4Hz)，2.42(2H，t，J＝7.4Hz)，2.31-2.44(1H，m)，3.74(2H，t，J＝7.4Hz)，3.73-3.83(1H，m)，3.95-4.06(1H，m)，4.03(3H，s)，4.10(2H，s)，4.83-4.91(1H，m)，5.19(1H，t，J＝5.0Hz)，7.45(1H，dd，J＝7.6，7.6Hz)，7.45(1H，s)，8.12(1H，s)，8.88(1H，s)，15.45(1H，s)

MS(ESI)：M+549

Embodiment 26

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.71(3H，d，J＝6.5Hz)，1.14(3H，d，J＝6.5Hz)，1.21(3H，t，J＝7.4Hz)，2.09(2H，tt，J＝7.4，7.4Hz)，2.31-2.43(3H，m)，2.87(2H，q，J＝7.4Hz)，3.72(2H，t，J＝7.4Hz)，3.75-3.81(1H，m)，3.94-4.02(1H，m)，4.24(2H，s)，4.90(1H，br?s)，5.16-5.22(1H，m)，7.41(1H，t，J＝7.8Hz)，8.01(1H，s)，8.08(1H，s)，8.90(1H，s)，15.23(1H，s)

MS(ESI)：M+547

Embodiment 27

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.4Hz)，2.36-2.43(1H，m)，2.63-2.66(4H，m)，3.47-3.49(4H，m)，3.76-3.83(1H，m)，3.97-3.98(1H，m)，4.03(2H，s)，4.06(3H，s)，4.85-4.90(1H，m)，5.19(1H，t，J＝5.1Hz)，6.90(1H，dd，J＝5.7，3.0Hz)，6.99(1H，dd，J＝6.0，3.0Hz)，7.46(1H，s)，7.97(1H，s)，8.88(1H，s)，15.43(1H，s)

MS(ESI)：M+549

Embodiment 28

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：1.21(3H，d，J＝6.4Hz)，2.76-2.98(1H，m)，3.03(4H，t，J＝4.5Hz)，3.43(3H，s)，3.80(4H，t，J＝4.7Hz)，3.83-3.93(1H，m)，3.98(3H，s)，4.04(2H，s)，4.19-4.36(2H，m)，4.64(1H，br?s)，6.57-6.64(1H，m)，6.74-6.81(1H，m)，6.98(1H，s)，8.21(1H，s)，8.84(1H，s)，15.25(1H，br?s)

MS(ESI)：M+549

Embodiment 29

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：2.07-2.21(1H，m)，2.22-2.37(1H，m)，3.03(4H，t，J＝4.7Hz)，3.22-3.31(5H，m)，3.45-3.54(1H，m)，3.79(4H，t，J＝4.7Hz)，3.99(3H，s)，4.04(2H，s)，4.08-4.20(2H，m)，5.09(1H，br?s)，6.56-6.63(1H，m)，6.75-6.80(1H，m)，7.22(1H，s)，8.18(1H，s)，8.86(1H，s)，15.46(1H，br?s)

MS(ESI)：M+549

Embodiment 32

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.8Hz)，1.16(3H，d，J＝6.4Hz)，1.39-1.49(2H，m)，1.78-1.80(2H，m)，2.36-2.41(1H，m)，2.83-2.87(2H，m)，3.42-3.82(4H，m)，3.97-3.99(1H，m)，4.03(2H，brs)，4.06(3H，s)，4.84-4.90(1H，m)，6.88-6.94(1H，m)，6.97-7.02(1H，m)，7.46(1H，br?s)，7.97(1H，br?s)，8.87(1H，s)

MS(ESI)：M+547

Embodiment 34

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.17(3H，d，J＝6.2Hz)，1.24(3H，t，J＝7.4Hz)，2.90(2H，q，J＝7.4Hz)，3.06-3.08(4H，m)，3.19(3H，s)，3.69-3.72(4H，m)，3.83-3.90(1H，m)，3.93-4.01(2H，m)，4.18(2H，s)，5.18-5.23(2H，m)，6.90(1H，dd，J＝5.6，3.0Hz)，7.03(1H，dd，J＝6.0，3.0Hz)，7.93(1H，s)，8.02(1H，s)，8.96(1H，s)，15.21(1H，s)

