CN1692101A

CN1692101A - 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors

Info

Publication number: CN1692101A
Application number: CN 200380100277
Authority: CN
Inventors: 佐藤元秀; 川上浩; 伊藤佳治; 新海久; 本村隆尚; 荒卷久晃; 松崎裕児; 渡辺渡; 和卷修一
Original assignee: Japan Tobacco Inc
Current assignee: Japan Tobacco Inc
Priority date: 2002-11-20
Filing date: 2003-11-20
Publication date: 2005-11-02
Anticipated expiration: 2023-11-20
Also published as: CN100375742C

Abstract

An anti-HIV agent containing, as an active ingredient, a 4-oxoquinoline compound represented by the following formula, wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.

Description

4-oxoquinoline compound and as the purposes of hiv integrase inhibitor

Technical field

The present invention relates to new 4-oxoquinoline compound and and pharmaceutically acceptable salt thereof as the anti-HIV medicament.The invention still further relates to some 4-oxoquinoline compound and pharmaceutically acceptable salt thereof new purposes as the anti-HIV medicament.More specifically, the present invention relates to contain the anti-HIV medicament of 4-oxoquinoline compound or its pharmaceutically acceptable salt, it is based on integrase inhibiting activities is demonstrated the anti-HIV effect especially.

Background technology

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

HIV with the CD4 positive cell group for example helper cell, scavenger cell and dendritic cell etc. be target, and destroy these immunologically competent cells, cause immune deficiency.

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

Have the bimolecular rna gene in the core protein of HIV, and it is coated with envelope protein.The characteristic of the some kinds of enzymes (proteolytic enzyme, reversed transcriptive enzyme, intergrase) of RNA coding virus etc. has the reversed transcriptive enzyme and the intergrase of translation in core, and have proteolytic enzyme inside and outside core.

HIV adheres to and attacks host cell, causes shelling, and discharges the mixture etc. of RNA and intergrase in 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 forms viral required range protein by this mRNA by hiv protease etc. is synthetic, finally forms virion, carries out sprouting and discharging of this virion then.

It is believed that these viral specific enzymes are that the HIV growth is necessary.These enzymes have attracted people's attention as the target of exploitation antiviral agent, and some kinds of anti-HIV medicaments of exploitation place.

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

In addition, use the multiple medicines thing conjoint therapy of these medicaments to adopt simultaneously.For example, united clinically and used two kinds of reverse transcriptase inhibitors (zidovudine and didanosine), and united three kinds of medicaments using reverse transcriptase inhibitors (zidovudine and lamivudine) and proteinase inhibitor (nelfinavir) etc.This multiple medicines thing conjoint therapy is becoming the main flow (for example referring to Guidelines for theUse of Antiretroviral Agents in HIV-Infected Adults and Adlescent, August 13,2001) of AIDS therapy.

Yet, known some this medicaments and caused such as liver failure, nervus centralis disorder side effects such as (as dizzy).In addition, obtaining resistance also is problem.Worse, recognized that the HIV emergence shows multi-drug resistant in multiple medicines thing conjoint 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.

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

Describe below and the more similar known compound of anti-HIV medicament of the present invention.

WO 02/0704865 has described following compounds [A], [B] etc., and it has integrase inhibiting activities (seeing 203 pages of example I-152 of the 118th page of example I-62, the of WO 02/0704865) as the anti-HIV medicament.

Compound [A] compound [B]

In addition, WO 02/36734 has described following compounds [C] etc., and it has integrase inhibiting activities (seeing the 106th page of embodiment 3 of WO 02/36734) as the anti-HIV medicament.

Compound [C]

And WO 02/55079 has described following compounds [D] etc., and it has integrase inhibiting activities (seeing the 79th page of embodiment 1 of WO 02/055079) as the anti-HIV medicament.

Compound [D]

Yet these publications do not comprise disclosed 4-oxoquinoline compound in the specification sheets of the present invention, do not comprise the hint description to this compound yet.

The compound more similar to compound of the present invention is described below.

US 3472859 has described following compounds [E] etc., and it is as antimicrobial agent or antimicrobial medicament (seeing US 3472859 the 11st hurdle the 10th row).

Compound [E]

In addition, JP-A-48-26772 has described following compounds [F] etc., and this compound has anti-microbial activity, and (for example referring to the 6th page of JP-A-48-26772, embodiment 9; KYUSHU KYORITSUUNIVERSITY, Memoirs Department of Engineering, No.14, pp.21-32, March1990; Memoirs Kyushu Inst.Tech. (Eng.) No.14, pp.13-16,1984).

Compound [F]

In addition, as dehydrogenase inhibitor, on pharmacology, estimated following compounds (see Journal of Medicinal Chemistry, table 1, vol.15, No.3, pp.235-237,1972) such as [G].

Compound [G]

In addition, JP-A-2002-534416 (patent families: WO00/40561, US 6248739, EP1140850) described following compounds [H] etc., it is as the synthetic intermediate (seeing the 141st page of JP-A-2002-534416, compound 60) of the compound with antiviral activity.

Compound [H]

JP-A-2002-534417 (patent families: WO00/40563, US 6248736, EP1140851) also described following compounds [J] etc., it is as the synthetic intermediate (seeing the 34th page of JP-A-2002-534417, compound 18) of the compound with antiviral activity.

Compound [J]

Moreover WO01/98275 (patent families: US 2001/103220) has also described following compounds [K] etc., and it is as the synthetic intermediate with compound of antiviral activity (seeing the 39th page of WO 01/98275, the 29th row).

Compound [K]

In addition, JP-A-4-360872 (patent families: US 5985894, EP 498721B1) has described following compounds [L] etc., and it is the compound (seeing the 64th page of JP-A-4-360872, table 1) that antagonism-angiotensin-ii receptor has antagonistic action.

Compound [L]

Summary of the invention

Pharmacological research and clinical effectiveness according to present gained find that the anti-HIV medicament can effectively prevent the outbreak of AIDS and treat AIDS effectively, and particularly having the inhibiting compound of intergrase can provide effective anti-HIV medicament.

Therefore, the purpose of this invention is to provide a kind of medicament, particularly have the inhibiting medicament of intergrase with anti-HIV effect.

The inventor has carried out deep research, tries to find out to have the compound of anti-HIV effect, particularly has the inhibiting compound of intergrase, and has finished the present invention thus.

Therefore, the present invention is shown in the item of following (1)～(41).

(1) a kind of anti-HIV medicament, it comprises the 4-oxoquinoline compound shown in the following formula [I] or its pharmaceutically acceptable salt as activeconstituents:

In the formula

Ring Cy has 1～5 substituent C that is selected from following A group for choosing wantonly _3-10Carbocylic radical, or optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of following A group,

Wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom, and the A group is made up of following groups: cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1And-NR ^A2COOR ^A3,

R wherein ^A1And R ^A2Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl;

R ¹For being selected from the substituting group of following B group, or optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, the optional optional heterocyclic radical (defining the same) that is replaced by 1～5 substituting group that is selected from above-mentioned A group that is replaced by 1～5 substituting group that is selected from above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, and R ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group;

R ²Be hydrogen atom or C _1-4Alkyl;

R ³¹Be hydrogen atom, cyano group, hydroxyl, amino, nitro, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Alkylthio, halo C _1-4Alkyl or halo C _1-4Alkoxyl group;

X is C-R ³²Or nitrogen-atoms; And

Y is C-R ³³Or nitrogen-atoms,

R wherein ³²And R ³³Identical or different, and the hydrogen atom of respectively doing for oneself, cyano group, nitro, halogen atom, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical is chosen wantonly by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl ,-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9,-COOR ^A10Or-N=CH-NR ^A10R ^A11,

R wherein ^A7And R ^A8Identical or different, and the hydrogen atom of respectively doing for oneself, B group group or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl, R ^A9Be C _1-4Alkyl, and R ^A10And R ^A11Identical or different, and respectively do for oneself hydrogen atom or C _1-4Alkyl.

(2) according to the anti-HIV medicament of above-mentioned (1), wherein X is C-R ³², Y is C-R ³³

(3), wherein encircle Cy and be according to the anti-HIV medicament of above-mentioned (1)

In the formula

R ⁴And R ⁶Identical or different, and respectively do for oneself and be selected from the substituting group of following A group

Wherein the A group is made up of following groups: cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1And-NR ^A2COOR ^A3,

R wherein ^A1And R ^A2Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, R ^A3Be C _1-4Alkyl;

R ⁵For being selected from the substituting group of hydrogen atom and A group, R ⁴And R ⁵Can form condensed ring with the phenyl ring that they replaced; And

M is 0 or 1～3 integer, and when m is 2 or 3, the R of each m ⁶Can be identical or different.

(4) according to the anti-HIV medicament of above-mentioned (1), R wherein ²Be hydrogen atom.

(5) 4-oxoquinoline compound or its pharmaceutically acceptable salt shown in the formula [II] below:

In the formula

R ⁴And R ⁶It is identical or different and respectively do for oneself and be selected from the substituting group of following A group,

Wherein the A group is made up of following groups: cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1With-NR ^A2COOR ^A3,

R wherein ^A1And R ^A2Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl;

R ⁵For being selected from the substituting group of hydrogen atom and above-mentioned A group, and R ⁴And R ⁵Can form condensed ring with the phenyl ring that they replaced;

M is 0 or 1～3 integer, and when m is 2 or 3, the R of each m ⁶Can be identical or different;

R ¹Be the substituting group that is selected from following B group or optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, it is optional that (wherein this heterocyclic radical is as defined above like that by 1～5 heterocyclic radical that substituting group replaced that is selected from above-mentioned A group, be saturated or undersaturated ring, it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional, and R by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group;

R ³¹Be hydrogen atom, cyano group, hydroxyl, amino, nitro, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Alkylthio, halo C _1-4Alkyl or a halo C _1-4Alkoxyl group; And

R ³²And R ³³Identical or the different and hydrogen atom of respectively doing for oneself, cyano group, nitro, halogen atom, the optional C that is replaced by 1～5 substituting group that is selected from above-mentioned A group _3-10Carbocylic radical is chosen wantonly by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, and is optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl, OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9,-COOR ^A10Or-N=CH-NR ^A10R ^A11,

(6) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ³¹Be hydrogen atom, cyano group, hydroxyl or C _1-4Alkoxyl group.

(7) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (6) ³¹Be hydrogen atom.

(8) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ³²And R ³³Identical or different, and the hydrogen atom of respectively doing for oneself, cyano group, halogen atom, optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of following A group,

R wherein ^A1And R ^A2Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl,

Optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional, and R by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group,

-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9,-COOR ^A10Or-N=CH-NR ^A10R ^A11,

(9) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ³²Be hydrogen atom, cyano group, halogen atom, optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical that substituting group replaced (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9Or-COOR ^A10,

R wherein ^A7And R ^A8Identical or different, and the hydrogen atom of respectively doing for oneself, B group group or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl, R ^A9Be C _1-4Alkyl, and R ^A10Be hydrogen atom or C _1-4Alkyl.

(10) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (9) ³²Be hydrogen atom ,-OR ^A7Or-NR ^A7R ^A8, R here ^A7And R ^A8Identical or different, and the hydrogen atom of respectively doing for oneself, B group group or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl.

(11) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (8) ³³Be hydrogen atom, optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

-OR ^A7Or-NR ^A7R ^A8,

R wherein ^A7And R ^A8Identical or different, and the hydrogen atom of respectively doing for oneself, B group or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl.

(12) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (11) ³³Be hydrogen atom ,-OR ^A7Or-NR ^A7R ^A8,

R wherein ^A7And R ^A8Identical or different, and the hydrogen atom of respectively doing for oneself, B group group or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl.

(13) according to each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (8)～(12), wherein

R ^A7And R ^A8Identical or different, and it is optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group respectively to do for oneself _1-10Alkyl, wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical that substituting group replaced (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4With-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional, and R by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group.

(14) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ⁴And R ⁵Identical or different, and respectively do for oneself and be selected from cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A2COOR ^A3And-COOR ^A1Substituting group,

R wherein ^A1And R ^A2Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl.

(15) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (14) ⁴Be phenyl, halogen atom, C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3Or-COOR ^A1,

(16) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (15) ⁴Be halogen atom.

(17) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ⁵Be hydrogen atom, cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2Or-NR ^A1COR ^A3,

(18) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ⁶Be halogen atom.

(19) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of above-mentioned (5), wherein m is 0 or 1.

(20) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (5) ¹For choosing wantonly by 1～5 C that is selected from the substituting group replacement of following A group _3-10Carbocylic radical,

Be selected from-NR ^A4R ^A5,-NR ^A4COR ^A6,-NR ^A4SO ₂R ^A6With-NR ^A5COOR ^A6Substituting group,

R wherein ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, or heterocyclic radical (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom), it is chosen wantonly by 1～5 substituting group that is selected from above-mentioned A group and replaces, and R ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, perhaps

Optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6(R wherein ^A4, R ^A5, R ^A6The same with the definition of A group).

(21) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of above-mentioned (20) ¹For choosing wantonly by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4With-NR ^A5COOR ^A6,

(22) according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of above-mentioned (5), it is selected from following compounds:

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-1),

6-(2, the 3-dichloro benzyl)-8-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-2),

6-(2, the 3-dichloro benzyl)-1-(2-methanesulfonamido ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-3),

6-(2, the 3-dichloro benzyl)-1-(2-imidazoles-1-base ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-4),

6-(2, the 3-dichloro benzyl)-1-dimethylamino formyl radical methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-5),

6-(2, the 3-dichloro benzyl)-1-methyl carbamyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-6),

1-carbamyl methyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-7),

6-(2, the 3-dichloro benzyl)-1-sec.-propyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-8),

6-(2, the 3-dichloro benzyl)-4-oxo-1-sulfamyl methyl isophthalic acid, 4-dihydroquinoline-3-carboxylic acid (embodiment 1-9),

1-(2-carboxy ethyl)-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-10),

1-(2-hydroxyethyl)-6-naphthalene-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-11),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate methyl ester (embodiment 1-12),

1-(2-carbamyl ethyl)-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-13),

6-(2, the 3-dichloro benzyl)-4-oxo-1-(2-oxopropyl)-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-14),

1-benzyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-15),

6-(2, the 3-dichloro benzyl)-4-oxo-1-styroyl-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-16),

6-(2, the 3-dichloro benzyl)-1-(3-phenyl propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-17),

6-(2, the 3-dichloro benzyl)-1-isobutyl--4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-18),

6-(2, the 3-dichloro benzyl)-1-(4-phenyl butyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-19),

1-biphenyl-2-ylmethyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-20),

6-(2, the 3-dichloro benzyl)-1-(4-hydroxybutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-21),

1-benzo [b] thiophene-2-ylmethyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-22),

6-(2, the 3-dichloro benzyl)-1-(3, the 4-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-23),

6-(2, the 3-dichloro benzyl)-1-(2-dimethylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-24),

6-(2, the 3-dichloro benzyl)-1-(3-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-25),

6-(2, the 3-dichloro benzyl)-1-(2-methoxy ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-26),

6-(2, the 3-dichloro benzyl)-1-(2,2, the 2-trifluoroethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-27),

1-carboxyl methyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-28),

6-(2, the 3-dichloro benzyl)-1-[2-(4-methylthiazol-5-yl) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-29),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-30),

6-(2, the 3-dichloro benzyl)-1-(2-methylmercaptoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-32),

6-(2-chloro-6-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-33),

6-(2, the 3-dichloro benzyl)-1-(5-hydroxyl amyl group)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-34),

6-(2, the 3-dichloro benzyl)-1-(2-morpholine-4-base ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-35),

6-(2, the 3-dichloro benzyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-36),

6-(2, the 3-dichloro benzyl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-37),

6-(2, the 3-dichloro benzyl)-4-oxo-1-propyl group-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-38),

1-butyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-39),

1-cyclopentyl-methyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-40),

6-(2, the 3-dichloro benzyl)-1-(2-methylsulfonyl ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-41),

1-cyclohexyl methyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-42),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyl-2-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-43),

6-(2, the 3-dichloro benzyl)-1-(2-fluoro ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-44),

6-(2, the 3-dichloro benzyl)-4-oxo-1-(2-pyridine-2-base ethyl)-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-45),

1-(2-amino-ethyl)-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-46),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxy-2-methyl propyl group)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-47),

1-(2-kharophen ethyl)-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-48),

6-(2, the 3-dichloro benzyl)-1-(2-ethoxy carbonyl amino-ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-49),

6-(2, the 3-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-50),

6-(2-chloro-4-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-51),

6-(2-benzyl chloride base)-4-oxo-1-styroyl-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-65),

6-(2-chloro-3-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-66),

6-(2, the 3-dichloro benzyl)-1-methylthiomethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-68),

6-(2, the 3-dichloro benzyl)-1-methylsulfonyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-69),

1-tertiary butyl sulfamyl methyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-70),

6-(2, the 3-dichloro benzyl)-1-methyl sulfamyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-71),

6-(2, the 3-dichloro benzyl)-1-dimethylamino alkylsulfonyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-72),

6-(2-chloro-3,6-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-73),

6-(2, the 3-dichloro benzyl)-1-(2, the 3-dihydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-74),

6-(2-chloro-6-luorobenzyl)-1-sulfamyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-75),

6-(2-chloro-6-luorobenzyl)-1-methyl sulfamyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-76),

6-(2-chloro-6-luorobenzyl)-1-dimethylamino alkylsulfonyl methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-77),

6-(2-chloro-3-methyl-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-79),

6-(2-bromobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-80),

6-(2-chloro-3-methoxy-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-82),

1-(2-hydroxyethyl)-6-(2-methylsulfonyl benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-85),

6-biphenyl-2-ylmethyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-86),

6-(2-benzyl chloride base)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-87),

6-(2-chloro-5-methylthio group benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-92),

1-(2-hydroxyethyl)-4-oxo-6-(2-trifluoro-methoxybenzyl)-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-93),

6-(2-chloro-5-methyl-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-97),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-99),

6-(3-chloro-2,6-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-100),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-101),

1-cyclopropyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 1-102),

1-amino-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-1),

6-(2, the 3-dichloro benzyl)-1-methoxycarbonyl amino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-2),

1-acetylaminohydroxyphenylarsonic acid 6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-3),

6-(2, the 3-dichloro benzyl)-1-methanesulfonamido-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-4),

6-(2, the 3-dichloro benzyl)-1-(N-methylsulfonyl-N-methylamino-)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-5),

6-(2, the 3-dichloro benzyl)-1-dimethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-6),

6-(2, the 3-dichloro benzyl)-1-methylamino--4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-7),

6-(2, the 3-dichloro benzyl)-1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 2-8),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-5-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-1),