MS(ESI)：M+547

Embodiment 35

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.16(3H，d，J＝6.5Hz)，1.25(3H，t，J＝7.4Hz)，2.92(2H，q，J＝7.4Hz)，3.07(4H，t，J＝4.8Hz)，3.25(3H，s)，3.70(4H，t，J＝4.8Hz)，3.78-3.80(1H，br?m)，3.98-4.07(2H，m)，4.18(2H，s)，5.12-5.19(1H，m)，5.17(1H，t，J＝5.1Hz)，6.92(1H，dd，J＝5.8，3.0Hz)，7.03(1H，dd，J＝5.8，3.0Hz)，7.94(1H，s)，8.04(1H，s)，8.90(1H，s)，15.18(1H，s)

MS(ESI)：M+547

Embodiment 36

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.73(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.4Hz)，2.34-2.39(1H，m)，3.78-3.80(1H，m)，3.98-4.00(1H，m)，4.05(3H，s)，4.21(2H，s)，4.86-4.89(1H，m)，5.19(1H，t，J＝5.1Hz)，7.36-7.40(1H，m)，7.47(1H，br?s)，7.89(1H，td，J＝7.7，1.5Hz)，8.01(1H，d，J＝8.3Hz)，8.07(1H，t，J＝3.2Hz)，8.09(1H，br?s)，8.19(1H，dd，J＝7.0，2.1Hz)，8.63-8.66(1H，m)，8.88(1H，s)，15.41(1H，br?s)

MS(ESI)：M+525

Embodiment 37

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.73(3H，d，J＝6.4Hz)，1.16(3H，d，J＝6.8Hz)，2.33-2.41(1H，m)，3.76-3.82(1H，m)，3.99(1H，t，J＝7.7Hz)，4.05(3H，s)，4.21(2H，s)，4.84-4.90(1H，m)，5.19(1H，t，J＝4.7Hz)，7.48(1H，br?s)，7.84(1H，d，J＝3.0Hz)，7.90(1H，dd，J＝6.4，2.3Hz)，7.93(1H，d，J＝3.4Hz)，8.02(1H，dd，J＝6.4，2.3Hz)，8.13(1H，s)，8.89(1H，s)，15.41(1H，s)

MS(ESI)：M+531

Embodiment 38

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.90(3H，t，J＝6.9Hz)，1.18(3H，d，J＝6.0Hz)，1.24(3H，t，J＝7.4Hz)，2.89(2H，q，J＝7.4Hz)，3.05-3.08(4H，m)，3.19-3.28(1H，m)，3.50-3.57(1H，m)，3.68-3.72(4H，m)，3.84-3.91(1H，m)，3.94-4.08(2H，m)，4.18(2H，s)，5.15-5.24(2H，m)，6.88(1H，dd，J＝5.6，3.0Hz)，7.03(1H，dd，J＝5.8，3.0Hz)，7.93(1H，s)，8.02(1H，s)，9.01(1H，s)，15.21(1H，s)

MS(ESI)：M+561

Embodiment 39

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.03(3H，t，J＝7.0Hz)，2.03(2H，tt，J＝7.8，7.5Hz)，2.48(2H，t，J＝7.8Hz)，3.41-3.50(2H，m)，3.79(2H，t，J＝7.5Hz)，3.83-4.02(4H，m)，4.03(3H，s)，4.11(2H，s)，5.26(1H，dd，J＝5.1，5.1Hz)，5.34-5.40(1H，br?m)，7.45(1H，s)，7.61(1H，dd，J＝6.1，2.8Hz)，7.80(1H，dd，J＝6.1，2.8Hz)，8.04(1H，s)，8.86(1H，s)，15.39(1H，s)

MS(ESI)：M+547

Embodiment 40

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.91(3H，t，J＝7.0Hz)，1.18(3H，d，J＝6.0Hz)，1.24(3H，t，J＝7.4Hz)，2.02(2H，tt，J＝7.5，7.7Hz)，2.47(2H，t，J＝7.7Hz)，2.88(2H，q，J＝7.4Hz)，3.20-3.29(1H，m)，3.50-3.58(1H，m)，3.78(2H，t，J＝7.5Hz)，3.84-4.09(3H，m)，4.26(2H，s)，5.16-5.21(1H，m)，5.23(1H，t，J＝5.0Hz)，7.57(1H，dd，J＝6.2，2.7Hz)，7.86(1H，dd，J＝6.2，2.7Hz)，7.95(1H，s)，8.03(1H，s)，9.01(1H，s)，15.21(1H，s)