6-(3-chloro-2-methyl-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-2),

6-(3-chloro-2-methoxy-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-3),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-4),

6-(2, the 3-dichloro benzyl)-5-hydroxyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-5),

6-(2, the 3-dichloro benzyl)-7-hydroxyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-6),

1-(2-hydroxyethyl)-6-(2-methylamino-benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-7),

6-(2-dimethylamino benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-8),

6-(2, the 3-dichloro benzyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-9),

6-(2, the 3-dichloro benzyl)-1-[2-hydroxyl-1-(methylol) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-10),

1-cyclobutyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-12),

1-cyclopentyl-6-(2, the 3-dichloro benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-13),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-14),

6-(2-dimethylamino Sulphonylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-16),

6-(3-chloro-2,4-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-17),

6-(2-carboxyl benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-18),

1-(2-hydroxyethyl)-6-(2-methyl sulfamyl benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-19),

6-(2, the 3-dichloro benzyl)-7-oxyethyl group-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-20),

7-chloro-6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-21),

6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-7-Trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-22),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-23),

(R)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-24),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-Trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-25),

6-(3-chloro-2-luorobenzyl)-1-[2-hydroxyl-1-(methylol) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-26),

7-cyano group-6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-27),

6-(2-ethyl methylamino-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-28),

6-[2-(N-methyl-N-propyl group amino) benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-29),

6-[2-(N-benzyl-N-methylamino-) benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-30),

6-[2-(N-methylsulfonyl-N-methylamino-) benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-31),

6-[2-(N-sec.-propyl-N-methylamino-) benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-32),

The 1-tertiary butyl-6-(3-chloro-2-luorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-33),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-34),

8-amino-6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-35),

7-carboxyl-6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-36),

6-(3-chloro-2,6-difluorobenzyl)-1-(2-hydroxyethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-37),

6-(3-chloro-2-luorobenzyl)-8-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-38),

8-acetylaminohydroxyphenylarsonic acid 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-39),

5-cyano group-6-(2, the 3-dichloro benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-40),

6-[2-(N-ethanoyl-N-methylamino-) benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-41),

6-(2-diethylin benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-42),

6-(3-chloro-2-luorobenzyl)-1-(1,1-dimethyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-43),

6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-44),

6-(3-chloro-2-luorobenzyl)-7,8-dimethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-45),

6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-47),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-8-methylamino--4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-48),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-propoxy--1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-49),

6-(3-chloro-2-luorobenzyl)-7-(dimethylamino methylene amino)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-50),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylate methyl ester (embodiment 3-51),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-phenoxy group-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-52),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-53),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-propyl group amino-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-54),

6-(3-chloro-2-luorobenzyl)-8-ethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-55),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-56),

(S)-and 6-(3-chloro-2,6-difluorobenzyl)-1-(2-hydroxyl-1-methylethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-57),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-propoxy--1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-58),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-59),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-60),

(S)-and 6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-(2-hydroxyl-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-61),

6-(3-chloro-2-luorobenzyl)-7-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-62),

6-(3-chloro-2-luorobenzyl)-7-cyclohexyl methoxyl group-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-63),

6-(3-chloro-2-luorobenzyl)-8-diethylin-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-64),

6-(3-chloro-2-luorobenzyl)-7-methylamino--1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-65),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-tetramethyleneimine-1-base-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-66),

(S)-and 6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-(2-hydroxyl-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-67),

(S)-6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-[1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-68),

6-(3-chloro-2-luorobenzyl)-8-cyclohexyl methoxyl group-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-69),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-70),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-3-methyl butyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-71),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-72),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-73),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-7-sec.-propyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-74),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-75),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-7-(2-hydroxyl-oxethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-76),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-7-(3-hydroxyl propoxy-)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-77),

6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyethyl)-8-(2-hydroxyethyl amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-78),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-79),

(S)-and 6-(3-chloro-2-luorobenzyl)-8-dimethylamino-1-(2-hydroxyl-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-80),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-81),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-82),

6-(3-chloro-2-luorobenzyl)-1-((1S, 2S)-1-methylol-2-methyl butyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-83),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-84),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-benzyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 3-85),

6-(2-chloro-5-methylsulfonyl benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-1),

6-(2-Ethylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-4),

6-(2-chloro-5-methyl-benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-5),

6-(2-chloro-5-luorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-6),

6-(5-bromo-2-benzyl chloride base)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-7),

6-(2, the 3-dichloro benzyl)-7-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-9),

6-(2-chloro-5-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-11),

6-(2, the 3-dichloro benzyl)-5-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-12),

6-(2-ethoxy benzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-13),

6-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-14),

6-(2, the 3-dichloro benzyl)-7-methyl isophthalic acid-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-15),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(2-hydroxyl-1-methylethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-16),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-17),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-18),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-2-methyl-propyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-19),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-20),

(S)-6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-[1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-21),

(S)-6-(3-chloro-2-luorobenzyl)-1-[2-cyclohexyl-1-(methylol) ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-22),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-3-methyl butyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-23),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-2-methyl-propyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-24),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-3-methyl butyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-25),

(S)-and 6-(3-chloro-2-luorobenzyl)-[2,2-dimethyl-1-(methylol) propyl group]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-26),

6-(3-chloro-2-luorobenzyl)-1-((1S, 2S)-1-methylol-2-methyl butyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-27),

6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-((1S, 2S)-1-methylol-2-methyl butyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-28),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) propyl group]-7-methylthio group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-29),

(S)-and 6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-(1-methylol-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-30),

(S)-and 6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-[2,2-dimethyl-1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-31),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-2-methyl-propyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-32),

(S)-and 6-(3-fluoro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-33),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-34),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) butyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-35),

(S)-6-(3-chloro-2-luorobenzyl)-7-oxyethyl group-1-[1-(methylol) butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-36),

(S)-and 6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-[2,2-dimethyl-1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-37),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) butyl]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-38),

6-(3-chloro-2-luorobenzyl)-1-((1S, 2S)-1-methylol-2-methyl butyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-39),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-40),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-oxyethyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-41),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-42),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-oxyethyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-43),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-44),

(S)-and 6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-(1-methylol-2-methyl-propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-45),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-methylol-2-methyl-propyl)-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-46),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) butyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-47),

(S)-6-(3-chloro-2-luorobenzyl)-8-oxyethyl group-1-[1-(methylol) butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-48),

(S)-6-(3-chloro-2-luorobenzyl)-1-[1-(methylol) butyl]-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-49),

(S)-and 6-(3-chloro-2-luorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-50), and

(S)-and 6-(3-chloro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-52).

(23) a kind of pharmaceutical composition, it comprises in above-mentioned (5)～(22) each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

(24) a kind of integrase inhibitor, its comprise in above-mentioned (1)～(22) each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

(25) a kind of antiviral agent, its comprise in above-mentioned (5)～(22) each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

(26) a kind of anti-HIV medicament, its comprise in above-mentioned (5)～(22) each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

(27) a kind of anti-HIV combination thing, it comprises in above-mentioned (1)～(22) each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and one or more other anti-HIV active substance is as activeconstituents.

(28) a kind of anti-HIV medicament, its comprise in above-mentioned (1)～(22) each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents, be used from multiple medicines thing therapy with other anti-HIV medicament one.

(29) each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22), the purposes in preparation anti-HIV medicament.

(30) each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22), the purposes in the preparation integrase inhibitor.

(31) each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22), the purposes in the preparation antiviral agent.

(32) method of a kind of prevention or treatment HIV transmissible disease, it comprises each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22) of significant quantity is delivered medicine to Mammals.

(33) according to the prevention of above-mentioned (32) or the method for treatment HIV transmissible disease, it comprises that further at least a different anti-HIV active substance with significant quantity delivers medicine to described Mammals.

(34) a kind of method that suppresses intergrase, it comprises each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22) of significant quantity is delivered medicine to Mammals.

(35) method of a kind of prevention or treatment viral infectious, it comprises each 4-oxoquinoline compound or its pharmaceutically acceptable salt in above-mentioned (5)～(22) of significant quantity is delivered medicine to Mammals.

(36) a kind of anti-HIV combination thing, it comprises in above-mentioned (5)～(22) each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

(37) a kind of pharmaceutical composition that suppresses intergrase, it comprises in above-mentioned (5)～(22) each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

(38) a kind of antiviral composition, it comprises in above-mentioned (5)～(22) each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

(39) a kind of commercial cartridge bag, it comprises the composition of above-mentioned (36) and associated specification sheets, described specification sheets explanation said composition can or should be used for prevention or treatment HIV transmissible disease.

(40) a kind of commercial cartridge bag, it comprises the composition of above-mentioned (37) and associated specification sheets, described specification sheets explanation said composition can or should be used to suppress intergrase.

(41) a kind of commercial cartridge bag, it comprises the composition of above-mentioned (38) and associated specification sheets, described specification sheets explanation said composition can or should be used for prevention or treatment viral infectious.

Each substituting group as used in this specification and each several part are defined as follows.

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

As R ³², R ³³, R ⁴, R ⁵, R ⁶, R ^{6 '}, R ^{6 "}, R ⁶With the A group, preferred especially fluorine atom and chlorine atom; As R ³²And R ⁵, more preferably chlorine atom; As R ³¹, R ³³, R ⁴, R ^{6 '}, R ⁶And it is " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl " in halogen atom, more preferably fluorine atom.

" C _1-4Alkyl " be meant straight or branched alkyl with 1～4 carbon atom, be specially methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl.

As R ², R ³¹And R ^A6, preferable methyl and ethyl; As R ⁴, R ⁵, R ⁶, R ^{6 '}, R ^{6 "}, R ⁶With A group, preferable methyl, ethyl and sec.-propyl, more preferably methyl; As R ^A1And R ^A2, preferable methyl, ethyl, propyl group and sec.-propyl, more preferably methyl; As R ^A3, R ^A9, R ^A10, R ^A11With A group, preferable methyl; As R ^A4And R ^A5, preferable methyl, ethyl and the tertiary butyl.

" halo C _1-4Alkyl " be " C defined above _1-4Alkyl ", it is by 1～9, and preferred 1～3 " halogen atom " defined above replaces.

Its specific examples comprises the 2-fluoro ethyl, 2-chloroethyl, 2-brooethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorine butyl, 4-chlorobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4,4-trifluoro butyl, pentafluoroethyl group, 2,2,2-three fluoro-1-trifluoromethyl-ethyls etc.

As R ³¹, R ⁴, R ⁵, R ⁶, R ^{6 '}, R ^{6 "}, R ⁶With the A group, preferred trifluoromethyl.

" C _1-4Alkoxyl group " be that wherein moieties is " C defined above _1-4Alkyl " alkoxyl group, its specific examples is a methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy etc.

For R ³¹, preferred methoxyl group.

" C _1-4Alkylthio " be that wherein moieties is " C defined above _1-4Alkyl " alkylthio.Its specific examples comprises methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, uncle's butylthio etc.

For R ³¹, preferred methylthio group.

" halo C _1-4Alkoxyl group " be halogenated C _1-4Alkoxyl group, wherein its haloalkyl partly is " halo C defined above _1-4Alkyl ".

Its specific examples comprises 2-fluorine oxyethyl group, 2-chloroethoxy, 2-bromine methoxyl group, 3-fluorine propoxy-, 3-chlorine propoxy-, 4-fluorine butoxy, 4-chlorine butoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 3,3,3-trifluoro propoxy-, 4,4,4-trifluoro butoxy, five fluorine oxyethyl groups, 2,2,2-three fluoro-1-trifluoromethyl-oxyethyl groups etc.

For R ³¹, R ⁴, R ⁵, R ⁶, R ^{6 '}, R ^{6 "}, R ⁶With the A group, preferred trifluoromethoxy.

" C _3-10Carbocylic radical " be saturated or undersaturated cyclic hydrocarbon radical with 3～10 carbon atoms, its specific examples is an aryl, cycloalkyl, cycloalkenyl group or their condensed ring radical.

The specific examples of " aryl " comprises phenyl, naphthyl, pentalene base, base difficult to understand etc., preferred phenyl and naphthyl, preferred especially phenyl.

The specific examples of " cycloalkyl " comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, adamantyl (adamantly), norcamphane base etc., preferred cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

" cycloalkenyl group " comprises at least one, preferred 1 or 2 two key, and its specific examples is a cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl (2,4-cyclohexadiene-1-base, 2,5-cyclohexadiene-1-base etc.), cycloheptenyl and cyclooctene base etc.

The specific examples of the condensed ring radical of these " aryl ", " cycloalkyl " and " cycloalkenyl group " comprises indenyl, indanyl, 1,4-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.Be preferably the condensed ring radical of phenyl and different rings, the example is an indenyl, indanyl, 1,4-dihydro naphthyl, 1,2,3,4-tetralyl etc., preferred especially indanyl.

" optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical " be " C defined above _3-10Carbocylic radical ", it is optional by 1～5, and preferred 1～3 substituting group that is selected from following A group replaces, and comprises " the C of non-replacement _3-10Carbocylic radical ".

" A group " comprises following groups: cyano group, phenyl, nitro, " halogen atom " defined above, " C defined above _1-4Alkyl ", " halo C defined above _1-4Alkyl ", " halo C defined above _1-4Alkoxyl group " ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1With-NR ^A2COOR ^A3, R wherein ^A1And R ^A2Identical or different, and the hydrogen atom of respectively doing for oneself, " C defined above _1-4Alkyl " or benzyl, and R ^A3Be " C defined above _1-4Alkyl ".

" OR ^A1" specific examples comprise hydroxyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, tert.-butoxy etc.,

" SR ^A1" specific examples comprise sulfydryl, methylthio group, ethylmercapto group, the rosickyite base, the iprotiazem base, uncle's butylthio etc.,

" NR ^A1R ^A2" specific examples comprise amino, methylamino-, ethylamino, third amino, isopropylamino, tertiary butyl amino, dimethylamino, diethylin, N-ethyl-N-methylamino-, N-methyl-N-third amino, N-sec.-propyl-N-methylamino-, N-benzyl-N-methylamino-etc.,

" CONR ^A1R ^A2" specific examples comprise carbamyl, amino-carbonyl, B aminocarbonyl, third aminocarboxyl, isopropyl amino-carbonyl, uncle's fourth aminocarboxyl, the dimethylamino carbonyl, diethylaminocarbonyl-, N-methyl-N-B aminocarbonyl etc.,

" SO ₂NR ^A1R ^A2" specific examples comprise sulfamyl, the methylamino-alkylsulfonyl, the ethylamino alkylsulfonyl, third amino-sulfonyl, the isopropylamino alkylsulfonyl, tertiary butyl amino-sulfonyl, the dimethylamino alkylsulfonyl, the diethylin alkylsulfonyl, N-methyl-N-ethylamino alkylsulfonyl etc.,

" COR ^A3" specific examples comprise ethanoyl, propionyl, butyryl radicals, isobutyryl, valeryl etc.,

" NR ^A1COR ^A3" specific examples comprise kharophen, propionamido, butyrylamino, isobutyryl amino, pivalyl amino, N-ethanoyl-N-methylamino-etc.,

" SO ₂R ^A3" specific examples comprise methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, different third alkylsulfonyl, uncle's fourth alkylsulfonyl etc.,

" NR ^A1SO ₂R ^A3" specific examples comprise methanesulfonamido, ethanesulfonamido, third sulfonamido, the sec.-propyl sulfonamido, tertiary butyl sulfonamido, N-methyl-N-(methylsulfonyl) amino etc.,

" COOR ^A1" specific examples comprise carboxyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, tert-butoxycarbonyl etc., and

" NR ^A2COOR ^A3" specific examples comprise methoxycarbonyl amino, ethoxy carbonyl amino, propoxycarbonyl amino, isopropoxy carbonyl amino, tert-butoxycarbonyl amino etc.

As the A group, preferred cyano group, phenyl, nitro; fluorine atom, chlorine atom, bromine atoms, methyl; ethyl, sec.-propyl, trifluoromethyl, trifluoromethoxy; hydroxyl, methoxyl group, oxyethyl group, propoxy-; methylthio group, amino, methylamino-, ethylamino; sec.-propyl amino, dimethylamino, diethylin, N-ethyl-N-methylamino-; N-methyl-N-propyl group amino, N-sec.-propyl-N-methylamino-, N-benzyl-N-methylamino-; carbamyl, amino-carbonyl, dimethylamino carbonyl; sulfamyl, methylamino-alkylsulfonyl, dimethylamino alkylsulfonyl; ethanoyl, kharophen, N-ethanoyl-N-methylamino-; methylsulfonyl, methanesulfonamido, N-methyl-N-(methylsulfonyl) amino; carboxyl, methoxycarbonyl, carboxyamino and methoxycarbonyl amino.

As the A group, preferred especially cyano group, phenyl; nitro, fluorine atom, chlorine atom; bromine atoms, methyl, trifluoromethyl; trifluoromethoxy, hydroxyl, methoxyl group; oxyethyl group, methylthio group, amino; methylamino-, dimethylamino, diethylin; N-ethyl-N-methylamino-, N-methyl-N-propyl group amino, N-sec.-propyl-N-methylamino-; N-benzyl-N-methylamino-, dimethylamino carbonyl, methylamino-alkylsulfonyl; the dimethylamino alkylsulfonyl, kharophen, N-ethanoyl-N-methylamino-; methylsulfonyl, N-methyl-N-(methylsulfonyl) amino and carboxyl, more preferably fluorine atom and chlorine atom.

Substituent number is preferably 1～3, and as " C _3-10Carbocylic radical " when being phenyl, preferably encircle Cy and be that the 2-position is mono-substituted, the 3-position is mono-substituted, 2, the 3-position is dibasic, 2; the 4-position is dibasic, 2, the 5-position is dibasic, 2, the 6-position is dibasic, 2; 3; the 4-position is trisubstituted, 2,3, the 5-position is trisubstituted, 2; 3; the 6-position is trisubstituted, and is preferred especially 2, the 3-position is dibasic.

" optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical " example comprise phenyl, naphthyl, 2-fluorophenyl; 2-chloro-phenyl-, 2-bromophenyl, 3-fluorophenyl; 3-chloro-phenyl-, 3-bromophenyl, 4-fluorophenyl; 2-nitrophenyl, 3-nitrophenyl, 2-cyano-phenyl; 3-cyano-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl; 4-aminomethyl phenyl, 2-ethylphenyl, 3-ethylphenyl; the 2-isopropyl phenyl, 3-isopropyl phenyl, 2-trifluoromethyl; the 3-trifluoromethyl, 2-hydroxy phenyl, 3-hydroxy phenyl; the 4-hydroxy phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl; the 2-ethoxyl phenenyl, 3-ethoxyl phenenyl, 2-propoxy-phenyl; 3-propoxy-phenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl; 2-(trifluoromethoxy) phenyl, 3-(trifluoromethoxy) phenyl, 2-methyl sulfamyl phenyl; 3-methyl sulfamyl phenyl, 2-aminophenyl, 3-aminophenyl; 2-(methylamino-) phenyl, 3-(methylamino-) phenyl, 2-(dimethylamino) phenyl; 3-(dimethylamino) phenyl, 2-(kharophen) phenyl, 3-(kharophen) phenyl; the 2-xenyl, 3-xenyl, 2-(methylsulfonyl) phenyl; 3-(methylsulfonyl) phenyl, 2-sulfamyl phenyl, 3-sulfamyl phenyl; 2-(methylamino-alkylsulfonyl) phenyl, 3-(methylamino-alkylsulfonyl) phenyl, 2-(dimethylamino alkylsulfonyl) phenyl; 3-(dimethylamino alkylsulfonyl) phenyl, 2-(two methylsulfonyls) phenyl, 2-(methanesulfonamido) phenyl; 3-(methanesulfonamido) phenyl, 2-carbamyl phenyl, 3-carbamyl phenyl; 2-(methyl carbamyl) phenyl, 3-(methyl carbamyl) phenyl, 2-(dimethylamino formyl radical) phenyl; 3-(dimethylamino formyl radical) phenyl, 2, the 3-difluorophenyl; 2,3-dichlorophenyl, 2; the 3-dibromo phenyl; the 2,4 difluorobenzene base, 2; the 4-dichlorophenyl; 2,5-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-5-nitrophenyl; 2-chloro-3-aminomethyl phenyl, 2-chloro-5-aminomethyl phenyl, 2-chloro-3-(trifluoromethyl) phenyl; 2-chloro-5-(trifluoromethyl) phenyl; 2-chloro-3-hydroxy phenyl, 2-chloro-5-hydroxy phenyl, 2-fluoro-3-p-methoxy-phenyl; 2-chloro-5-p-methoxy-phenyl; 2-chloro-3-methyl sulfamyl phenyl, 2-chloro-5-methyl sulfamyl 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-fluoro-3-(kharophen) phenyl, 2-chloro-5-(kharophen) phenyl, 2-chloro-3-(methylsulfonyl) phenyl; 2-chloro-5-(methylsulfonyl) phenyl; 2-chloro-3-(methanesulfonamido) phenyl, 2-chloro-5-(methanesulfonamido) phenyl, 2; 3; the 4-trifluorophenyl, 2-chloro-3,4-difluorophenyl; 2-chloro-3; the 5-difluorophenyl, 2-chloro-3,6-difluorophenyl; 2-chloro-4; the 5-difluorophenyl, 2-chloro-4,6-difluorophenyl; 3-chloro-2; the 4-difluorophenyl, 3-chloro-2,5-difluorophenyl; 3-chloro-2; the 6-difluorophenyl, 2,3-two chloro-4-fluorophenyls; 3-chloro-2-fluoro-5-trifluoromethyl; 2-chloro-3,5, the 6-trifluorophenyl; 3-chloro-2; 4,5-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; 3-hydroxyl cyclobutyl; 3-hydroxycyclopent base, 2-hydroxy-cyclohexyl, 3-hydroxy-cyclohexyl; the 4-hydroxy-cyclohexyl, 4-indanyl 1H-indenes-4-base.

Preferred ring Cy is a phenyl, naphthyl, 2-chloro-phenyl-; the 3-chloro-phenyl-, 2-bromophenyl, 3-bromophenyl; the 2-ethylphenyl; the 3-ethylphenyl, 2-hydroxy phenyl, 2-ethoxyl phenenyl; 3-(trifluoromethoxy) phenyl; 3-(methylsulfonyl) phenyl, 2, the 3-difluorophenyl; 2; the 3-dichlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl; 2-chloro-5-fluorophenyl; 2-chloro-6-fluorophenyl, 3-chloro-2-fluorophenyl, 5-bromo-2-chloro-phenyl-; 2-chloro-5-aminomethyl phenyl; 2-chloro-5-hydroxy phenyl, 2-chloro-5-(methylsulfonyl) phenyl, 2-chloro-3; the 6-difluorophenyl; 3-chloro-2,4 difluorobenzene base, 3-chloro-2; the 6-difluorophenyl; 2-chloro-3-aminomethyl phenyl, 3-chloro-2-aminomethyl phenyl, 2-chloro-3-p-methoxy-phenyl; 3-chloro-2-p-methoxy-phenyl; the 3-nitrophenyl, 3-cyano-phenyl, 4-aminomethyl phenyl; the 3-trifluoromethyl; 2-(trifluoromethoxy) phenyl, 3-hydroxy phenyl, 3-ethoxyl phenenyl; the 3-aminophenyl; 2-(methylamino-) phenyl, 2-(dimethylamino) phenyl, 2-(diethylin) phenyl; 2-(N-ethyl-N-methylamino-) phenyl; 2-(N-sec.-propyl-N-methylamino-) phenyl, 2-(N-benzyl-N-methylamino-) phenyl, 2-(N-ethanoyl-N-methylamino-) phenyl; 2-(N-methyl-N-methyl sulphonyl amino) phenyl; 3-(methylamino-) phenyl, 2-carboxyl phenyl, 3-(dimethylamino carbonyl) phenyl; 3-(kharophen) phenyl; the 2-xenyl, 2-(methylsulfonyl) phenyl, 2-chloro-5-methylthio group phenyl; 2-chloro-5-aminomethyl phenyl; 2-(methylamino-alkylsulfonyl) phenyl, 2-(dimethylamino alkylsulfonyl) phenyl or 3-(dimethylamino alkylsulfonyl) phenyl

Preferred especially 2-chloro-phenyl-, 2-bromophenyl, 2-ethylphenyl; the 2-hydroxy phenyl, 2-ethoxyl phenenyl, 2; the 3-difluorophenyl, 2, the 3-dichlorophenyl; 2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl; 2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl, 5-bromo-2-chloro-phenyl-; 2-chloro-5-hydroxy phenyl, 2-chloro-5-(methylsulfonyl) phenyl, 2-chloro-3; the 6-difluorophenyl, 3-chloro-2,6-difluorophenyl; 2-chloro-3-aminomethyl phenyl, 2-chloro-3-p-methoxy-phenyl, 2-trifluoromethyl; 2-(methylsulfonyl) phenyl; 2-chloro-5-methylthio group phenyl, 2-chloro-5-aminomethyl phenyl or 2-(dimethylamino alkylsulfonyl) phenyl, and

More preferably 2,3-dichlorophenyl, 2,3-difluorophenyl, 2-chloro-3-fluorophenyl or 3-chloro-2-fluorophenyl.

R1 and B group group are preferably phenyl, and 3,4-dichlorophenyl, 2-xenyl, cyclopropyl, 2-hydroxyl cyclopropyl, cyclobutyl, 2-hydroxyl cyclobutyl, 3-hydroxyl cyclobutyl, cyclopentyl, 2-hydroxycyclopent base, 3-hydroxycyclopent base, cyclohexyl, the 2-hydroxy-cyclohexyl, 3-hydroxy-cyclohexyl and 4-hydroxy-cyclohexyl are preferably phenyl especially, 3,4-dichlorophenyl, 2-xenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As R ³², R ³³, R ¹With B group group, preferred phenyl and cyclohexyl.

" heterocyclic radical " is meant 5 or 6 Yuans monocyclic heterocycles of saturated or unsaturated (comprising that part is unsaturated or unsaturated fully), it also comprises at least one except that carbon atom, preferred 1～4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, these heterocyclic condensed ring, perhaps C _3-10Carbocyclic ring and heterocyclic condensed ring, wherein this carbocyclic ring is selected from benzene, pentamethylene and hexanaphthene.

The example of " saturated monocyclic heterocycles base " comprises pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, imidazolidyl, pyrazolidyl, 1,3-dioxolanyl, 1,3-oxygen thiophene alkyl ， oxazolidinyl, thiazolidyl, piperidyl, piperazinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, dioxane base, morpholinyl, thio-morpholinyl, 2-oxa-pyrrolidyl, 2-oxa-piperidyl, 4-oxa-piperidyl, 2,6-two oxa-piperidyls etc.Be preferably pyrrolidyl, piperidyl or morpholinyl.

The example of " unsaturated monocyclic heterocycles base " comprises pyrryl, furyl, thienyl, imidazolyl, 1,2-dihydro-2-oxa-imidazolyl, pyrazolyl, di azoly ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-triazolyl, the 1,2,3-triazoles base, tetrazyl, 1,3,4-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, furazan base, pyridyl, pyrimidyl, 3,4-dihydro-4-oxa-pyrimidyl, pyridazinyl, pyrazinyl, the 1,3,5-triazines base, imidazolinyl, pyrazolinyl ， oxazolinyl (2-oxazolinyl, 3-oxazolinyl, 4-oxazolinyl) isoxazoline-3-yl, thiazolinyl, isothiazoline base, pyranyl, 2-oxa-pyranyl, 2-oxo-2,5-dihydrofuran base and 1,1-dioxo-1H-isothiazolyl.Preferred examples comprises pyrryl, furyl, thienyl, imidazolyl, pyrazolyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, pyridyl, 2-oxo-2,5-dihydrofuran base and 1,1-dioxo-1H-isothiazolyl.

As " heterocyclic radical of condensed ring ", can mention indyl (as the 4-indyl, 7-indyl etc.), pseudoindoyl, 1,3-dihydro-1,3-dioxo pseudoindoyl, benzofuryl (as the 4-benzofuryl, 7-benzofuryl etc.), indazolyl, isobenzofuran-base, benzothienyl is (as the 4-benzothienyl, 7-benzothienyl etc.), benzoxazolyl (as the 4-benzoxazolyl, 7-benzoxazolyl etc.), benzimidazolyl-(as the 4-benzimidazolyl-, 7-benzimidazolyl-etc.), benzothiazolyl is (as the 4-benzothiazolyl, 7-benzothiazolyl etc.), indolinyl, quinolyl, isoquinolyl, 1,2-dihydro-2-oxa-quinolyl, quinazolyl, quinoxalinyl, cinnolines base, the 2 base, quinolizinyl, purine radicals, pteridine radicals, indolinyl, iso-dihydro-indole-group, 5,6,7,8-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-dioxy pyridyl, 4,5-ethylenedioxy pyrimidyl, chromenyl, chromanyl, isochroman base etc.

The condensed ring of preferred 5 or 6 Yuans monocyclic heterocycles and phenyl ring.Its specific examples comprises indyl, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl and benzo [1,3] dioxolyl etc.

" optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group " is " heterocyclic radical " defined above, and it is optional by 1～5, and preferred 1～3 substituting group that is selected from " A group " defined above replaces, and comprises " heterocyclic radical " of non-replacement.

Preferably " heterocyclic radical " for containing 1 or 2 heteroatomic monocyclic heterocycles, perhaps itself and phenyl ring condensed heterocycle.

The specific examples of " optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group " comprises pyrrolidyl, piperidyl, morpholino, pyrryl, 2-pyrryl, 3-pyrryl, the 2-furyl, 3-furyl, 2-thienyl, the 3-thienyl, 4,5-dichloro-thiophene-3-base, 2-oxo-2,5-dihydrofuran-3-base, 1,1-dioxo-1H-isothiazole-5-base, 4-methylthiazol-5-base, imidazolyl, the 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, pyrazolyl, 2-oxazolyl, 3-isoxazolyl, the 2-thiazolyl, 3-isothiazolyl, 3-fluorine pyridine-2-base, 3-chloropyridine-2-base, 3-chloro-4-fluorine pyridine-2-base, 3,5-dichloropyridine-2-base, 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, 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, 2-indyl, 3-indyl, the 4-indyl, the 7-indyl, 2-benzofuryl, 4-benzofuryl, the 7-benzofuryl, the 2-benzothienyl, 4-benzothienyl, 7-benzothienyl, the 2-benzimidazolyl-, the 4-benzimidazolyl-, 2-benzoxazolyl, 4-benzoxazolyl, the 7-benzoxazolyl, the 2-[4-morpholinodithio base, 4-benzothiazolyl, 7-benzothiazolyl, 2-benzo [1,3] dioxolyl, 4-benzo [1,3] dioxolyl, 5-benzo [1,3] dioxolyl etc.

As ring Cy, preferred 2-pyridyl and 4-pyridyl; As R ¹With B group group, preferred imidazolyl, 2-pyridyl, 2-benzothienyl, morpholino and 4-methylthiazol-5-base; As R ³²And R ³³, preferred pyrrolidyl.

" optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl " be the optional C that is replaced by the substituting group of " the B group " that be selected from " halogen atom " defined above and define below _1-10Alkyl also can be the alkyl of non-replacement.Moieties is the straight or branched alkyl with 1～10 carbon atom.Its specific examples comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1-methyl butyl, 1-ethyl propyl, the 2-ethyl propyl, 1,1-dimethyl propyl, 1, the 2-dimethyl propyl, tertiary amyl, hexyl, isohexyl, the 1-methyl amyl, 1,1-dimethylbutyl, 1, the 2-dimethylbutyl, 1,3-dimethylbutyl, 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, 1-ethyl-1-methyl-propyl, heptyl, different heptyl, 1-methyl hexyl, 1,1-dimethyl amyl group, 1,2-dimethyl amyl group, 1,3-dimethyl amyl group, 1,4-dimethyl amyl group, 1,1,2-trimethylammonium butyl, 1,1,3-trimethylammonium butyl, 1,2,2-trimethylammonium butyl, 1,2,3-trimethylammonium butyl, 1,3,3-trimethylammonium butyl, 1-ethyl pentyl group, 1-ethyl-2-methyl butyl, 1-ethyl-3-methyl butyl, 2-ethyl-1-methyl butyl, 1-propyl group butyl, 1-ethyl-2,2-dimethyl propyl, 1-sec.-propyl-2-methyl-propyl, 1-sec.-propyl-1-methyl-propyl, 1,1-diethyl propyl group, 1,1,2,2-tetramethyl-propyl group, 1-sec.-propyl butyl, 1-ethyl-1-methyl butyl, octyl group, nonyl, decyls etc. preferably have the straight or branched alkyl of 1～6 carbon atom, especially preferably have the branched-chain alkyl alkyl of 1～6 carbon atom.

" B group " comprises following groups: defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical ", " optional " defined above ,-OR by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6

As used herein, R ^A4And R ^A5Identical or different, and the hydrogen atom of respectively doing for oneself, " C defined above _1-4Alkyl ", defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical " or " optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group " defined above, R ^A6Be " C defined above _1-4Alkyl ", defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical " or " optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group " defined above.

-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4With-NR ^A5COOR ^A6Specific examples be included in the " OR of " A group " respectively ^A1", " SR ^A1", " NR ^A1R ^A2", " CONR ^A1R ^A2", " SO ₂NR ^A1R ^A2", " COR ^A3", " NR ^A1COR ^A3", " SO ₂R ^A3", " NR ^A1SO ₂R ^A3", " COOR ^A1" reach " NR ^A2COOR ^A3" definition in the substituting group mentioned etc.

" optional by 1～3 C that is selected from the substituting group replacement of halogen atom and B group _1-10Alkyl " example comprise methyl, ethyl, propyl group; sec.-propyl, butyl, isobutyl-; sec-butyl, the tertiary butyl, amyl group; isopentyl, 1-methyl butyl, 1-ethyl propyl; 2-ethyl propyl, 1,1-dimethyl propyl; 1,2-dimethyl propyl, tertiary amyl; hexyl, isohexyl, 1-methyl amyl; 1,1-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; 1-ethyl-1-methyl-propyl, heptyl, different heptyl; 1-methyl hexyl, 1,1-dimethyl amyl group; 1,2-dimethyl amyl group, 1; 3-dimethyl amyl group, 1,4-dimethyl amyl group; 1,1,2-trimethylammonium butyl; 1,1,3-trimethylammonium butyl; 1,2,2-trimethylammonium butyl; 1,2,3-trimethylammonium butyl; 1,3,3-trimethylammonium butyl; the 1-ethyl pentyl group, 1-ethyl-2-methyl butyl, 1-ethyl-3-methyl butyl; 2-ethyl-1-methyl butyl, 1-propyl group butyl, 1-ethyl-2; the 2-dimethyl propyl, 1-sec.-propyl-2-methyl-propyl, 1-sec.-propyl-1-methyl-propyl; 1,1-diethyl propyl group, 1; 1,2,2-tetramethyl-propyl group; 1-sec.-propyl butyl, 1-ethyl-1-methyl butyl, methyl fluoride; trifluoromethyl, chloroethyl, 2-fluoro ethyl; the 2-chloroethyl, 3-fluoropropyl, 2-chloropropyl; 2,2, the 2-trifluoroethyl; the 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyl-1-methylethyl; 2-hydroxyl-1,1-dimethyl ethyl, 1-(methylol) propyl group; the 3-hydroxypropyl, 2-hydroxybutyl, 4-hydroxybutyl; 2-hydroxyl amyl group, 5-hydroxyl amyl group, 2; the 3-dihydroxypropyl, 2,3-dihydroxyl butyl; 2-hydroxyl-1-(methylol) ethyl, 2-hydroxy-2-methyl propyl group, 1-(methylol) butyl; 1-(methylol)-2-methyl-propyl, 1-(methylol)-2,2-dimethyl propyl; 1-(methylol)-2-methyl butyl, 2-hydroxyl-1-phenylethyl, 2-hydroxyl-2-phenylethyl; 1-(methylol)-2-phenylethyl, 3-methyl isophthalic acid-(methylol) butyl, 2-ethyl-1-(methylol) butyl; 3-hydroxyl-1-methyl-propyl, 1,1-dimethyl-3-hydroxypropyl; 1,2-dimethyl-3-hydroxypropyl, 1-sec.-propyl-3-hydroxypropyl; 2,2-dimethyl-1-(2-hydroxyethyl) propyl group, 1-ethyl-3-hydroxypropyl; 2-hydroxyl-1-sec.-propyl propyl group, 1-ethyl-1-(methylol) propyl group, 1; 1-dimethyl-2-hydroxypropyl, 1,2-dimethyl-2-hydroxypropyl; 1-ethyl-2-hydroxypropyl, 4-hydroxyl-1-methyl butyl, 2-ethyl-1-(methylol)-2-methyl butyl; 3,3-dimethyl-1-(methylol) butyl, 1-(methylol) amyl group; 4-methyl isophthalic acid-(methylol) amyl group, methoxymethyl, 2-methoxy ethyl; methylthiomethyl, 2-(methylthio group) ethyl, 2-amino-ethyl; 2-(dimethylamino) ethyl, carboxyl methyl, 2-carboxy ethyl; 2-carboxyl propyl group, 3-carboxyl propyl group, carbamyl methyl; 2-carbamyl ethyl, amino-carbonyl methyl, dimethylamino carbonyl methyl; 2-(phenyl amino carbonyl) ethyl, 2-oxopropyl, methylsulfonyl methyl; 2-(methylsulfonyl) ethyl, sulfamyl methyl, methylamino-alkylsulfonyl methyl; dimethylamino alkylsulfonyl methyl, tertiary butyl aminosulfonyl ylmethyl, 2-(kharophen) ethyl; 2-(methanesulfonamido) ethyl, 2-(ethoxy carbonyl amino) ethyl, benzyl; styroyl, 3-phenyl propyl, 4-phenyl butyl; 2-xenyl methyl, 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 carbonyl methyl, 2-pyridine-2-base ethyl; 2-imidazoles-1-base ethyl; 2-thionaphthene-2-base ethyl, 2-morpholino ethyl, 2-(4-methylthiazol quinoline-5-yl) ethyl; the 1-carboxy ethyl; 1-carbamyl ethyl, 1-carboxyl-2-methyl-propyl, 1-carbamyl-2-methyl-propyl; 2-hydroxyl-1-(methylol) propyl group; 1-(methylol)-2-mercaptoethyl, 1-(methylol)-3-(methylthio group) propyl group, 2-carboxyl-1-(methylol) ethyl; 2-carbamyl-1-(methylol) ethyl; 2-(indol-3-yl)-1-(methylol) ethyl, 2-(imidazol-4 yl)-1-(methylol) ethyl, 2-(4-hydroxy phenyl)-1-(methylol) ethyl; 3-carbamyl-1-(methylol) propyl group, 5-amino-1-(methylol) amyl group etc.