MS(ESI)：M+559

Embodiment 41

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.16-1.19(3H，m)，1.24(3H，t，J＝7.5Hz)，2.03(2H，tt，J＝7.3，7.3Hz)，2.45-2.51(2H，m)，2.89(2H，q，J＝7.5Hz)，3.20(3H，s)，3.79(2H，t，J＝7.3Hz)，3.83-3.90(1H，m)，3.93-4.01(2H，m)，4.25(2H，s)，5.18-5.25(2H，m)，7.58(1H，dd，J＝6.4，2.7Hz)，7.85(1H，dd，J＝6.4，2.7Hz)，7.95(1H，s)，8.03(1H，s)，8.96(1H，s)，15.20(1H，br?s)

MS(ESI)：M+545

Embodiment 42

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.91(3H，s)，1.45(3H，s)，3.04-3.10(4H，m)，3.14(3H，s)，3.66-3.75(4H，m)，3.94-4.05(1H，m)，4.03(2H，s)，4.06(3H，s)，4.11-4.19(1H，m)，4.95-5.01(1H，m)，5.17-5.24(1H，m)，6.88-6.94(1H，m)，6.98-7.03(1H，m)，7.49(1H，s)，7.94(1H，s)，9.09(1H，s)，15.38(1H，br?s)

MS(ESI)：M+563

Embodiment 43

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，s)，1.24(3H，t，J＝7.6Hz)，1.45(3H，s)，2.85-2.98(2H，m)，3.04-3.10(4H，m)，3.14(3H，s)，3.67-3.74(4H，m)，3.95-4.05(1H，m)，4.10-4.20(1H，m)，4.18(2H，s)，4.97-5.02(1H，m)，5.21-5.27(1H，m)，6.88-6.93(1H，m)，7.01-7.05(1H，m)，7.91(1H，s)，8.14(1H，s)，9.08(1H，s)，15.21(1H，br?s)

MS(ESI)：M+561

Embodiment 44

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.26(3H，t，J＝7.5Hz)，2.11-2.27(2H，m)，2.90(2H，q，J＝7.4Hz)，3.06(4H，t，J＝4.7Hz)，3.11(3H，s)，3.19-3.22(2H，m)，3.37-3.41(2H，m)，3.70(4H，t，J＝4.7Hz)，3.81-3.93(2H，m)，4.18(2H，s)，5.19-5.31(1H，m)，5.23(1H，t，J＝5.3Hz)，6.89(1H，dd，J＝5.8，2.7Hz)，7.03(1H，dd，J＝5.8，2.7Hz)，7.94(1H，s)，7.98(1H，s)，8.91(1H，s)，15.25(1H，s)

MS(ESI)：M+547

Embodiment 45

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.98(9H，s)，2.03(2H，tt，J＝8.2，7.2Hz)，2.46(2H，t，J＝8.2Hz)，3.79(2H，t，J＝7.2Hz)，4.02-4.16(4H，m)，4.05(3H，s)，5.10(1H，t，J＝4.7Hz)，5.14-5.18(1H，m)，7.52(1H，s)，7.60(1H，dd，J＝6.0，2.6Hz)，7.82(1H，dd，J＝6.4，2.6Hz)，8.03(1H，s)，8.78(1H，s)，15.36(1H，br?s)

MS(ESI)：M+545

Embodiment 46

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.98(9H，s)，2.10(2H，tt，J＝8.0，7.1Hz)，2.41(2H，t，J＝8.0Hz)，3.73(2H，t，J＝7.1Hz)，4.03(3H，s)，4.05-4.11(4H，m)，5.11(1H，t，J＝4.5Hz)，5.13-5.17(1H，m)，7.42(1H，t，J＝7.9Hz)，7.51(1H，s)，8.11(1H，s)，8.79(1H，s)，15.38(1H，br?s)

MS(ESI)：M+563

Embodiment 47

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.99-2.07(2H，m)，2.09-2.26(2H，m)，2.47(2H，t，J＝7.6Hz)，3.14(3H，s)，3.21-3.29(1H，m)，3.33-3.41(1H，m)，3.79(2H，t，J＝7.6Hz)，3.79-3.97(2H，m)，4.03(3H，s)，4.12(2H，s)，5.17-5.26(1H，m)，5.25(1H，t，J＝5.3Hz)，7.46(1H，s)，7.61(1H，dd，J＝6.2，2.7Hz)，7.81(1H，dd，J＝6.2，2.7Hz)，8.03(1H，s)，8.90(1H，s)，15.42(1H，s)

MS(ESI)：M+547

Embodiment 48

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.18(3H，d，J＝6.5Hz)，1.99-2.07(2H，m)，2.48(2H，t，J＝7.9Hz)，3.21(3H，s)，3.79(2H，t，J＝7.1Hz)，3.84-3.91(1H，m)，3.93-4.00(2H，m)，4.03(3H，s)，4.11(2H，s)，5.17-5.22(1H，m)，5.21(1H，t，J＝5.3Hz)，7.45(1H，s)，7.61(1H，dd，J＝6.2，2.8Hz)，7.81(1H，dd，J＝6.2，2.8Hz)，8.03(1H，s)，8.94(1H，s)，15.40(1H，s)

MS(ESI)：M+547

Embodiment 49

MS(ESI)：M+565

Embodiment 50

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.93(3H，t，J＝7.1Hz)，1.19(3H，d，J＝6.0Hz)，3.04-3.10(4H，m)，3.21-3.31(1H，m)，3.50-3.60(1H，m)，3.67-3.73(4H，m)，3.84-4.10(3H，m)，4.04(5H，s)，5.14-5.25(2H，m)，6.88-6.92(1H，m)，6.98-7.02(1H，m)，7.44(1H，s)，7.95(1H，s)，8.97(1H，s)，15.40(1H，br?s)

MS(ESI)：M+563

Embodiment 51

MS(ESI)：M+515

Embodiment 52

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.97(9H，s)，1.24(3H，t，J＝7.50Hz)，2.03(2H，tt，J＝7.5，7.5Hz)，2.45-2.51(2H，m)，2.88-2.95(2H，m)，3.78(2H，t，J＝7.5Hz)，4.03-4.11(2H，m)，4.26(2H，s)，5.12(1H，t，J＝5.0Hz)，5.16-5.22(1H，m)，7.57(1H，dd，J＝6.4，2.7Hz)，7.86(1H，dd，J＝6.4，2.7Hz)，7.95(1H，s)，8.17(1H，s)，8.80(1H，s)，15.18(1H，br?s)

MS(ESI)：M+543

Embodiment 53

MS(ESI)：M+517

Embodiment 54

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.96(9H，s)，2.12(2H，tt，J＝7.9，6.9Hz)，2.43(2H，t，J＝7.9Hz)，3.75(2H，t，J＝6.9Hz)，4.00-4.11(2H，m)，4.24(2H，s)，5.07-5.12(2H，m)，7.62(1H，t，J＝7.9Hz)，7.82(1H，dd，J＝9.1，2.0Hz)，8.26(1H，d，J＝2.0Hz)，8.37(1H，d，J＝9.1Hz)，8.82(1H，s)，15.16(1H，br?s)

MS(ESI)：M+533

Embodiment 55

¹H?NMR(CHCl ₃?400MHz)(δ)ppm：1.06(9H，s)，1.30(3H，t，J＝7.5Hz)，2.17(2H，tt，J＝7.5，7.9Hz)，2.49(2H，t，J＝7.9Hz)，2.77-2.84(2H，m)，3.75(2H，t，J＝7.5Hz)，4.14(2H，dd，J＝16.5，19.3Hz)，4.28-4.35(2H，m)，4.95(1H，dd，J＝9.0，5.1Hz)，6.94(1H，t，J＝7.8Hz)，7.68(1H，s)，8.25(1H，s)，8.84(1H，s)，15.14(1H，s)

MS(ESI)：M+561

Embodiment 56

MS(ESI)：M+535

Embodiment 57

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.73(1H，d，J＝6.4Hz)，1.16(1H，d，J＝6.4Hz)，2.30-2.46(1H，m)，2.65(3H，s)，3.74-3.85(1H，m)，3.93-4.08(4H，m)，4.22(2H，s)，4.82-4.94(1H，m)，5.19(1H，t，J＝5.3Hz)，7.47(1H，s)，7.89(1H，dd，J＝6.4，2.3Hz)，8.01(1H，dd，J＝6.8，2.3Hz)，8.16(1H，s)，8.89(1H，s)，15.41(1H，s)

MS(ESI)：M+530

Embodiment 58

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.96(9H，s)，3.70(2H，t，J＝4.9Hz)，3.98(2H，t，J＝5.3Hz)，4.01-4.11(2H，m)，4.24(4H，s)，5.06-5.15(2H，m)，7.72(1H，dd，J＝7.9，7.9Hz)，7.83(1H，d，J＝9.4Hz)，8.27(1H，s)，8.34(1H，d，J＝9.4Hz)，8.82(1H，s)，15.19(1H，br?s)

MS(ESI)：M+549

Embodiment 59

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.96(9H，s)，2.96-3.02(4H，m)，3.70-3.76(4H，m)，4.00-4.12(2H，m)，4.21(2H，s)，5.07-5.12(2H，m)7.22(1H，dd，J＝7.7，7.7Hz)，7.83(1H，dd，J＝9.0，2.4Hz)，8.24(1H，d，J＝2.0Hz)，8.36(1H，d，J＝9.0Hz)，8.82(1H，s)，15.18(1H，br?s)

MS(ESI)：M+535

Experimental example 1

The following describes the hiv integrase of estimating compound of the present invention and suppress active method.