R ¹Be preferably methyl; ethyl, propyl group, sec.-propyl; butyl; isobutyl-, the tertiary butyl, 2-fluoro ethyl; 2; 2,2-trifluoroethyl, 2-hydroxyethyl; the 2-hydroxypropyl; the 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxyl amyl group; 2; the 3-dihydroxypropyl, 2-hydroxyl-1-methylethyl, 2-hydroxyl-1; the 1-dimethyl ethyl; 2-hydroxyl-1-(methylol) ethyl, 1-(methylol) propyl group, 2-hydroxy-2-methyl propyl group; 1-(methylol) butyl; 1-(methylol)-2-methyl-propyl, 1-(methylol)-2,2-dimethyl propyl; 1-(methylol)-2-methyl butyl; 1-(methylol)-3-methyl butyl, 2-hydroxyl-1-phenylethyl, 2-hydroxyl-2-phenylethyl; 1-(methylol)-2-phenylethyl; the 2-methoxy ethyl, methylthiomethyl, 2-(methylthio group) ethyl; the 2-amino-ethyl; 2-(dimethylamino) ethyl, carboxyl methyl, 2-carboxy ethyl; 3-carboxyl propyl group; the carbamyl methyl, 2-carbamyl ethyl, amino-carbonyl methyl; dimethylamino carbonyl methyl; 2-(phenyl amino carbonyl) ethyl, 2-oxopropyl, methylsulfonyl methyl; 2-(methylsulfonyl) ethyl; the sulfamyl methyl, methylamino-alkylsulfonyl methyl, dimethylamino alkylsulfonyl methyl; tertiary butyl aminosulfonyl ylmethyl; 2-(kharophen) ethyl, 2-(methanesulfonamido) ethyl, 2-(ethoxy carbonyl amino) ethyl; benzyl; styroyl, 3-phenyl propyl, 4-phenyl butyl; 2-xenyl methyl; 3,4-dichloro benzyl, cyclopentyl-methyl; cyclohexyl methyl; 1-cyclohexyl-2-hydroxyethyl, 1-cyclohexyl methyl-2-hydroxyethyl, 2-pyridine-2-base ethyl; 2-imidazoles-1-base ethyl; 2-morpholino ethyl, 2-(4-methylthiazol quinoline-5-yl) ethyl and thionaphthene-2-ylmethyl, preferred especially 1-position has the alkyl of side chain and/or the alkyl that is replaced by hydroxyl.Its specific examples comprises 2-hydroxyl-1-methylethyl, 1-(methylol)-2-methyl-propyl, 1-(methylol)-2,2-dimethyl propyl, 1-(methylol)-2-methyl butyl, 2-hydroxyl-1-(methylol) ethyl and 2-phenyl-1-(methylol) ethyl.If these particularly preferred substituting groups are optically-active, more preferably S type then.

R ³²And R ³³Be preferably methyl, ethyl and trifluoromethyl, R ^A7And R ^A8Be preferably methyl, ethyl, propyl group, sec.-propyl, 2-hydroxyethyl, 3-hydroxypropyl and cyclohexyl methyl, more preferably methyl, ethyl and sec.-propyl, special preferable methyl.

Ring Cy in the preferred formula [I] is defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical ", more preferably

R in the formula ⁴, R ⁵, R ⁶And the definition of m is the same.Preferred embodiment is identical with the 4-oxoquinoline compound shown in the formula [II] among the present invention, and wherein m is preferably 0 or 1, and more preferably 0.

The A group group of preferred ring Cy is a cyano group, phenyl, nitro, " halogen atom " defined above, " C defined above _1-4Alkyl ", " halo C defined above _1-4Alkyl ", " halo C defined above _1-4Alkoxyl group ", " OR defined above ^A1", " SR defined above ^A1", " NR defined above ^A1R ^A2", " CONR defined above ^A1R ^A2", " SO defined above ₂NR ^A1R ^A2", " NR defined above ^A1COR ^A3", " SO defined above ₂R ^A3" or " NR defined above ^A1SO ₂R ^A3",

Cyano group more preferably, phenyl, nitro, " halogen atom ", " C _1-4Alkyl ", " halo C _1-4Alkyl ", " halo C _1-4Alkoxyl group ", " OR ^A1", " SR ^A1", " NR ^A1R ^A2", " SO ₂R ^A3", " SO ₂NR ^A1R ^A2" or " NR ^A1COR ^A3", " halogen atom " especially preferably defined above.

More preferably encircling Cy is

R in the formula ^{6 '}R ^{6 "}And R ⁶For being selected from the substituting group of hydrogen atom and " A group " defined above, and R ⁴And R ⁵Definition the same.

R ⁴Be preferably phenyl, " halogen atom " defined above, " C defined above _1-4Alkyl ", " halo C defined above _1-4Alkoxyl group ", " OR defined above ^A1", " NR defined above ^A1R ^A2", " SO defined above ₂NR ^A1R ^A2", " NR defined above ^A1COR ^A3", " SO defined above ₂R ^A3", " COOR defined above ^A1" or " NR defined above ^A1SO ₂R ^A3", more preferably " halogen atom ", " C _1-4Alkyl ", " halo C _1-4Alkoxyl group ", " OR ^A1" or " NR ^A1R ^A2", " halogen atom " especially preferably defined above.

R ⁵Be preferably hydrogen atom, cyano group, nitro, " halogen atom " defined above, " C defined above _1-4Alkyl ", " halo C defined above _1-4Alkyl ", " OR defined above ^A1", " SR defined above ^A1", " NR defined above ^A1R ^A2", " CONR defined above ^A1R ^A2", " SO defined above ₂NR ^A1R ^A2" or " NR defined above ^A1COR ^A3", hydrogen atom more preferably, " halogen atom " or " C _1-4Alkyl ", preferred " halogen atom " especially.

R ⁶Be preferably " halogen atom " defined above, " C defined above _1-4Alkyl ", " SO defined above ₂R ^A3", " OR defined above ^A1" or " SR defined above ^A1", more preferably " halogen atom ".

R ^{6 '}And R ⁶Preferred identical or different, and respectively do for oneself hydrogen atom or " halogen atom " defined above, R ^{6 "}Be preferably hydrogen atom, " halogen atom " defined above, " C defined above _1-4Alkyl ", " SO defined above ₂R ^{A3 "}, " OR defined above ^A1" or " SR defined above ^A1", hydrogen atom more preferably, " halogen atom ", " C defined above _1-4Alkyl " or " SR defined above ^A1", most preferably be hydrogen atom.

R ¹Be preferably defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical ", " optional " defined above, " OR defined above by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group ^A4" (the preferred methoxyl group of the specific examples here), " NR defined above ^A4R ^A5" (the specific examples here is preferably amino, methylamino-, ethylamino or dimethylamino), " NR defined above ^A4COR ^A6" (the specific examples here is preferably acetylamino), " NR defined above ^A4SO ₂R ^A6" (the specific examples here is preferably methanesulfonamido or N-methyl-N-(methylsulfonyl) amino), " NR defined above ^A5COOR ^A6" (the specific examples here is preferably methoxycarbonyl amino) or defined above " choosing wantonly by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl ", more preferably defined above " optional by 1～5 C that is selected from the substituting group replacement of A group _3-10Carbocylic radical " or " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl ", more preferably defined above " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and top B group _1-10Alkyl ".

R ²Be preferably hydrogen atom.

R ³¹Be preferably hydrogen atom, cyano group, " halogen atom " defined above, hydroxyl " C defined above _1-4Alkoxyl group ", hydrogen atom more preferably, cyano group, " halogen atom " defined above or " C defined above _1-4Alkoxyl group ", most preferably be hydrogen atom, cyano group or " C defined above _1-4Alkoxyl group ", preferred especially hydrogen atom.

R ³²Be preferably hydrogen atom, cyano group, " halogen atom " defined above, and " choosing wantonly " defined above by 1～5 heterocyclic radical that is selected from the substituting group replacement of A group, defined above " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl ", " OR defined above ^A7", " SR defined above ^A7", " NR defined above ^A7R ^A8", " COOR defined above ^A10" or " N=CH-NR defined above ^A10R ^A11", hydrogen atom more preferably, " OR defined above ^A7", " SR defined above ^A7" or " NR defined above ^A7R ^A8", most preferably be hydrogen atom or " OR defined above ^A7", be preferably " OR especially ^A7".

R ³³Be preferably hydrogen atom, defined above " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl ", " OR defined above ^A7" or " NR defined above ^A7R ^A8", hydrogen atom more preferably, " OR defined above ^A7" or " NR defined above ^A7R ^A8", most preferably be hydrogen atom or " OR defined above ^A7", be preferably hydrogen atom especially.

Preferred R ³²And R ³³One of be hydrogen atom, another is " OR defined above ^A7".

Preferred R ³¹Be hydrogen atom, and R ³²Or R ³³Be different from hydrogen atom.

" its pharmaceutically acceptable salt " can be any salt, as long as it is the non-toxic salt with the compound formation of above-mentioned formula [I] or [II].For example, it can obtain by reacting with mineral acid, organic acid, mineral alkali, organic bases or amino acid, and described mineral acid has hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide etc.; Described organic acid has oxalic acid, propanedioic acid, citric acid, fumaric acid, lactic acid, oxysuccinic acid, succsinic acid, tartrate, acetate, trifluoroacetic acid, gluconic acid, xitix, methylsulfonic acid, benzene methanesulfonic acid etc.; Described mineral alkali comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide etc.; Described organic bases comprises methylamine, diethylamine, triethylamine, trolamine, quadrol, trihydroxymethylaminomethane, guanidine, choline, cinchonine etc.; Described amino acid comprises Methionin, arginine, L-Ala etc.The present invention includes the aqueous product of each compound, hydrate and solvate.

In addition, the compound shown in above-mentioned formula [I] and [II] has various isomer.For example, the geometrical isomer that exists with E type and Z type, and when having unsymmetrical carbon, have enantiomer and diastereomer based on unsymmetrical carbon, also may there be tautomer.Therefore, the present invention includes all these isomer and composition thereof.Preferred compound of the present invention is separated from various isomer, by product, metabolite or prodrug and purifying, and preferably its purity is 90% or higher, and more preferably its purity is 95% or higher.

The present invention also comprises the prodrug and the metabolite of each compound.

" 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 delivering medicine to body, to show its inherent effect, to comprise complex compound and the salt that does not contain covalent linkage.

For instance, prodrug is used to improve peroral administration absorption and aimed objective site.

As the position that will modify in the compound of the present invention, what can mention is the functional group of height reactive behavior wherein, as hydroxyl, and carboxyl, amino, thiol group etc.

The examples of groups of hydroxyl modified comprises ethanoyl, propionyl, isobutyryl, valeryl, benzoyl, 4-methyl benzoyl, dimethylamino formyl radical, sulfo group etc.The examples of groups of carboxyl modified 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.Amido modified examples of groups comprises the 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 1-4-yl) methyl etc.

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

When compound of the present invention is used as pharmaceutical preparation, itself and pharmaceutically acceptable carrier, vehicle, thinner, swelling agent, disintegrating agent, stablizer, sanitas, buffer reagent, emulsifying agent, seasonings, tinting material, sweeting agent, thickening material, corrigent, dissolution aids and other additive mix, described other additive itself is known, the example comprises water, vegetables oil, alcohol (as 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, granula, suppository, injection, eye drops, liquid, capsule, lozenge, aerosol, elixir, suspension, emulsion, syrup etc., and per os or non-through stomach and intestine whole body or topical.

Although dosage changes with age, body weight, disease, result of treatment, medication etc., adult's dosage is generally each administration 0.01mg to 1g, its per os or to be administered once to several times every days such as injection type such as intravenous injection.

The anti-HIV medicament generally need keep its effect 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.

In view of this, preferably one of mode is, 4-oxoquinoline compound of the present invention is such compound, and it allows high absorption ground oral administration, and can keep the Plasma Concentration to drug compound for a long time.

For instance, " prevention AIDS " is meant: medicament is delivered medicine to the individuality of testing the HIV positive but not developing the AIDS symptom as yet, medicament delivered medicine to show the AIDS symptom of improvement after the treatment but still carry needs the HIV that eradicates, the individuality of worrying the AIDS recurrence, and owing to worry possible infection with medicament administration before infected by HIV.

" other anti-HIV medicament " that be used for multiple medicines agent conjoint therapy reaches " other anti-HIV active substance " and comprises anti-HIV antibody, the HIV vaccine, immunostimulant such as Interferon, rabbit etc., the HIV ribozyme, HIV antisensitizer thing, reverse transcriptase inhibitors, proteinase inhibitor, the bind receptor (CD4, CXCR4, CCR5 etc.) of the host cell of virus identification and the binding inhibitors between this virus etc.

The specific examples of hiv reverse transcriptase inhibitor comprises Zidovodine (R) (zidovudine), lamivudine (R) (lamivudine), Zerit (R) (sanilvudine), Videx (R) (didanosine), Hivid (R) (zalcitabine), (R) (abacavir sulfate) advanced in match, the happy life of dimension (R) (nevirapine), Stocrin (R) (efavirenz), U-90152 (R) (delavirdine mesylate), Combivir (R) (zidovudine+lamivudine), three associations are (R) (abacavir sulfate+lamivudine+zidovudine) only, Coactinon (R) (emivirine), Phosphonovir (R), Coviracil (R), Aovudine (3 '-fluoro-3 '-deoxythymidine), Thiovir (thiophosphoryl formic acid), capravirine (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)-q 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, UC-781, 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), other medicament name is called common name.

The specific examples of hiv protease inhibitor comprises Crixivan (R) (sulfuric acid oxyacetic acid Indinavir); Saquinavir; saquinavir mesylate (R) (Ro-31-8959); Nuo Wei (R) (ritonavir); viracept see nelfinaivr (R) (Viracept); rltonavir; chlorpromazine (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 specific examples of hiv integrase inhibitor comprises S-1360, L-870810 etc., and the example of archaeal dna polymerase inhibitor or DNA synthetic inhibitor comprises Trisodium phosphonoformate hexahydrate (R); ACH-126443 (L-2 ', 3 '-two dehydrogenations-dideoxy-5-fluorine cytidine), Entecavir ((1S; 3S, 4S)-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl] guanine), calanolide A ([10R-(10 α; 11 β; 12 α)] 12-dihydro-12-hydroxyl-6,6-11; 10; 11-tetramethyl--4-propyl group-2H, 6H, 10H-benzo [1; 2-b:3; 4-b ': 5,6-b "] three pyran-2-ones), calanolide B; NSC-674447 (1; 1 '-Cellmic C 121), iscador (viscum alubm extract), Rubutecan etc.; the example of HIV antisensitizer thing comprises HGTV-43; GEM-92 etc., and the example of anti-HIV antibody or other antibody comprises NM-01, PRO-367; KD-247; cytolipin (R), TNX-355 (CD4 antibody), AGT-1; PRO-140 (CCR5 antibody); anti--CTLA-4 MAb etc., the example of HIV vaccine or other vaccine comprises ALVAC (R), AIDSVAX (R); Remune (R); HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine; HIV gp160 vaccine; HIV p17 vaccine, HIV p24 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 example of Interferon, rabbit or Interferon, rabbit agonist comprises phenothrin (R); MultiFeron (R), interferon, Reticulose; humanleukocyteinterferon-etc.; the example of CCR5 antagonist comprises SCH-351125 etc., and the example that acts on the medicament of HIV p24 has GPG-NH2 (glycyl-prolyl-G-NH2) etc., and the example of HIV fusion inhibitor comprises 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, No. the 3rd, synthetic paradigmatic structure, pentafuside; FP-21399; PRO-542, Enfuvirtide etc., the example of IL-2 agonist or antagonist comprises interleukin II; Imunace (R); rIL-2 (R), Multikine (R), Ontak (R) etc.; the example of TNF-alpha-2 antagonists comprises Thalomid (R) (Thalidomide); Remicade (R) (infliximab), sulfogel polysaccharide etc., the example of alpha-glucosidase inhibitor comprise Bucast (R) etc.; the example of purine nucleoside phosphorylase inhibitor comprises peldesine (2-amino-4-oxo-3H; the 5H-7-[(3-pyridyl) methyl] pyrrolo-[3,2-d] pyrimidine) etc., the example of apoptosis agonist or inhibitor comprises Arkin Z (R); Panavir (R); Coenzyme Q10 99.0 (2-ten (3-methyl-2-crotonylidene)-5,6-dimethoxy-3-methyl-para benzoquinone) etc., the example of acetylcholinesterase depressant comprises tacrine (R) etc.; the example of immunomodulator comprises Imunox (R); Prokine (R), and 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, can also exemplify Neurotropin (R), V-1326 (R), Ancer 20 (R), Polyinosinic-polycytidylic acid (R), Anticort (R), Inactivin (R) etc., 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, 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 anti-HIV active substance " as the multiple medicines agent conjoint therapy that uses with compound of the present invention is preferably reverse transcriptase inhibitors and proteinase inhibitor.Two or three in addition more kinds of medicament can unite use, unite wherein that to use the medicament with different mechanisms of action be one of preferred embodiment.In addition, the preferred selection do not have the medicament that doubles side effect.