(i) structure of recombination and integration enzyme gene expression system

With wherein at the phenylalanine phenylalanine of codon 185 by the displaced hiv integrase full-length gene of Histidine (J.Virol., 67,425-437 (1993)) is embedded into NdeI and the XhoI site of plasmid pET21a (+) restriction enzyme (Novagen), made up intergrase expression vector pET21a-IN-F185H thus.

The (ii) preparation of integrase protein and purifying

The intestinal bacteria recombinant chou BL21 (DE3) that will transform with the plasmid pET21a-IN-F185H that derives from (i) in comprising the liquid nutrient medium of penbritin in 30 ℃ of following wave and culture.When culture reaches logarithmic growth during the stage, add sec.-propyl-β-D-thio-galactose pyran-glucoside, to promote the expression of integrase gene.Continue to cultivate 3 hours, to promote gathering of integrase protein.By the recombination bacillus coli of centrifugation collecting granules shape, and be deposited under-80 ℃.

Intestinal bacteria are suspended in lysis buffer (the 20mM HEPES (pH7.5) that comprises the 1M sodium chloride, 5mM DTT, 10mM CHAPS, 10% glycerine) in, carry out the multiple supercharging and decompression is broken making it, and at 4 ℃ with 40000 * g centrifugation 60 minutes, to reclaim water miscible part (supernatant liquor).It with 10 times of the lysis buffer dilutions that does not contain sodium chloride, is mixed with SP-Sepharose (Pharmacia Corporation), and stirred 60 minutes down, so that integrase protein is adsorbed on the resin at 4 ℃.With the lysis buffer washing resin that contains the 100mM sodium chloride, and with the lysis buffer wash-out integrase protein that contains the 1M sodium chloride.

Make the integrase protein solution of wash-out be used for Superdex 75 (Pharmacia Corporation) pillar and carry out gel-filtration.With the lysis buffer elute protein that contains the 1M sodium chloride.

The integrase protein cut that collection obtains, and be deposited under-80 ℃.

The (iii) preparation of dna solution

Be dissolved in the TE damping fluid (10mMTris-hydrochloric acid (pH 8.0), 1mM EDTA) by Greiner or FASMAC synthetic DNA following, and be mixed to 1 μ M with donor dna, target dna and each complementary strand (+and-chain).Under 95 ℃, heated this mixture 5 minutes, heated 10 minutes down at 80 ℃, added 10 minutes down at 70 ℃, heated 10 minutes down at 60 ℃, heating is 10 minutes under 50 ℃, heated 10 minutes down at 40 ℃, and be preserved under 25 ℃, obtain the double-stranded DNA that is used to test.

Donor dna (chain has the vitamin H that is connected 5 ' end)

Donor+chain: 5 '-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTCTAG CA-3 ' (SEQ ID NO:1)

Donor-chain: 5 '-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAAG-3 ' (SEQ ID NO:2)

Target dna (+,-chain, the two all has the digitoxin that is added in 3 ' end)

Target+chain: 5 '-TGA CCA AGG GCT AAT TCA CT-Dig-3 ' (SEQ IDNO:3)

Target-chain: 5 '-AGT GAA TTA GCC CTT GGT CA-Dig-3 ' (SEQ IDNO:4)

(iv) enzyme (hiv integrase) suppresses active mensuration

Donor dna is diluted to 10nM with the TE damping fluid, gets 50 μ l and add in each hole of the microtiter plate (Roche) that scribbles streptavidin, and it was adsorbed 60 minutes down at 37 ℃.Contain 0.1% polysorbas20 phosphate buffered saline buffer (Dulbecco PBS, Sanko Junyaku Co., Ltd.) and phosphate buffered saline buffer wash this plate.Then, with enzyme reaction reaction mixture (70 μ l), be added in each hole with the substances (10 μ l) of this enzyme reaction mixture diluted and the integrase protein (10 μ l) of 100 μ g/ml (or 64 μ g/ml (2 μ M)), and 37 ℃ of reactions 60 minutes down.

The composition of enzyme reaction mixture: 30mM MOPS (morpholine propane sulfonic acid), 5mM magnesium chloride, mM DTT (dithiothreitol (DTT)), 0.1mg/ml BSA (bovine serum albumin), 5% glycerine, 10%10%DMSO (methyl-sulphoxide), 0.01% polysorbas20.

Then, add the target dna (10 μ l) of 50nM (or 25nM), reacted 10 minutes down, and wash termination reaction with the phosphate buffered saline buffer that contains 0.1% polysorbas20 at 37 ℃.

Then, add the anti--digitoxin antibody-solutions (Roche, 100 μ l) of 100mU/ml peroxidase labelling, under 37 ℃, make this mixture reaction 60 minutes, then with the phosphate buffered saline buffer washing that contains 0.1% polysorbas20.

Add peroxidase chromophoric solution (Bio Rad, 100 μ l), it was at room temperature reacted 4 minutes or (or 3 minutes).By adding the reaction of 1N sulfuric acid (100 μ l) color development stopping.Measurement is in the absorbancy at 450nm place.

According to following formula, the hiv integrase that is calculated compound of the present invention by inhibiting rate suppresses active (IC ₅₀).

Inhibiting rate (%)=[1-(target-blank)/(contrast-blank)] * 100

Target; The absorbancy that has the hole of test compound

Contrast; The absorbancy that does not have the hole of test compound

Blank; Do not exist test compound not have the absorbancy in the hole of integrase protein yet

The result is presented in table 8 and 9 wherein, and each symbol refers to IC ₅₀Fall in the following ranges.

A：1μM≤IC ₅₀＜10μM

B：0.1μM≤IC ₅₀＜1μM

C：0.01μM≤IC ₅₀＜0.1μM

D：IC ₅₀＜0.01μM

Table 8

The embodiment numbering	Hiv integrase suppresses active (IC ₅₀)	The embodiment numbering	Hiv integrase suppresses active (IC ₅₀)
				1	D	16	D
2	D	17	D

  D
  D
  D
  D
  D
  D
- D
+ C
  D
  D
  D
  D
  D
- D

Table 9

The embodiment numbering	Hiv integrase suppresses active (IC ₅₀)	The embodiment numbering	Hiv integrase suppresses active (IC ₅₀)
				32	D	46	D
34	D	47	C
				35	C	48	D
36	D	49	D
				37	C	50	C
38	D	51	D
				39	D	52	C

40	C	53	D
				41	C	54	D
42	D	55	C
				43	D	56	D
44	C	57	D
				45	D	59	C

The evaluation of experimental example 2 antiviral activities

Can measure the effect that compound of the present invention and existing anti-HIV medicament are used in combination as follows.

For example, can be according to the XTT method, the CEM-SS cell that utilizes HIV-1 IIIB-to infect is estimated existing nucleoside reverse transcriptase inhibitor (zidovudine, lamivudine, tynofovir), non-nucleoside reverse transcriptase inhibitor (efavirenz) or two kinds of effects that medicament is used in combination such as proteinase inhibitor (Indinavir, nelfinavir) and substances A.

In addition, evaluation test substance A, zidovudine and lamivudine, perhaps three kinds of effects that medicament is used in combination such as substances A, tynofovir and lamivudine.

Before being used in combination test, measure the independent IC of each medicament ₅₀And CC ₅₀The medicament B of medicament A and 9 kinds of concentration of 5 kinds of concentration of combination estimates the effect that is used in combination of two kinds of medicaments, and it is based on these results' mensuration.For being used in combination of three kinds of medicaments, the medicament B of high density being mixed with medicament C, and each concentration thing of being obtained and medicament A made up estimate.

Based on Prichard and Shipman MacSynergy II version 2.01 and Delta graphversion 1.5d program, the substances that analysis is used alone or in combination and the testing data of medicinal composition.With the cofidence limit of 95% (or 68%99%), by the inhibition percentage ratio drawing three-dimensional graphic representation under each combination medicament concentration, described inhibition percentage ratio is to be obtained by three tests, and according to the numerical value of the μ M2% that therefrom calculates, estimates the effect that is used in combination.The standard of estimating shows below.