The concrete combination of medicament comprises following combination: efavirenz, tynofovir, emtricitabine, Indinavir, nelfinavir, Atanazavir, ritonavir+Indinavir, ritonavir+rltonavir, ritonavir+Saquinavir, didanosine+lamivudine, zidovudine+didanosine, stavudine+didanosine, zidovudine+lamivudine, stavudine+lamivudine, and the combination (Guidelines for the Use of Antiretroviral Agentsin HIV-Infected Adults and Adolescents.August 13,2001) of Emtriva and 4-oxoquinoline compound of the present invention [I].Preferred especially and efavirenz, Indinavir, nelfinavir, tynofovir, emtricitabine, two medicament conjoint therapies 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, efavirenz+zidovudine, and three combined drug therapies of efavirenz+Indinavir.

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 by following method when needed: protecting group is incorporated in the functional group, goes protection then in subsequent step; Utilization has the precursor of the compound of functional group as each step, and in proper step this groups converted is become required functional group; Exchange the order of each preparation method and step; Perhaps by means of other method.

All can use ordinary method in each step and carry out, wherein separation and purifying are to pass through to select or make up ordinary method, for example crystallization, recrystallization, distillation, distribution, silica gel chromatography, preparation HPLC to wait as required to carry out.

Preparation method 1-1

Wherein Hal is halogen atom such as chlorine atom, bromine atoms etc.; Hal ¹Be halogen atom such as bromine atoms, iodine atom etc.; R ^1AFor previously defined " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and previously defined B group _1-10Alkyl "; R ^2ABe previously defined " C _1-4Alkyl ", it is preferably methyl or ethyl; In compound [6], each R ^2ACan be different, but preferably mutually the same; (R ³) _nBe R ³¹, R ³²And R ³³In any substituting group, it can be identical or different; N is 1～3 integer; If substituent R ³Be not substituted in two * positions simultaneously, then the definition of other symbol is the same.

Step 1

Under argon or nitrogen gas stream, by heating zinc powder and glycol dibromide are reacted in solvent, and the adding trimethylsilyl chloride is reacted.Then, the solution that adds compound [1] in reaction soln reacts, to obtain compound [2].

As preferred solvent, can mention ether solvents as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) (THF) etc.; Hydrocarbon solvent such as benzene, toluene, hexane, dimethylbenzene etc.; Or the like.

Step 2

Under argon or nitrogen gas stream, by cooling or heating, make compound [2] and compound [3] at catalyzer and ligand such as triphenylphosphine when needing, existence such as three (2-furyl) phosphine are descended to react in solvent, obtain compound [4].

As catalyzer, can mention that palladium catalyst closes palladium as two (dibenzalacetones), three (dibenzalacetones) close two palladiums, dichloro two (triphenylphosphine) closes palladium, and dichloro two (benzonitrile) closes palladium, and the dichloro quadrol closes palladium, acid chloride, four (triphenylphosphines) close palladium etc., nickel catalyzator etc.

As preferred solvent, can mention ether solvents as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) (THF) etc.; Hydrocarbon solvent such as benzene, toluene, hexane, dimethylbenzene etc., or the like.

Step 3

By ordinary method reducing compound [4], for example neutrality or alkaline condition adopt the reduction of zinc or iron down; Adopt iron and sour reduction; Adopt the reduction of tin or tindichloride (II) and concentrated hydrochloric acid; Adopt the reduction of alkaline sulfides; Adopt the reduction of alkaline hydrosulphite etc., perhaps by the reducing compounds such as catalytic reduction method [4] under the nitrogen atmosphere, to obtain compound [5].

For example, under cooling, in compound [4], add acetate and zinc powder, and mixture is at room temperature reacted, obtain compound [5].As selection, palladium-carbon can be added in the solution of compound [4] in the mixed solvent of THF and methyl alcohol, and mixture is being reacted under nitrogen atmosphere and room temperature, obtain compound [5].

Step 4

By heating compound [5] and compound [6] are reacted in solvent.

As preferred solvent, can mention alcoholic solvent such as methyl alcohol, ethanol, n-propyl alcohol, Virahol etc.; Hydrocarbon solvent such as benzene, toluene, hexane, dimethylbenzene etc.; Halogenated hydrocarbon solvent such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc. and their mixed solvent.

Then, remove desolvate after, by heating residuum is for example reacted among the mixture of phenyl ether or phenyl ether and biphenyl such as the Dowtherm A (trade mark Fluka) etc. at solvent, obtain compound [7].

Step 5

In the presence of alkali, compound [7] and compound [8] are reacted in solvent, obtain compound [I-1].

As alkali, that can mention has salt of wormwood, yellow soda ash, lithium hydride, sodium hydride, potassium hydride KH etc., preferred salt of wormwood.

As solvent, that can mention has hydrocarbon solvent such as benzene, toluene, hexane, a dimethylbenzene etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent such as dimethyl formamide, methyl-sulphoxide, acetonitrile etc., and their mixed solvent.

Step 6

Under room temperature or heating, make compound [I-1] in solvent under the alkaline condition that adopts sodium hydroxide, potassium hydroxide, lithium hydroxide etc. or adopting hydrolysis under the acidic conditions of hydrochloric acid, sulfuric acid etc., obtain compound [I-2].

As solvent, that can mention has alcoholic solvent such as methyl alcohol, ethanol, n-propyl alcohol, a Virahol etc.; Hydrocarbon solvent such as benzene, toluene, hexane, dimethylbenzene etc.; Halogenated hydrocarbon solvent such as methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent such as dimethyl formamide, methyl-sulphoxide, acetonitrile etc.; Water; And their mixed solvent.

By with preparation method 1-1 in the reaction of same procedure, utilize the compound shown in the following formula [20]

Replace compound [3], can obtain compound [I].

Preparation method 1-2 adopts the preparation method's of the compound [9] of wherein having introduced hydroxyl protecting group example

Wherein r is 1～6 integer, R ^P1Be hydroxyl protecting group, the definition of other symbol is the same.

Step 1

By compound [7] and compound [9] that the method identical with preparation method 1-1 obtains, the method reaction by identical with the step 5 of preparation method 1-1 obtains compound [10].

Step 2

Compound [10] goes protection by ordinary method, obtains compound [I-3].

As hydroxyl protecting group, that can mention has ethanoyl, methoxycarbonyl, methoxymethyl, methoxy ethoxy methyl, trimethyl silyl, t-butyldimethylsilyl, a t-butyldiphenylsilyl etc.

For example, work as R ^P1During for ethanoyl or methoxycarbonyl, reaction can realize protection under heating in the presence of alkali such as sodium hydroxide, the potassium hydroxide etc.Operable processing comprises: add concentrated hydrochloric acid and heating, heat in strong aqua etc.

For example, work as R ^P1During for t-butyldimethylsilyl; can realize going protection by following processing: the processing of in THF, carrying out at room temperature with tetrabutyl ammonium fluoride; the processing of in the presence of sodium hydroxide, in THF, being undertaken by heating, with acetate-water-THF under room temperature or heating and the processing carried out etc.In this step, R ^P1Go the protection and R ^2AHydrolysis can carry out in two stages.

Preparation method 2-1

Hal wherein ²Be halogen atom and preferred fluorine atom or chlorine atom, R ^C3And R ^C4Identical or different and respectively do for oneself low alkyl group such as methyl, ethyl etc., R ^1BPreviously defined " optional by 1～3 C that is selected from the substituting group replacement of halogen atom and top definition B group _1-10Alkyl ", previously defined " the optional C that is replaced by 1～5 substituting group that respectively is selected from the A group _3-10Carbocylic radical ", previously defined " optional heterocyclic radical that is replaced by 1～5 substituting group that respectively is selected from the A group " or previously defined " OR ^A4", the definition of other symbol is the same, wherein substituent R ³Be not substituted on the * position.

Step 1

Here, Hal ¹Be preferably bromine or iodine, and compound [12] can obtain by the halogenation of routine.

For example, under room temperature or heating, compound [11] and halogenating agent such as N-bromine succinimide, N-iodine succinimide etc. are at solvent such as trifluoromethanesulfonic acid, and acetate reacts in the vitriol oil, DMF etc., obtains compound [12].

Step 2

Carboxylic acid halides is by ordinary method, for example makes compound [12] and halogenating agent such as oxalyl chloride, thionyl chloride etc. at solvent such as hydrocarbon solvent (as toluene, dimethylbenzene etc.) under heating; Halogenated hydrocarbon solvent (as methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride etc.); Reaction obtains in the ethyl acetate etc.

Here, for example, when using thionyl chloride, can add the DMF of catalytic amount as halogenating agent.

Then, add compound [13], make it under room temperature or heating, at alkali such as triethylamine, diisopropyl ethyl amine, salt of wormwood reacts under the existence such as pyridine, thereafter, makes gained compound and compound [14] reaction under room temperature or heating, obtains compound [15].

As solvent, that can mention has hydrocarbon solvent such as benzene, toluene, hexane, a dimethylbenzene etc.; Halogenated hydrocarbon solvent such as methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent such as acetonitrile etc.; Ethyl acetate; And their mixed solvent.

Step 3

Compound [15] is at alkali such as yellow soda ash, salt of wormwood, and sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert.-butoxide, sodium hydride, potassium hydride KHs etc. exist down, react in solvent, obtain compound [16].

As one of preferred manufacturing procedure, compound [15] can be under room temperature or heating, and 1,8-diazacyclo [5.4.0]-7-hendecene reacts in solvent under existing, and obtains compound [16].

As solvent, that can mention has hydrocarbon solvent such as benzene, toluene, hexane, a dimethylbenzene etc.; Halogenated hydrocarbon solvent such as methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent such as dimethyl formamide, methyl-sulphoxide, acetonitrile etc.; And their mixed solvent.

Step 4

Compound [16] reacts by the method identical with the step 2 of preparation method 1-1 with compound [2], obtains compound [I-4].

Step 5

Compound [I-4] obtains compound [I-5] by the method hydrolysis identical with the step 6 of preparation method 1-1.

Preparation method 2-2 comprises the example of introducing and removing the preparation method of hydroxyl protecting group

Wherein the definition of each symbol is the same.

Step 1

Compound [12] by the method identical with the step 1 of preparation method 2-1 obtains by the method identical with the step 2 of preparation method 2-1, with compound [13] and compound [17] reaction, obtains compound [18].

Step 2

Protecting group is introduced in the hydroxyl of compound [18] by ordinary method, made the compound cyclisation by the method identical then, obtain compound [19] with the step 3 of preparation method 2-1.

As selection, compound [18] is pressed step 3 cyclisation with preparation method 2-1, by ordinary method protecting group is introduced in the hydroxyl then, obtains compound [19].

For example, work as R ^P1During for t-butyldimethylsilyl, compound [18] can at room temperature react in DMF and toluene equal solvent with imidazoles and tert-butyldimethylsilyl chloride.

Work as R ^P1During for methoxycarbonyl, compound [18] can react in the chloroform equal solvent with pyridine and methyl-chloroformate under cooling or room temperature.

For the NH that replaces compound [17] ₂-R ^{1A '}, can use the preparation method of class, wherein R ^1A' for choosing the C that is replaced by at least one hydroxyl wantonly _1-10Alkyl.

Step 3

Compound [19] is reacted by the method identical with the step 2 of preparation method 1-1 with compound [2], obtain compound [I-6].

Step 4

Compound [I-6] by the ordinary method hydrolysis, obtains compound [I-7] by the method identical with the step 2 of preparation method 1-2.In this step, R ^P1Removal and R ^2AHydrolysis can carry out in two steps.

The preparation method 3

R wherein ^{A7 '}For choosing wantonly by 1～3 C that is selected from the substituting group replacement of halogen atom and B group _1-10Alkyl, the definition of other symbol is the same.

Fluorine atom on the 4-Oxoquinoline can change into-OR by reacting with nucleophilic reagent according to conventional methods ^A7,-SR ^A7Or-NR ^A7R ^A8They can further change into-NR according to conventional methods ^A7COR ^A9Or-N=CH-NR ^A10R ^A11

This preparation method is suitable for substituting group is incorporated into the 7-position of 4-Oxoquinoline.

Preparation method 3-1

By ordinary method alkoxyl group is incorporated in the compound [21], obtains compound [I-8].

For example, compound [I-8] can be by reacting in alcoholic solvents such as methyl alcohol, ethanol, propyl alcohol, butanols with metal alkoxide under heating, hydrolysis and obtaining then.

Solvent and metal alkoxide need be determined according to required alkoxyl group.For methoxyl group, sodium methylate or potassium methylate are reacted in methyl alcohol, for oxyethyl group, sodium ethylate or potassium ethylate are reacted in ethanol.

Preparation method 3-2

Compound [21] carries out ammonification according to conventional methods, obtains compound [I-9].

For example, compound [I-9] can be under heating, by with amine at inert organic solvents such as THF, dioxane, chloroform, methylene dichloride, methyl alcohol, ethanol, reaction in the pyridine etc. and obtaining.

In addition, compound [I-9] can also be by means of microwave radiation, by obtaining with the amine reaction in DMF.

The preparation method 4

Provide the preparation method's of intermediate compound [12] example below.

Wherein the definition of each symbol is the same.

Step 1

Protecting group is incorporated in the carboxylic acid of compound [22] according to conventional methods, obtains compound [23].

With regard to esterification, for example, compound [23] can be in the presence of alkali such as yellow soda ash, salt of wormwood, sodium hydride, potassium hydride KH etc., in DMF, THF, toluene equal solvent, by obtaining with reactions such as alkylating reagent such as methyl iodide.

Step 2

Compound [23] by the method reduction identical with the step 3 of preparation method 1-1, obtains compound [24] by ordinary method.

Step 3

Compound [24] carries out halogenation by ordinary method by the method identical with the step 1 of preparation method 2-1, obtains compound [25].

Step 4

Compound [25] is under cooling or room temperature, in water or inert organic solvents such as THF, dioxane, ethyl acetate, chloroform, methylene dichloride, methyl alcohol, ethanol, pyridine etc., carry out diazotization with Sodium Nitrite and hydrochloric acid or sulfuric acid, then under cooling or heating, carry out halogenation with cuprous halide such as cuprous chloride etc. with concentrated hydrochloric acid, obtain compound [26].Here, Hal ²Be preferably the chlorine atom.

Step 5

Make the hydroxyl of compound [26] go protection by ordinary method, obtain compound [27].

For example, work as R ^P1During for methyl, compound [27] can obtain by reacting in methylene dichloride with boron tribromide under cooling.

Step 6

Compound [27] and compound [8] are reacted in solvent in the presence of alkali, obtain compound [28].

As compound [8], for example, can mention alkylating reagent such as iodoethane etc.

As alkali, can mention salt of wormwood, yellow soda ash, lithium hydride, sodium hydride, potassium hydride KH etc., preferred salt of wormwood.

As solvent, that can mention has alcoholic solvent such as methyl alcohol, ethanol, n-propyl alcohol, a Virahol etc.; Hydrocarbon solvent such as benzene, toluene, hexane, dimethylbenzene etc.; Halogenated hydrocarbon solvent such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride etc.; Ether solvents is as 1,4-dioxane, ether, 1,2-glycol dimethyl ether, tetrahydrofuran (THF) etc.; Polar solvent such as dimethyl formamide, methyl-sulphoxide, acetonitrile etc.; Water; And their mixed solvent.

Step 7

Compound [28] by the method hydrolysis identical with the step 6 of preparation method 1-1, obtains compound [12 '] by ordinary method.

Step 8

R in compound [26] ^P1During for required substituting group, compound [12 '] can by with step 7 in identical method obtain.

The preparation method 5

Wherein the definition of each symbol is the same.

Step 1

Compound [29] by the method halogenation identical with the step 1 of preparation method 2-1, obtains compound [30] by ordinary method.

Step 2

Compound [30] reacts by the method identical with the step 2 of preparation method 2-1 with compound [13] and compound [17], obtains compound [31].

Step 3

Compound [31] obtains compound [32] by the method reaction identical with the step 3 of preparation method 2-1.

Step 4

Compound [32] obtains compound [33] by the method reaction identical with the step 2 of preparation method 2-2.

Step 5

Compound [33] reacts by the method identical with the step 2 of preparation method 1-1 with compound [2], obtains compound [I-10].

Step 6

Compound [I-10] obtains compound [I-11] by the method hydrolysis identical with the step 2 of preparation method 1-2.

Step 7

Compound [I-12] can by the method identical with preparation method 3-1, obtain to compound [I-11] by introducing alkoxyl group according to conventional methods.

Now, in detail the 4-oxoquinoline compound shown in the formula of the present invention [I] is described in detail with reference to embodiment, and pharmaceutically acceptable salt and preparation method, can not be interpreted as described embodiment restrictive.

Reference example 1

Preparation 2, the THF solution of 3-dichloro benzyl chlorination zinc

Under argon gas stream, to zinc powder (55.1g, tetrahydrofuran (THF) (THF 843mmol); (2.9ml 33.8mmol) and with this mixture heating up refluxed 5 minutes 56ml) to add glycol dibromide in the suspension.Then, (8.6ml 67.5mmol), and stirs this mixture 5 minutes down at 0 ℃, drips 2 down, 3-dichlorobenzyl chloride (82.4g, THF 421.7mmol) (330ml) solution ice-cooled thereafter to add down trimethylsilyl chloride at 0 ℃.Finish after the dropping, mixture is warming up to room temperature and stirred 1 hour, obtain 2, the THF solution of 3-dichloro benzyl chlorination zinc.

Embodiment 1-1 6-(2, the 3-dichloro benzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid's is synthetic

Step 11,2-two chloro-3-(4-nitrobenzyl) benzene synthetic

Under argon gas stream, two (dibenzalacetones) are closed palladium (0), and (3.2g, 5.6mmol) (2.6g 11.2mmol) is dissolved in THF (310ml) with three (2-furyl) phosphine.Ice-cooled following what undertaken by sleeve pipe, in this solution, drip and derive from 2 of reference example 1, the THF solution of 3-dichloro benzyl chlorination zinc (421.7mmol) drips 4-iodo oil of mirbane (70.0g, THF 281mmol) (700ml) solution then.After at room temperature stirring 2 hours, in reaction soln, add saturated aqueous ammonium chloride solution, and by this mixture of Sai Lite diatomite filtration.Concentrated filtrate under reduced pressure.Add water in the residuum and use ethyl acetate extraction.Organic layer water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and collect precipitated solid between diakinesis by filtering.Concentrated filtrate under reduced pressure once more, and collect precipitated solid between diakinesis by filtering.Merga pass filters the solid that obtains, and with normal hexane washing and vacuum-drying, obtains target product (60.2g, yield 76%), and it is the light brown solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：4.24(2H，s)，7.09(1H，d，J＝7.7Hz)，7.18(1H，dd，J＝7.8Hz，7.9Hz)，7.32(2H，d，J＝8.9Hz)，7.40(1H，d，J＝8.0Hz)，8.15(2H，d，J＝8.7Hz)

MS(ESI)：M-280

Synthesizing of step 2 4-(2, the 3-dichloro benzyl) phenyl amine

To derive from 1 of step 1,2-two chloro-3-(4-nitrobenzyl) benzene (25.0g, 88.6mmol) be dissolved in acetate (400ml) and 0 ℃ down by part ground add a zinc powder (70g, 1.1mol).This mixture was at room temperature stirred 1 hour.By Sai Lite diatomite filtration reaction mixture and use washing with alcohol.Concentrated filtrate under reduced pressure, and collect precipitated solid between diakinesis by filtering.To wash with ether by the solid that filtration obtains, and be dissolved in ethyl acetate (500ml) and the water (500ml).Add the 4N aqueous sodium hydroxide solution, with in and water layer.Separate organic layer, water layer is further used ethyl acetate extraction.Merge organic layer, water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and collect precipitated solid between diakinesis by filtering.The solid that obtains by filtration washs and vacuum-drying with normal hexane, obtains target product (18.1g, yield 81%), and it is the light brown solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：3.52(2H，brs)，4.01(2H，s)，6.63(2H，d，J＝8.2Hz)，6.97(2H，d，J＝8.1Hz)，7.02(1H，d，J＝7.6Hz)，7.09(1H，dd，J＝7.8Hz，7.8Hz)，7.31(1H，d，J＝7.8Hz)

MS(ESI)：M+252

Step 36-(2, the 3-dichloro benzyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester synthetic

With derive from step 2 4-(2, the 3-dichloro benzyl) aniline (10.0g, 39.7mmol) be dissolved in toluene (100ml) and add ethoxy methylene diethyl malonate (8.8ml, 43.7mmol).With reaction mixture reflux 3 hours.The concentrating under reduced pressure reaction soln, and add phenyl ether (100ml) with the dissolving residuum.Mixture was stirred 3 hours under 250 ℃ of heating.After treating this mixture cooling, adding normal hexane and by filtering collecting precipitation, with chloroform washing and vacuum-drying, obtaining target product (10.1g, yield 68%) to reaction soln, it is a faint yellow solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.27(3H，t，J＝7.1Hz)，4.20(2H，q，J＝7.1Hz)，4.27(2H，s)，7.34-7.41(2H，m)，7.55-7.57(3H，m)，7.90(1H，s)，8.49(1H，d，J＝6.6Hz)，12.26(1H，brs)

MS(ESI)：M+376

Step 41-(2-acetoxyl group ethyl)-6-(2, the 3-dichloro benzyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester synthetic

To derive from the 6-(2, the 3-dichloro benzyl)-1 of step 3, (400mg 1.1mmol) is suspended in dimethyl formamide (DMF to 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester; 8ml) and acetate 2-bromine ethyl ester (152 μ l, 1.4mmol) in and add salt of wormwood (440mg, 3.2mmol).With mixture 80 ℃ of following heated and stirred.During the stirring, add acetate 2-bromine ethyl ester (152 μ l, 1.4mmol) twice, and mixture stirred 1.5 hours altogether under 80 ℃ of heating.After treating this mixture cooling, add saturated aqueous ammonium chloride solution in reaction soln, and by filtering collecting precipitation, wash with water and vacuum-drying, obtain target product (468mg, yield 95%), it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm?1.25(3H，t，J＝9.3Hz)，1.88(3H，s)，4.20(2H，q，J＝9.3Hz)，4.27(2H，s)，4.33-4.41(2H，m)，4.59-4.62(2H，m)，7.32-7.41(3H，m)，7.54(1H，dd，J＝2.9Hz，10.2Hz)，7.64(1H，dd，J＝2.4Hz，11.2Hz)，7.81(1H，d，J＝11.7Hz)，7.88(1H，d，J＝2.4Hz)，8.57(1H，s)

Step 5 6-(2, the 3-dichloro benzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid's is synthetic

To derive from 1-(2-acetoxyl group the ethyl)-6-(2, the 3-dichloro benzyl)-1 of step 4,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester (6.0g, 13.0mmol) be suspended in the ethanol (480ml) and add the 4N aqueous sodium hydroxide solution (84ml, 21mmol).With reaction mixture reflux 30 minutes.After treating the cooling of this mixture, concentrating under reduced pressure reaction soln partly.Add hydrochloric acid and pass through and filter collecting precipitation, water and washing with alcohol and vacuum-drying obtain target product (4.5g, yield 85%), and it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(2H，t，J＝4.7Hz)，4.36(2H，s)，4.60(2H，t，J＝4.8Hz)，4.98(1H，brs)，7.37-7.39(1H，m)，7.45(1H，dd，J＝1.4，7.6Hz)，7.57(1H，dd，J＝1.5，8.0Hz)，7.81(1H，dd，J＝2.1，8.9Hz)，8.02(1H，d，J＝8.8Hz)，8.15(1H，d，J＝1.8Hz)，8.86(1H，s)，15.18(1H，brs)

MS(ESI)：M+392

m.p.：247-249℃

Embodiment 1-2 6-(2, the 3-dichloro benzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid's is synthetic

Step 12,3-two fluoro-5-iodo-benzoic acids synthetic

With 2, the 3-difluoro-benzoic acid (5.0g 31.6mmol) is dissolved in the trifluoromethanesulfonic acid (25ml), and argon gas stream and 0 ℃ down by part ground add a N-iodosuccinimide (8.55g, 38.0mmol).This mixture was at room temperature stirred 3 hours, and reaction soln is poured in the frozen water solution of S-WAT.Stir this mixture, and by filtering collecting precipitation, wash with water and vacuum-drying obtains target product (7.5g, yield 84%), it is the pale pink solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：7.74(1H，m)，8.11(1H，m)

MS(ESI)：M-283

Step 2Synthesizing of 2-(2,3-two fluoro-5-iodobenzene formyl radicals)-3-(2-hydroxyethyl amino) ethyl propenoate

To derive from 2 of step 1,3-two fluoro-5-iodo-benzoic acids (3.0g 10.6mmol) is dissolved in toluene, and add thionyl chloride (3.0ml, 41.1mmol) and DMF (catalytic amount).With reaction mixture reflux 3 hours.With the reaction soln concentrating under reduced pressure and add THF (15ml) with the dissolving residuum.With the drips of solution that obtains be added to 3-dimethylamino ethyl propenoate (1.66g, 11.6mmol) and triethylamine (1.77ml, in THF 12.7mmol) (10ml) solution, and with mixture 50 ℃ of following heated and stirred 2.5 hours.After treating this mixture cooling, filter reaction mixture is also used THF (10ml) washing.(0.77ml 12.7mmol), and stirs mixture 1 hour under 40 ℃ of heating to add monoethanolamine in filtrate.After treating this mixture cooling, add water to reaction soln and use ethyl acetate extraction.Organic layer water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=2: 1), obtain target product (3.8g, yield 85%), it is the yellow solid mixture of E type and Z type.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm?0.91-1.09(3H，m)，1.80-1.89(1H，m)，3.52-3.63(2H，m)，3.83-3.91(2H，m)，3.98-4.09(2H，m)，7.36-7.52(2H，m)，8.15(1H，d，J＝14.4Hz)，9.6(0.22H，brs)，11.0(0.78H，brs)

MS(ESI)：M+426

Step 32-(2,3-two fluoro-5-iodobenzene formyl radicals)-3-[2-(t-butyldimethylsilyloxy base) ethylamino] ethyl propenoate synthetic

The 2-(2 of step 2 will be derived from; 3-two fluoro-5-iodobenzene formyl radicals)-3-(2-hydroxyethyl amino) ethyl propenoate (2.0g; 4.7mmol) be dissolved in DMF (10ml); add imidazoles (705mg; 10.4mmol) and tert-butyldimethylsilyl chloride (1.49g; 9.9mmol), and at room temperature stirred 4 hours.Add water to reaction soln and use ethyl acetate extraction.Organic layer water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 4), obtain target product (2.3g, yield 91%), it is a white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.07(6H，s)，0.90(9H，s)，1.07(3H，t，J＝7.1Hz)，3.45-3.55(2H，m)，3.70-3.80(2H，m)，4.04(2H，q，J＝7.1Hz)，7.30-7.50(2H，m)，8.14(1H，d，J＝14.1Hz)，10.80-11.10(1H，m)

MS(ESI)：M+540

Step 41,4-dihydro-8-fluoro-6-iodo-1-[2-(t-butyldimethylsilyloxy base) ethyl]-4-oxo-3-quinoline carboxylic acid ethyl ester synthetic

The 2-(2 of step 3 will be derived from; 3-two fluoro-5-iodobenzene formyl radicals)-and 3-[2-(t-butyldimethylsilyloxy base) ethylamino] ethyl propenoate (2.3g; 4.3mmol) be dissolved in THF (25ml) and ice-cooled add down sodium hydride (256mg, 6.4mmol).This mixture was stirred 1 hour down at 0 ℃.(6.4ml is 6.4mmol) with neutralization reaction solution to add 1N hydrochloric acid.Further add water, and use ethyl acetate extraction.Organic layer water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 2 is to ethyl acetate: hexane=2: 1), obtain target product (2.0g, yield 92%), it is a white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.12(6H，s)，0.79(9H，s)，1.38(3H，t，J＝7.1Hz)，3.90-4.00(2H，m)，4.37(2H，q，J＝7.1Hz)，4.40-4.50(2H，m)，7.69(1H，dd，J＝2.0Hz，13.7Hz)，8.40(1H，s)，8.69(1H，d，J＝2.0Hz)

MS(ESI)：M+520

Step 56-(2, the 3-dichloro benzyl)-1,4-dihydro-8-fluoro-1-[2-(t-butyldimethylsilyloxy base) ethyl]-4-oxo-3-quinoline carboxylic acid ethyl ester synthetic

Under nitrogen gas stream, will be by 2 of the 1M that obtains with reference example 1 same procedure, THF solution (the 2.9ml of 3-dichloro benzyl chlorination zinc, 2.9mmol) be added among the THF (20ml), add then two (dibenzalacetones) close palladium (0) (22mg, 0.039mmol), three (2-furyl) phosphine (18mg, 0.077mmol) and derive from 1 of step 4,4-dihydro-8-fluoro-6-iodo-1-[2-(t-butyldimethylsilyloxy base) ethyl]-4-oxo-3-quinoline carboxylic acid ethyl ester (1.0g, 1.9mmol).This mixture was at room temperature stirred 17 hours, add 2 then, and the THF solution of 3-dichloro benzyl chlorination zinc (1.0ml, 1.0mmol).With reaction mixture reflux 1 hour.After treating this mixture cooling, saturated aqueous ammonium chloride solution is added in the reaction soln, and leaches insolubles with Sai Lite diatomite.Filtrate is used ethyl acetate extraction, and organic layer water and saturated brine wash, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (ethyl acetate: hexane=1: 1) through silica gel chromatography, use PTLC purifying (ethyl acetate: chloroform=1: 2) then, obtain target product (562mg, yield 53%), it is faint yellow oily thing.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.13(6H，s)，0.79(9H，s)，1.38(3H，t，J＝7.1Hz)，3.90-4.00(2H，m)，4.23(2H，s)，4.37(2H，q，J＝7.1Hz)，4.40-4.50(2H，m)，7.10-7.50(4H，m)，8.20-8.30(1H，m)，8.39(1H，s)

MS(ESI)：M+552

Step 66-(2, the 3-dichloro benzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid ethyl ester synthetic

The 6-(2 of step 5 will be derived from, the 3-dichloro benzyl)-1,4-dihydro-8-fluoro-1-[2-(t-butyldimethylsilyloxy base) ethyl]-(350mg 0.63mmol) is dissolved in THF (25ml) and add tetrabutylammonium (1M THF solution to 4-oxo-3-quinoline carboxylic acid ethyl ester; 1.9ml, 1.9mmol).This mixture was at room temperature stirred 1 hour.Add water to reaction soln, and by filtering collecting precipitation, wash with water and vacuum-drying, obtain target product (279mg, quantitative yield), it is a faint yellow solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.27(3H，t，J＝7.1Hz)，3.65-3.80(2H，m)，4.21(2H，q，J＝7.1Hz)，4.40-4.50(2H，m)，4.99(1H，m)，7.30-7.90(5H，m)，8.47(1H，s)

MS(ESI)：M+438

Step 76-(2, the 3-dichloro benzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid's is synthetic

The 6-(2 of step 6 will be derived from, the 3-dichloro benzyl)-1, (80mg 0.18mmol) is dissolved in the mixture of ethanol (2ml) and THF (1ml) 4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline carboxylic acid ethyl ester, and adding 1N aqueous sodium hydroxide solution (1ml, 1.0mmol).Mixture was stirred 1 hour under 60 ℃ of heating.After treating this mixture cooling, in reaction soln, add 10% aqueous citric acid solution.By filtering collecting precipitation, aqueous ethanolic solution washing and vacuum-drying with 30% obtain target product (70mg, yield 93%), and it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.78(2H，m)，4.35(2H，s)，4.64(2H，m)，5.00(1H，m)，7.39(2H，m)，7.47(1H，m)，7.58(1H，m)，8.00(1H，m)，8.81(1H，s)，14.80(1H，s)

MS(ESI)：M+409

Embodiment 3-38

Step 1

With 2-chloro-3-nitrobenzoic acid (6.00g, 29.77mmol) be dissolved in trifluoromethanesulfonic acid (40ml) and 0 ℃ down by part ground add a N-iodosuccinimide (7.37g, 32.76mmol).This mixture was stirred 4 hours at 40 ℃, and reaction soln is added in the frozen water.After the stirring,, wash with water and vacuum-drying by filtering collecting precipitation.The gained solid is dissolved in methyl alcohol (50ml), adds the vitriol oil (catalytic amount), and this mixture heating up was refluxed 5.5 hours.With the reaction soln concentrating under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 4), obtain target product (5.35g, yield 53%), it is a faint yellow solid.

1H?NMR(CDCl ₃?300MHz)(δ)ppm：3.98(3H，s)，8.11(1H，d，J＝2.1Hz)，8.24(1H，d，J＝2.1Hz)

Step 2

With derive from step 1 compound (5.35g, 15.67mmol) be dissolved in methyl alcohol (25ml) and add the 4N potassium hydroxide aqueous solution (10.00ml, 4.00mmol).With reaction mixture reflux 30 minutes.After treating this mixture cooling, add 1N hydrochloric acid in reaction soln, by filtering the solid and the vacuum-drying of collecting precipitation, obtain target product (4.99g, yield 97%), it is a white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：8.14(1H，d，J＝2.0Hz)，8.39(1H，d，J＝2.1Hz)

Step 3

With derive from step 2 compound (4.99g 15.24mmol) is dissolved in toluene (50ml), and add thionyl chloride (5.00ml, 68.54mmol) and dimethyl formamide (catalytic amount).With reaction mixture reflux 1 hour.With the reaction soln concentrating under reduced pressure and add tetrahydrofuran (THF) (80ml) with the dissolving residuum.The gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (2.29g, 16.00mmol) and triethylamine (2.55ml, in tetrahydrofuran (THF) 18.30mmol) (50ml) solution, and with this mixture 50 ℃ of following heated and stirred 10 hours.After treating the cooling of this mixture, with monoethanolamine (1.10ml 18.23mmol) is added in the reaction mixture, and with mixture 40 ℃ of following heated and stirred 1.5 hours.After treating this mixture cooling, add water to reaction mixture, and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=2: 1), obtain target product (5.35g, yield 75%), it is the yellow solid mixture of E type and Z type.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.82-1.01(3H，m)，3.63(2H，br)，3.85-4.06(4H，m)，7.65-7.68(1H，m)，8.02-8.06(1H，m)，8.21-8.36(1H，m)，9.78(0.16H，br)，11.15(0.84H，br)

Step 4

With derive from step 3 compound (5.35g 11.42mmol) is dissolved in dimethyl formamide (50ml), and add imidazoles (1.71g, 25.12mmol) and tert-butyldimethylsilyl chloride (3.62g, 24.02mmol).This mixture was at room temperature stirred 30 minutes.Add water to reaction mixture, and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrating under reduced pressure obtains crude product (7.10g), and it is a faint yellow solid.