Interactional definition μ M ²%

Strong synergy＞100

Weak synergy+51-+100

Summation action+50--50

Weak antagonistic action-51--100

Strong antagonistic action＜-100

The test of experimental example 3 metabolic stabilities

Metabolic stability test in liver microsome is with the mankind or animal class (rat or monkey) liver microsome (Xenotech LLC (Lenexa, KS, USA), 20mg albumen/mL, 2.5 μ L) and NADPH prepare system coenzyme solution (β-Triphosphopyridine nucleotide, reduced: 5.2mM, D-G-6-P salt: 13.2mM, magnesium chloride: 13.2mM, glucose-6-phosphate dehydrogenase (G6PD): 1.8U/mL) (50 μ L) is suspended in the potassium phosphate buffer of 100mM (pH 7.4,147.5 μ L), with its be dissolved in the acetonitrile that contains 0.5%DMSO in the mixing of substances (2 μ L).Cultivated this mixture 0,10 and 60 minutes down at 37 ℃, to wherein adding the acetonitrile that contains formic acid (ultimate density 0.1%) and centrifugal this mixture.By the substances (unconverted compound) of high performance liquid chromatography/mass spectrum (LC/MS) measurement in supernatant liquor.The observed value that use obtains, calculate residual rate (%) according to following formula:

Amount (0,10 or 60 minute)/amount * 100 of substances when cultivating 0 minute of residual rate (%)=cultivation back substances

Compound of the present invention preferably demonstrated at 60 minutes and is not less than 40% residual rate, more preferably was not less than 60%, still more preferably was not less than 80%.

Example of formulations is as follows.This embodiment only is the purpose of example, and does not limit the present invention.

Example of formulations

(a) the compound 10g of embodiment 1

(b) lactose 50g

(c) W-Gum 15g

(d) Xylo-Mucine 44g

(e) Magnesium Stearate 1g

The (a) and (b) of the whole amount kneaded and (c) and (d) and the water of 30g, dry in a vacuum and granulate.The particle that obtains is mixed with (d) of 14g and (e) of 1g, it is processed into tablet with the tabletting machine compressing tablet, obtain 1000, (a) of each self-contained 10mg.

Industrial applicibility

Therefore, these compounds can be effectively to be used for such as the medicament that prevents or treat AIDS, integrase inhibitor, antiviral agent, anti-HIV medicament etc., and it has hiv integrase and suppresses active. In addition, by their anti-HIV medicaments are used in combination such as protease inhibitors, RTI etc. and can become more effective anti-HIV medicament with it. And because integrase is had the high active specificity that suppresses, they can be for human-body safety, side effect medicament seldom.

The application is based on patent application Nos.2006-174331,2006-220082 and the 2006-274143 of Japanese publication, and its content is incorporated herein by reference.

Sequence table (non-text)

SEQ ID NO:1: donor+chain is used for the hiv integrase determination of activity

SEQ ID NO:2: donor-chain is used for the hiv integrase determination of activity

SEQ ID NO:3: target+chain is used for the hiv integrase determination of activity

SEQ ID NO:4: target-chain is used for the hiv integrase determination of activity

Sequence table

＜110〉Japan tobacco Inc

＜120〉6-(benzyl of heterocyclic substituted)-4-oxoquinoline compound and as the purposes of hiv integrase inhibitor

<130>091080

<150>JP?2006-174331

<151>2006-06-23

<150>JP?2006-220082

<151>2006-08-11

<150>JP?2006-274143

<151>2006-10-05

<160>4

<170>PatentIn?version?3.3

<210>1

<211>32

<212>DNA

＜213〉artificial sequence

<220>

＜223〉be used for the donor+chain of hiv integrase determination of activity

<400>1

acccttttag?tcagtgtgga?aaatctctag?ca 32

<210>2

<211>31

<212>DNA

＜213〉artificial sequence

<220>

＜223〉be used for the donor-chain of hiv integrase determination of activity

<400>2

actgctagag?attttccaca?ctgactaaaa?g 31

<210>3

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉be used for the target+chain of hiv integrase determination of activity

<400>3

tgaccaaggg?ctaattcact 20

<210>4

<211>20

<212>DNA

＜213〉artificial sequence

<220>

＜223〉be used for the target-chain of hiv integrase determination of activity

<400>4

agtgaattag?cccttggtca 20

Claims

1. the compound or pharmaceutically acceptable salt thereof of following formula [I] representative:

Wherein

Group A is by halogen atom, C _1-4Alkyl ,-(CH ₂) _n-OR ^A1, and-COR ^A2The group of forming, wherein R ^A1Be hydrogen atom, R ^A2Be C _1-4Alkyl and n are 0;

R ¹Be the C that is randomly replaced by 1 to 3 substituting group that is selected from following group of B _1-6Alkyl;

Group B is the group of being made up of following:

-OR ^b1，

R wherein ^B1Be C _1-4Alkyl;

R ²Be hydrogen atom, C _1-4Alkyl or-OR ¹¹, R wherein ¹¹Be C _1-4Alkyl;

R ³And R ⁴Identical or different, the halogen atom of respectively doing for oneself;

R ⁵Be halogen atom;

M is 0 or 1; With

R ⁶Be hydrogen atom.