Step 5

With the crude product (7.10g) that derives from step 4 be dissolved in tetrahydrofuran (THF) (70ml) and ice-cooled add down sodium hydride (731mg, 18.27mmol).This mixture was stirred 45 minutes down at 0 ℃.In reaction soln, add 1N hydrochloric acid (18.3ml) and water and stirring, thereafter with this mixture of ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and (ethyl acetate: hexane=1: 4 to 1: 2), obtain target product (5.58g, yield 84%), it is a yellow solid to carry out purifying by silica gel chromatography.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.14(6H，s)，0.73(9H，s)，1.39(3H，t，J＝7.1Hz)，3.74(2H，t，J＝4.6Hz)，4.02(2H，t，J＝4.6Hz)，4.39(2H，q，J＝7.1Hz)，8.13(1H，d，J＝2.2Hz)，8.50(1H，s)，9.02(1H，d，J＝2.2Hz)

Step 6

With derive from step 5 compound (5.00g 9.15mmol) is dissolved in tetrahydrofuran (THF) (100ml), and under argon gas stream, add two (dibenzalacetones) close palladium (0) (105mg, 0.18mmol) and three (2-furyl) phosphine (85mg, 0.37mmol).Under 60 ℃, drip tetrahydrofuran solution as the prepared 3-chloro-2-luorobenzyl bromination zinc (11.90mmol) of the step 4 of embodiment 4-32.After being added dropwise to complete, with reaction mixture reflux 4 hours.After treating this mixture cooling, saturated aqueous ammonium chloride solution is added in the reaction soln, and leaches insolubles by Sai Lite diatomite.Filtrate is used ethyl acetate extraction, and organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 2 to 1: 1), obtain target product (2.67g, yield 52%), it is a brown oil.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.19(6H，s)，0.70(9H，s)，1.39(3H，t，J＝7.1Hz)，3.73(2H，t，J＝4.6Hz)，4.03(2H，t，J＝4.6Hz)，4.14(2H，s)，4.38(2H，q，J＝7.1Hz)，7.02-7.14(2H，m)，7.29-7.35(1H，m)，7.73(1H，d，J＝2.2Hz)，8.50(1H，s)，8.59(1H，s)

Step 7

With derive from step 6 compound (1.00g, 1.79mmol) be dissolved in acetate (20ml) and add zinc powder (1.16g, 17.76mmol).This mixture was at room temperature stirred 4 hours.By Sai Lite diatomite filtration reaction mixture, and in filtrate, add saturated sodium bicarbonate aqueous solution.This mixture ethyl acetate extraction.Organic layer is used saturated sodium bicarbonate aqueous solution, water and saturated salt water washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (ethyl acetate) through silica gel chromatography.In the gained residuum, add ether, and this mixture is carried out ultrasonication.After the filtration, with its vacuum-drying, obtain target product (730mg, yield 77%), it is the light orange solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.06(6H，s)，0.77(9H，s)，1.41(3H，t，J＝7.1Hz)，4.01(2H，s)，4.08(2H，t，J＝4.7Hz)，4.39(2H，q，J＝7.1Hz)，4.50(2H，brs)，4.75(2H，t，J＝4.7Hz)，6.81(1H，s)，6.94-7.08(2H，m)，7.20-7.26(1H，m)，7.91(1H，s)，8.34(1H，s)

Step 8

With derive from step 7 compound (100mg 0.19mmol) is dissolved in dimethyl formamide (2ml), and add methyl iodide (0.029ml, 0.47mmol) and sodium hydride (23mg, 0.56mmol).This mixture was at room temperature stirred 2 hours.The aqueous citric acid solution of adding 10% stirs this mixture and uses ethyl acetate extraction in reaction mixture.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and carry out silica gel chromatography and separate that (ethyl acetate: hexane=2: 1), obtain the product (45mg) of rough purifying, it is the incarnadine solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.33--0.29(6H，m)，0.64-0.69(9H，m)，1.23-1.41(3H，m)，2.66-2.70(6H，m)，3.55-3.59(2H，m)，4.36-4.4.2(4H，m)，4.82-4.96(2H，m)，6.96-7.11(2H，m)，7.23-7.30(2H，m)，8.16-8.15(1H，m)，8.40-8.66(1H，m)

Step 9

The product (45mg) that derives from the rough purifying of step 8 is dissolved in tetrahydrofuran (THF) (1ml), and the THF solution of the tetrabutyl ammonium fluoride of adding 1M (1.00ml, 1.00mmol).This mixture was at room temperature stirred 5 minutes.In reaction soln, add ethanol (1ml) and 1N aqueous sodium hydroxide solution (1ml, 1.00mmol), and with reaction mixture reflux 2 hours.After treating this mixture cooling, in reaction soln, add 10% aqueous citric acid solution.Stir this mixture, and with twice of chloroform extraction.Organic layer washs with saturated brine, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate and carry out silica gel chromatography and separate (chloroform: methyl alcohol: acetate=10: 1: 0.1), obtain the product of rough purifying under reduced pressure.In the product of this rough purifying, add aqueous ethanolic solution, and it is carried out ultrasonication.After the filtration, with filtrate vacuum-drying, obtain target product (22mg, yield 27%), it is a beige solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.67(6H，s)，3.39(2H，m)，4.21(2H，s)，4.72(1H，t)，4.97(2H，t)，7.20-7.22(1H，m)，7.40-7.50(2H，m)，7.65(1H，s)，7.84(1H，s)，15.10(1H，s)

MS(ESI)：M+419

Embodiment 3-62

Step 1

With derive from embodiment 4-33 step 12,4-two fluoro-5-iodo-benzoic acids (3.00g 10.60mmol) is dissolved in toluene (10ml), and add thionyl chloride (3.00ml, 41.10mmol) and dimethyl formamide (catalytic amount).With reaction mixture reflux 1.5 hours.With the reaction soln concentrating under reduced pressure, and add tetrahydrofuran (THF) (15ml), with the dissolving residuum.The gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (1.66g, 11.60mmol) and triethylamine (1.77ml, in tetrahydrofuran (THF) 12.70mmol) (10ml) solution, and with this mixture 50 ℃ of following heated and stirred 2.5 hours.After treating this mixture cooling, filter reaction mixture is also used tetrahydrofuran (THF) (10ml) washing.In filtrate, add monoethanolamine (0.77ml, 12.76mmol), and with mixture 40 ℃ of following heated and stirred 1 hour.After treating this mixture cooling, add water to reaction soln and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=2: 1), obtain the product (3.00g, yield 67%) of rough purifying, it is the yellow solid mixture of E type and Z type.

Step 2

With derive from step 1 compound (3.00g, 7.06mmol) be dissolved in dimethyl formamide (15ml) and add imidazoles (1.06g, 15.52mmol) and tert-butyldimethylsilyl chloride (2.23g, 14.82mmol).This mixture was at room temperature stirred 14 hours.Add water to reaction mixture and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 4), obtain target product (3.22g, yield 85%), it is a white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.06(6H，s)，0.90(9H，s)，1.08(3H，t，J＝7.1Hz)，3.51(2H，br)，3.79(2H，t，J＝4.9Hz)，4.05(2H，q，J＝7.1Hz)，6.78(1H，dd，J＝7.9，9.4Hz)，7.71(1H，dd，J＝7.3，7.3Hz)，8.11(1H，d，J＝14.0Hz)，10.91(1H，br)

Step 3

With derive from step 2 compound (3.22g, 5.97mmol) be dissolved in tetrahydrofuran (THF) (35ml) and ice-cooled add down sodium hydride (358mg, 8.95mmol).This mixture was stirred 2.5 hours down at 0 ℃.In reaction mixture, add 1N hydrochloric acid (8.90ml, 8.90mmol) and water (35ml) and stir this mixture.By filtering collecting precipitation, and (ethyl acetate: hexane=1: 2 to 2: 1) carry out purifying, obtain target product (2.52g, yield 81%), it is a faint yellow solid by silica gel chromatography.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.11(6H，s)，0.79(9H，s)，1.39(3H，t，J＝7.1Hz)，3.96(2H，t，J＝4.8Hz)，4.23(2H，t，J＝4.8Hz)，4.38(2H，q，J＝7.1Hz)，7.14(1H，d，J＝9.3Hz)，8.47(1H，s)，8.93(1H，d，J＝7.2Hz)

Step 4

(1.00g 1.93mmol) is dissolved in tetrahydrofuran (THF) (20ml) with the compound that derives from step 3.Under nitrogen gas stream, add two (dibenzalacetones) close palladium (0) (22mg, 0.039mmol) and three (2-furyl) phosphine (18mg, 0.077mmol).Under 60 ℃, in this mixture, drip the tetrahydrofuran solution of the 3-chloro-2-luorobenzyl bromination zinc (2.89mmol) for preparing previously.After being added dropwise to complete, with reaction mixture reflux 1 hour.After treating this mixture cooling, in reaction soln, add saturated aqueous ammonium chloride solution.Leach insolubles by Sai Lite diatomite.Filtrate is used ethyl acetate extraction, and organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=2: 1), obtain target product (573mg, yield 55%), it is a faint yellow solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.12(6H，s)，0.78(9H，s)，1.38(3H，t，J＝7.1Hz)，3.99(2H，t)，4.13(2H，s)，4.23(2H，t)，4.37(2H，q，J＝7.1Hz)，6.96-7.13(3H，m)，7.25-7.31(1H，m)，8.39(1H，d)，8.46(1H，s)

Step 5

With derive from step 4 compound (170mg, 0.32mmol) be dissolved in tetrahydrofuran (THF) (1ml) and add the 2N aqueous sodium hydroxide solution (4.00ml, 2.00mmol).With reaction mixture reflux 3.5 hours.After treating this mixture cooling, add 10% aqueous citric acid solution in reaction soln, and by filtering collecting precipitation, aqueous ethanolic solution washing and vacuum-drying with 50% obtain target product (117mg, yield 94%), it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.73(2H，br)，4.25(2H，s)，4.58(2H，br)，4.96(1H，br)，7.19-7.22(1H，m)，7.30-7.36(1H，m)，7.49-7.54(1H，m)，8.03(1H，d)，8.30(1H，d)，8.88(1H，s)，15.42(1H，brs)

Step 6

With derive from step 5 compound (65mg 0.17mmol) is dissolved in methyl-sulphoxide (2.5ml), and under 120 ℃ or lower temperature with the microwave exposure of 50W 20 minutes.After treating the cooling of this mixture, add 10% aqueous citric acid solution in reaction soln, and by filtering collecting precipitation, wash with water and vacuum-drying obtains target product (66mg, yield 96%), it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.88(6H，s)，3.70-3.80(2H，m)，4.22(2H，s)，4.60-4.70(2H，m)，5.05(1H，t)，7.20-7.31(3H，m)，7.50-7.60(1H，m)，7.80(1H，s)，8.78(1H，s)，15.30-15.40(1H，brs)

MS(ESI)：M+419

Embodiment 3-73

Step 1

With 2,4-two fluoro-5-iodo-benzoic acids (5.00g 17.60mol) is dissolved in toluene (25ml), and add oxalyl chloride (2.00ml, 22.93mmol) and dimethyl formamide (catalytic amount).This mixture was at room temperature stirred 12 hours.After the filtering reacting solution, concentrated filtrate and add toluene (20ml) under reduced pressure.Leach insolubles by Sai Lite diatomite.Concentrated filtrate and add tetrahydrofuran (THF) (20ml) under reduced pressure is with dissolving gained residuum.The gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (3.28g, 22.91mmol) and triethylamine (3.70ml is in tetrahydrofuran (THF) 26.55mmol) (20ml) solution.With reaction mixture reflux 1 hour.After treating this mixture cooling, in reaction mixture, add entry and ethyl acetate (50ml).Stir this mixture and distribution.Organic layer is used 1N hydrochloric acid (20ml) and water (200ml) washing successively, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains crude product (7.24g), and it is a brown oil.

Step 2

The crude product (7.24g) that derives from step 1 is dissolved in tetrahydrofuran (THF) (20ml) and add (S)-2-amino-1-butanols (1.89g, 21.24mmol).With mixture 60 ℃ of following heated and stirred 1.5 hours.After treating the cooling of this mixture,, and the gained residuum is dissolved in dimethyl formamide (20ml) with the reaction soln concentrating under reduced pressure.Add salt of wormwood (7.33g, 53.02mmol) and with mixture 70 ℃ of following heated and stirred 1 hour.After treating this mixture cooling, with the reaction mixture concentrating under reduced pressure.Add water (150ml) to residuum, and this mixture was at room temperature stirred 30 minutes.Filter the collecting precipitation thing.Gained solid water (50ml) washing, use hexane then: mixture (50ml) washing of ether=7: 3, and vacuum-drying, obtain target product (4.69g, yield 61%), it is a white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.97(3H，t，J＝7.4Hz)，1.40(3H，t，J＝7.1Hz)，1.95-2.05(1H，m)，2.11-2.21(1H，m)，4.05(1H，br)，4.34-4.39(5H，m)，5.59(1H，br)，7.30(1H，d，J＝10.0Hz)，8.04(1H，d，J＝7.1Hz)，8.58(1H，s)

Step 3

With derive from step 2 compound (4.69g 10.82mmol) is dissolved in dimethyl formamide (20ml), and add imidazoles (950mg, 13.95mmol) and tert-butyldimethylsilyl chloride (1.95g, 12.96mmol).This mixture was at room temperature stirred 14.5 hours.Add water to reaction mixture and use ethyl acetate (50ml) extraction.Organic layer washes with water 3 times, carries out drying then with the saturated brine washing, and by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=3: 7), obtain target product (5.06g, yield 86%), it is a yellow oil.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.08(3H，s)，-0.05(3H，s)，0.77(9H，s)，0.98(3H，t，J＝7.5Hz)，1.40(3H，t，J＝7.2Hz)，1.94-2.10(2H，m)，3.90(2H，br)，4.35-4.43(3H，m)，7.26(1H，d，J＝9.9Hz)，8.59(1H，s)，8.95(1H，d，J＝7.2Hz)

Step 4

With derive from step 3 compound (5.06g 9.24mmol) is dissolved in tetrahydrofuran (THF) (20ml), and under argon gas stream, add two (dibenzalacetones) close palladium (0) (266mg, 0.46mmol) and three (2-furyl) phosphine (215mg, 0.92mmol).Drip the tetrahydrofuran solution of the 3-chloro-2-luorobenzyl bromination zinc (18.50mmol) for preparing previously.After being added dropwise to complete, with mixture 60 ℃ of following heated and stirred 1 hour.After treating this mixture cooling, add water and ethyl acetate, stir this mixture and distribution to reaction soln.Organic layer is used 1N hydrochloric acid successively, water, and saturated sodium bicarbonate aqueous solution and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, (ethyl acetate: hexane=1: 1 to 2: 1) carry out purifying, obtain target product (3.86g, yield 74%), it is a brown oil to residuum by silica gel chromatography.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.10(3H，s)，-0.06(3H，s)，0.752(9H，s)，0.98(3H，t，J＝7.4Hz)，1.403H，t，J＝7.1Hz)，1.90-2.12(2H，m)，3.89(2H，br)，4.12(2H，s)，4.35-4.49(3H，m)，6.97-7.08(2H，m)，7.22-7.29(2H，m)，8.40(1H，d，J＝8.7Hz)，8.58(1H，s)

Step 5

To the compound that derives from step 4 (3.86g, add in 6.85mmol) 28% methanol solution of sodium methylate (40.00ml, 0.20mol) and water (2.00ml, 0.11mol), and with reaction mixture reflux 5.5 hours.After treating this mixture cooling,, in the gained residuum, add 6N hydrochloric acid with the reaction soln concentrating under reduced pressure.Stir this mixture, and with twice of ethyl acetate extraction.Organic layer is water and saturated brine washing successively, uses dried over mgso, filters and concentrating under reduced pressure.The gained residuum obtains target product (2.03g, yield 68%) with ethanol (200ml) recrystallization, and it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.87(3H，t，J＝7.3Hz)，1.80-2.10(2H，m)，3.70-3.90(2H，m)，4.02(3H，s)，4.11(2H，s)，5.00-5.19(2H，m)，7.16-7.24(2H，m)，7.44-7.48(2H，m)，8.04(1H，s)，8.78(1H，s)，15.44(1H，s)

MS(ESI)：M+434

Embodiment 3-75

Step 1

With 2-fluoro-5-iodo-benzoic acid (6.60g, 24.81mmol) be dissolved in chloroform (70ml) and add oxalyl chloride (4.30ml, 49.29mmol) and dimethyl formamide (catalytic amount).This mixture was at room temperature stirred 3 hours.With the reaction soln concentrating under reduced pressure, and add chloroform (35ml) with the dissolving residuum.The gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (4.26g, 29.75mmol) and triethylamine (5.19ml in chloroform 37.24mmol) (35ml) solution, and at room temperature stirred this mixture 15 hours.Add water to distribute reaction soln, organic layer washs with saturated brine, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 2 to 1: 1), obtain target product (6.40g, yield 66%), it is the orange solids mixture of E type and Z type.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：0.94(3H，t，J＝7.2Hz)，2.88(3H，brs)，3.31(3H，brs)，3.97(2H，q)，6.78(1H，dd，J＝8.4，10.0Hz)，7.65-7.67(1H，m)，7.78(1H，s)，7，85(1H，brs)

MS(ESI)：M+392

Step 2

With derive from step 1 compound (300mg, 0.77mmol) be dissolved in tetrahydrofuran (THF) (1.5ml) and add (S)-(+)-uncle's leucinol (0.12ml, 0.92mmol).With mixture 60 ℃ of following heated and stirred 1 hour.With the reaction soln concentrating under reduced pressure, and the gained residuum is dissolved in dimethyl formamide (1.2ml).Add salt of wormwood (318mg, 2.30mmol) and with this mixture 70 ℃ of following heated and stirred 5.5 hours.After the cooling, in reaction mixture, add 1N hydrochloric acid (5ml), and this mixture was stirred 30 minutes down ice-cooled.Filter the collecting precipitation thing, the gained solid is used hexane then with 30% aqueous ethanolic solution (6ml) washing: the also vacuum-drying of mixture (5ml) washing of ether=2: 1, obtain target product (276mg, yield 81%), and it is a faint yellow solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.98(9H，s)，1.41(3H，t，J＝7.0Hz)，4.25-4.41(4H，m)，4.64-4.70(1H，m)，5.14(1H，br)，7.46(1H，d，J＝9.0Hz)，7.89(1H，dd，J＝2.2，9.1Hz)，8.06(1H，d，J＝2.1Hz)，8.69(1H，s)

Step 3

With derive from step 2 compound (276mg, 0.62mmol) be dissolved in dimethyl formamide (1ml) and add imidazoles (51mg, 0.75mmol) and tert-butyldimethylsilyl chloride (122mg, 0.81mmol).This mixture was at room temperature stirred 30 minutes.Add water to reaction mixture, and with this mixture twice of ethyl acetate extraction, organic layer washes twice with water, carry out drying then with the saturated brine washing, and by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=3: 5), obtain target product (314mg, yield 91%), it is the amorphous substance of white.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.09(3H，s)，-0.01(3H，s)，0.66(9H，s)，1.04(9H，s)，1.41(3H，t，J＝7.2Hz)，4.10-4.14(2H，m)，4.40(2H，q，J＝7.0Hz)，4.58-4.63(1H，m)，7.39(1H，d，J＝9.3Hz)，7.89(1H，dd，J＝2.2，8.8Hz)，8.67(1H，s)，8.87(1H，d，J＝2.1Hz)

Step 4

With derive from step 3 compound (314mg 0.56mmol) is dissolved in tetrahydrofuran (THF) (1.2ml), and under argon gas stream, add two (dibenzalacetones) close palladium (0) (16mg, 0.028mmol) and three (2-furyl) phosphine (13mg, 0.056mmol).Drip the tetrahydrofuran solution of the 3-chloro-2-luorobenzyl bromination zinc (1.13mmol) for preparing previously.After being added dropwise to complete, with mixture 50 ℃ of following heated and stirred 1.5 hours.After treating this mixture cooling, in reaction soln, add water and ethyl acetate, and stir this mixture.Leach insolubles by Sai Lite diatomite.Distribute filtrate, organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 1), obtain target product (283mg, yield 87%), it is brown amorphous substance.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.11(3H，s)，-0.01(3H，s)，0.63(9H，s)，1.06(9H，s)，1.41(3H，t，J＝7.0Hz)，4.08-4.16(4H，m)，4.38(2H，q，J＝7.0Hz)，4.61-4.67(1H，m)，6.95-7.08(2H，m)，7.23-7.27(1H，m)，7.47-7.49(1H，m)，7.53-7.55(1H，m)，8.41(1H，d，J＝2.0Hz)，8.68(1H，s)

Step 5

With derive from step 4 compound (283mg, 0.49mmol) be dissolved in ethanol (2ml) and add the 1N aqueous sodium hydroxide solution (1.00ml, 1.00mmol).With reaction mixture reflux 1 hour.After treating this mixture cooling, in reaction soln, add acetate (0.35ml) and stir this mixture.Filter the collecting precipitation thing, and with this solid suspension in ether (10ml).After the filtration, this mixture of vacuum-drying obtains target product (157mg, yield 74%), and it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.00(9H，s)，4.07-4.12(2H，m)，4.30(2H，s)，5.12-5.14(2H，m)，7.20-7.25(1H，m)，7.40-7.45(1H，m)，7.51-7.53(1H，m)，7.87(1H，d)，8.25(1H，s)，8.41(1H，d，J＝9.2Hz)，8.85(1H，s)，15.20-15.21(1H，br)

MS(ESI)：M+432

Embodiment 4-20

Step 1

With 2-chloro-4-hydroxy-benzoic acid (5.18g 30.02mmol) is dissolved in trifluoromethanesulfonic acid (25g), and 0 ℃ down by part ground add a N-iodosuccinimide (6.75g, 30.00mmol).This mixture is at room temperature stirred 15 hours, and add trifluoromethanesulfonic acid (25g) again.0 ℃ down by part ground add a N-iodosuccinimide (2.02g, 8.98mmol).This mixture was at room temperature stirred 13.5 hours, and reaction mixture is added in the frozen water (300ml).This mixture was stirred 2 hours.By filtering collecting precipitation, wash with water and vacuum-drying, obtain target product, it is 2-chloro-4-hydroxyl-5-iodo-benzoic acid and 2-chloro-3, the mixture (5.76g) of 5-two iodo-4-hydroxy-benzoic acids (8: 2).