2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein encircling A is the monocyclic heterocycles base that comprises at least one nitrogen-atoms, described monocyclic heterocycles base is randomly replaced by 1 to 5 substituting group that is selected from group A, and via nitrogen atom bonding to phenyl ring.

3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein encircling A is to be selected from following heterocyclic radical: 1-pyrrolidyl, 2-oxo-pyrrolidine-1-base, piperidino-(1-position only), 2-oxo-piperidine-1-base, 1-piperazinyl, beautiful jade subbase, thiomorpholine subbase, 3-oxo morpholine-4-base, 1,1-dioxy isothiazolidine-2-base, 2-Yang Dai oxazolidine-3-base and 3-oxo pyrazoles alkane-1-base, wherein said heterocyclic radical are randomly replaced by 1 to 5 substituting group that is selected from above-mentioned group of A.

4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R ²Be C _1-4Alkyl or-OR ¹¹, R wherein ¹¹Be C _1-4Alkyl.

5. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R ²Be hydrogen atom.

6. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein m is 1.

7. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein m is 0.

8. the compound or pharmaceutically acceptable salt thereof of claim 1, it is selected from:

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(tetramethyleneimine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-Yang Dai oxazolidine-3-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(piperidines-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-piperidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-((R)-3-hydroxyl pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-((S)-3-hydroxyl pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-methyl-3-oxo pyrazoles alkane-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[5-(4-ethanoyl piperazine-1-yl)-3-chloro-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-5-(3,3-two fluoropyrrolidines-1-yl)-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-((R)-3-fluoropyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-((S)-3-fluoropyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-the 7-ethyl-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-5-(1,1-dioxo isothiazolidine-2-yl)-2-luorobenzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(R)-2-hydroxyl-1-(methoxymethyl) ethyl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(thiomorpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((1R, 2S)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(4-hydroxy piperidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((1R, 2S)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(pyridine-2-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(thiazol-2-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((R)-1-ethoxyl methyl-2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-hydroxymethyl-2-methoxyl group-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((R)-1-hydroxymethyl-2-methoxyl group-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-3-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((1R, 2R)-1-hydroxymethyl-2-methoxy-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-[(1R, 2R)-2-oxyethyl group-1-(hydroxymethyl) propyl group]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(2-oxo-pyrrolidine-1-yl) benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2-fluoro-5-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) benzyl]-1-((S)-1-hydroxymethyl-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-[3-chloro-2,4-two fluoro-5-(3-oxo morpholine-4-yl) benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and

6-[3-chloro-2,4-two fluoro-5-(morpholine-4-yl) benzyl]-1-((R)-1-hydroxymethyl-2,2-dimethyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

9. the compound or pharmaceutically acceptable salt thereof of following formula representative

10. the compound or pharmaceutically acceptable salt thereof of following formula representative

11. the compound or pharmaceutically acceptable salt thereof of following formula representative

12. the compound or pharmaceutically acceptable salt thereof of following formula representative

13. the compound or pharmaceutically acceptable salt thereof of following formula representative

14. the compound or pharmaceutically acceptable salt thereof of following formula representative

15. the compound or pharmaceutically acceptable salt thereof of following formula representative

16. the compound or pharmaceutically acceptable salt thereof of following formula representative

17. the compound or pharmaceutically acceptable salt thereof of following formula representative

18. a pharmaceutical composition, it comprises in the claim 1 to 17 each compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

19. an anti-HIV medicament, it comprises as each compound or pharmaceutically acceptable salt thereof in the claim 1 to 17 of activeconstituents.

20. a hiv integrase inhibitor, it comprises as each compound or pharmaceutically acceptable salt thereof in the claim 1 to 17 of activeconstituents.

21. the purposes of each compound or pharmaceutically acceptable salt thereof in the anti-HIV medicament of preparation in the claim 1 to 17.

22. the purposes of each compound or pharmaceutically acceptable salt thereof in the preparation hiv integrase inhibitor in the claim 1 to 17.

23. an anti-HIV composition, it comprises in the claim 1 to 17 each compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

24. a pharmaceutical composition that is used to suppress hiv integrase, it comprises in the claim 1 to 17 each compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.