Step 2

The mixture (3.89g) that derives from step 1 is dissolved in dimethyl formamide (20ml), and add salt of wormwood (8.97g, 64.90mmol) and isopropyl iodide (6.50ml, 65.15mmol).With this mixture 80 ℃ of following heated and stirred 2.5 hours.Reaction mixture is added in the 1N hydrochloric acid (100ml), and further adds toluene (100ml).Stir this mixture and leach insolubles by the diatom body.Distribute filtrate, organic layer washes with water 3 times, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (ethyl acetate: hexane=1: 9), obtain the mixture (4.08g) of target product through silica gel chromatography.

Step 3

The mixture (4.08g) that derives from step 2 is dissolved in ethanol (20ml) and add the 1N aqueous sodium hydroxide solution (20.00ml, 20.00mmol).With reaction mixture reflux 24 hours.After treating this mixture cooling, in reaction soln, add 1N hydrochloric acid (30ml) and stir this mixture.Ethyl acetate extraction 3 times of this mixture.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrating under reduced pressure obtains the mixture (3.40g) of target product.

Step 4

The mixture (3.40g) that derives from step 3 is dissolved in toluene (35ml) and add thionyl chloride (3.40ml, 46.61mmol) and dimethyl formamide (catalytic amount).With reaction mixture reflux 1.5 hours.With the reaction soln concentrating under reduced pressure, and add tetrahydrofuran (THF) (25ml) with the dissolving residuum.The gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (4.29g, 30.00mmol) and triethylamine (4.17ml in tetrahydrofuran (THF) 30.00mmol) (10ml) solution, and refluxes this mixture heating up 14 hours.After treating this mixture cooling, in reaction mixture, add entry and ethyl acetate, stir this mixture and distribution.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (ethyl acetate: hexane=1: 1.5 to 1.5: 1), obtain the mixture (2.71g) of target product through silica gel chromatography.

Step 5

The mixture (300mg) that derives from step 4 is dissolved in tetrahydrofuran (THF) (2ml), and adding (S)-(+)-uncle's leucinol (0.10ml, 0.77mmol).With reaction mixture reflux 20 minutes.After treating the cooling of this mixture,, and the gained residuum is dissolved in dimethyl formamide (4ml) with the reaction soln concentrating under reduced pressure.Add imidazoles (110mg, 1.61mmol) and tert-butyldimethylsilyl chloride (214mg 1.42mmol), and at room temperature stirred this mixture 20 minutes.Add water to reaction soln and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (ethyl acetate: hexane=1: 4), obtain the mixture (391mg) of target product through silica gel chromatography.

Step 6

With the mixture (391mg) that derives from step 5 be dissolved in toluene (5ml) and ice-cooled add down sodium hydride (29mg, 0.73mmol).This mixture is at room temperature stirred 30 minutes, and in reaction mixture, adds dimethyl formamide (3ml), salt of wormwood (100mg, 0.72mmol) and iodoethane (0.058ml, 0.73mmol).With mixture 60 ℃ of following heated and stirred 30 minutes.After treating this mixture cooling, reaction mixture is added in the frozen water.Add 1N hydrochloric acid with neutralization, and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate gained residuum carries out purifying through silica gel chromatography (ethyl acetate: hexane=4: 5 to 2: 1), obtain target product (258mg, yield 19%), it is the yellowish white solid.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.09(3H，s)，0.00(3H，s)，0.67(9H，s)，1.05(9H，s)，1.40(3H，t，J＝7.1Hz)，1.46(6H，d，J＝6.0Hz)，4.09-4.20(2H，m)，4.39(2H，q，J＝7.1Hz)，4.43-4.49(1H，m)，4.61-4.69(1H，m)，6.87(1H，s)，8.60(1H，s)，8.94(1H，s)

Step 7

To derive from 1 of step 6,4-dihydro-1-{2,2-dimethyl-1-[(t-butyldimethylsilyloxy base) methyl] propyl group }-(258mg 0.42mmol) is dissolved in tetrahydrofuran (THF) (5ml) to 6-iodo-7-isopropoxy-4-oxo-3-quinoline carboxylic acid ethyl ester.Under nitrogen gas stream, add two (dibenzalacetones) and close palladium (0) (9.7mg, 0.017mmol) and three (2-furyl) phosphine (7.8mg, 0.034mmol), and at 60 ℃ of tetrahydrofuran solutions that drip the 3-chloro-2-luorobenzyl bromination zinc (0.63mmol) for preparing previously down.After being added dropwise to complete, with reaction mixture reflux 1 hour.After treating this mixture cooling, in reaction soln, add saturated aqueous ammonium chloride solution, stir this mixture, and filter by Sai Lite diatomite.In filtrate, add water, and use ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum by silica gel chromatography (ethyl acetate: purifying roughly hexane=1: 1 to 2: 1), obtain the product (216mg) of rough purifying, it is flaxen oily matter.

Step 8

The product (216mg) that derives from the rough purifying of step 7 is dissolved in the mixture of ethanol (2ml) and tetrahydrofuran (THF) (1ml), add the 1N aqueous sodium hydroxide solution (2.00ml, 2.00mmol).With reaction mixture reflux 1 hour.After treating this mixture cooling, in reaction soln, add 10% aqueous citric acid solution, and stir this mixture.This mixture ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure.The residuum mixture process of ether and hexane.After the filtration, the vacuum-drying solid obtains target product (140mg, yield 68%), and it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.97(9H，s)，1.18(3H，d，J＝5.9Hz)，1.26(3H，d，J＝6.0Hz)，4.04-4.09(4H，m)，5.09-5.13(3H，m)，7.12-7.21(2H，m)，7.43-7.51(2H，m)，8.19(1H，s)，8.78(1H，s)，15.46(1H，s)

MS(ESI)：M+490

Embodiment 4-32

Step 1

With 2,4-two fluoro-5-iodo-benzoic acids (650.57g 2.29mol) is dissolved in toluene (1300ml), and add thionyl chloride (184ml, 2.52mol) and dimethyl formamide (catalytic amount).This mixture was stirred 2 hours down at 90 ℃.After treating this mixture cooling, the concentrating under reduced pressure reaction soln.Residuum is dissolved in toluene (330ml), and concentrating under reduced pressure repeats once more then.Residuum is dissolved in toluene (690ml), and the gained drips of solution is added to 3, and 3-dimethylamino ethyl propenoate (361.52g, 2.525mol) and diisopropyl ethyl amine (480ml, 2.75mol) toluene (690ml) solution in, with this mixture 90 ℃ of following heated and stirred 3 hours.After treating the cooling of this mixture, (260.00g 2.52mol), and at room temperature stirred this mixture 1 hour to add (S)-(+)-valerian ammonia alcohol (valinol) in reaction mixture.In reaction mixture, add water (2600ml), and distribute this mixture.Water layer extracts with toluene (680ml).Merge organic layer, water (2000ml) washed twice, and carry out drying by sodium sulfate.After the filtration, concentrating under reduced pressure obtains crude product (1180g), and it is a brown oil.

Step 2

The crude product (1180g) that derives from step 1 is dissolved in dimethyl formamide (2500ml), and the salt of wormwood of adding fine grinding (292.00g, 1.06mol).This mixture was at room temperature stirred 22 hours.Reaction mixture is added in the frozen water (ca.10L), and stirred this mixture 30 minutes.Filter the collecting precipitation thing, and water (2000ml) washing.The gained solid carries out vacuum-drying, and is suspended in the ethyl acetate (5000ml).Filter and vacuum-drying, obtain target product (774.63g, yield 82%), it is a 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)

MS(ESI)：M+448

Step 3

With derive from step 2 compound (626.15g 1.40mol) is dissolved in chloroform (1250ml), and add pyridine (433ml, 5.60mol) and 4-(dimethylamino) pyridine (17.10g, 0.14mol).Under 10 ℃ or lower temperature, drip methyl-chloroformate (529.30g, chloroform 5.60mol) (1250ml) solution.After being added dropwise to complete, this mixture was stirred 30 minutes under uniform temp.Reaction mixture is water (1250ml) successively, 2N hydrochloric acid (1250ml), and water (630ml) and saturated sodium bicarbonate aqueous solution (630ml) wash, and carry out drying by sodium sulfate.After the filtration, the concentrating under reduced pressure residuum obtains thick target product (834.02g), and it is a brown oil.

Step 4

(3-chloro-2-luorobenzyl bromination zinc Preparation of lithium triethylborohydride)

Under nitrogen gas stream, with zinc powder (113.02g 1.73mol) is suspended in the tetrahydrofuran (THF) (350ml), and 60 ℃ add down glycol dibromides (1.207ml, 14.00mmol) and trimethylsilyl chloride (8.88ml, 70.00mmol).To stir 30 minutes under the mixture heating up.Drip 3-chloro-2-fluoro benzyl bromide (406.73g, tetrahydrofuran (THF) 1.82mol) (700ml) solution down at 60 ℃.This mixture heating up was stirred 1 hour, obtain 3-chloro-2-luorobenzyl bromination zinc solution.

(main step)

The crude product (834.02g) that derives from step 3 is dissolved in tetrahydrofuran (THF) (1060ml), under argon gas stream, add dichloro two (triphenylphosphine) and close palladium (II) (19.65g, 28.00mmol), and under 60 ℃, drip 3-chloro-2-luorobenzyl bromination zinc (1.82mol) solution.After being added dropwise to complete, with reaction mixture reflux 1.5 hours.After treating this mixture cooling, in reaction soln, add toluene (2120ml) and 20% aqueous ammonium chloride solution (1410ml), stir this mixture and distribution.Organic layer is with 20% aqueous ammonium chloride solution (710ml) washed twice, and with saturated sodium bicarbonate aqueous solution (710ml) washed twice, carries out drying with sal epsom.After the filtration, under reduced pressure concentrated filtrate obtains crude product (849.34g), and it is a brown oil.

Step 5

The crude product (849.34g) that derives from step 4 is dissolved in Virahol (1100ml) and add the 4N aqueous sodium hydroxide solution (1050ml, 4.20mmol).Mixture was stirred 1.5 hours under 50 ℃ of heating.In reaction soln, add activated carbon (37g), and this mixture was at room temperature stirred 30 minutes.By this mixture of Sai Lite diatomite filtration, and in filtrate, add 6N hydrochloric acid (740ml) and ethyl acetate (3650ml).Stir this mixture and distribution.The concentrating under reduced pressure organic layer, and residuum is suspended in Virahol (1070ml).This mixture was stirred 1 hour down at 60 ℃.After treating this mixture cooling, pass through solid collected by filtration.The gained solid obtains target product (446.51g, yield 73%) with Virahol (740ml) washing and vacuum-drying, and it is a faint yellow solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.71(3H，d，J＝6.5Hz)，1.13(3H，d，J＝6.5Hz)，2.36(1H，br)，3.77(1H，br)，3.94(1H，br)，4.25(2H，s)，4.77(1H，br)，5.16(1H，t，J＝2.4Hz)，7.19-7.23(1H，m)，7.32-7.35(1H，m)，7.48-7.52(1H，m)，8.24-8.28(2H，m)，9.00(1H，s)，15.00(1H，s)

MS(ESI)：M+436

Step 6

With derive from step 5 compound (443.59g 1.02mol) is dissolved in methyl alcohol (2400ml), and add 28% methanol solution of sodium methylate (2077ml, 10.17mol) and water (44.30ml, 2.46mol).With reaction mixture reflux 17.5 hours.In reaction soln, add activated carbon (22g), and this mixture was at room temperature stirred 1 hour.By this mixture of Sai Lite diatomite filtration, and concentrated filtrate under reduced pressure.Add water (1770ml) to residuum, and this mixture was stirred 1 hour down ice-cooled.Then, add 6N hydrochloric acid (1790ml) again, and this mixture was at room temperature stirred 2 hours.Add ethyl acetate (1770ml), stir this mixture and distribution.Organic layer is with 10% salt solution (890ml) washed twice, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and part residuum recrystallization is (last recrystallization solvent is a methanol-water) several times, obtains target product (28.60g, yield 67%), and it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：?0.72(3H，d，J＝6.5Hz)，1.16(3H，d，J＝6.5Hz)，2.30-2.50(1H，m)，3.70-3.90(1H，m)，3.90-4.00(1H，m)，4.03(3H，s)，4.12(2H，s)，4.80-4.90(1H，m)，5.19(1H，t，J＝5.2Hz)，7.19-7.25(2H，m)，7.46-7.51(2H，m)，8.04(1H，s)，8.88(1H，s)，15.44(1H，s)

MS(ESI)：M+448

Embodiment 4-33

Step 1

With 2,4 difluorobenzene formic acid (600.00g 3.80mol) is dissolved in the vitriol oil (2400ml), and under 5 ℃ or lower temperature, by part ground add a N-iodosuccinimide (854.40g, 3.60mol).After being added dropwise to complete, this mixture was stirred 3 hours under uniform temp.Pour into reaction mixture in the frozen water (about 10L) and add 10% sodium sulfite aqueous solution (40ml).This mixture was stirred 30 minutes.Filter the collecting precipitation thing.Be suspended in water (about 3L) neutralization and filter, becoming until the pH of filtrate is not less than till 3.The wet solid (1677g) of gained obtains target product (824.70g, yield 76%) with 50% aqueous ethanolic solution (3000ml) recrystallization, and it is a white solid.

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

Step 2

With derive from step 1 compound (150.00g 0.53mol) is dissolved in ethyl acetate (750ml), and add oxalyl chloride (51.0ml, 0.581mol) and dimethyl formamide (catalytic amount).This mixture was at room temperature stirred 3.5 hours.After the filtering reacting solution, concentrated filtrate under reduced pressure.Residuum is dissolved in toluene (150ml) afterwards, with this mixture concentrating under reduced pressure, repeats once again.Add tetrahydrofuran (THF) (300ml) with the dissolving residuum, and the gained drips of solution be added to 3,3-dimethylamino ethyl propenoate (83.2g, 0.581mol) and triethylamine (96ml is in tetrahydrofuran (THF) 0.686mol) (450ml) solution.With reaction mixture reflux 15 hours.After treating the cooling of this mixture, filter reaction mixture, and concentrated filtrate under reduced pressure.Add ethyl acetate (750ml) with the dissolving residuum.This mixture is used aqueous ammonium chloride solution (400ml) successively, and saturated sodium bicarbonate aqueous solution (200ml) and saturated brine wash, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains thick target product (206.50g), and it is a brown oil.

Step 3

The crude product (206.50g) that derives from step 2 is dissolved in tetrahydrofuran (THF) (800ml), and add (S)-(+)-uncle's leucinol hydrochloride (81.10g, 0.53mol) and triethylamine (74ml, 0.53mol).This mixture was at room temperature stirred 50 minutes.After the filter reaction mixture, concentrated filtrate under reduced pressure, and the gained residuum is dissolved in dimethyl formamide (1000ml).(146.0g 1.06mol), and stirs mixture 3 hours under 90 ℃ of heating to add salt of wormwood.Add water (700ml) to reaction mixture down ice-cooled, filter the collecting precipitation thing, and wash with water.Solid suspension that filter to collect in 30% aqueous ethanolic solution (1000ml), and is collected by filtering.Use hexane: the mixture of ether=1: 1 repeats this operation.After the filtration, with filtrate vacuum-drying, obtain target product (184.74g, yield 76%), it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm?0.968(9H，s)，1.27(3H，t)，3.96-3.98(2H，m)，4.18-4.27(2H，m)，4.80(1H，t，J＝7.0Hz)，5.05(1H，br)，8.22(1H，d，J＝11.2Hz)，8.60(1H，s)，8.61(1H.d，J＝7.2Hz)

Step 4

With derive from step 3 compound (150.00g 0.33mol) is dissolved in dimethyl formamide (600ml), and add imidazoles (28.80g, 0.42mol) and tert-butyldimethylsilyl chloride (28.80g, 0.42mol).This mixture was at room temperature stirred 6 hours.Add water (1200ml) to reaction mixture, and extract with ethyl acetate (800ml).Organic layer washes with water three times, carries out drying then with the saturated brine washing, and by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 3 to 1: 2), obtain target product (164.30g, yield 88%), it is the amorphous substance of white.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.08(3H，s)，0.00(3H，s)，0.67(9H，s)，1.06(9H，s)，1.41(3H，t，J＝7.1Hz)，4.05-4.18(2H，m)，4.36-4.43(3H，m)，7.32(1H，d，J＝10.3Hz)，8.65(1H，s)，8.95(1H，d，J＝7.4Hz)

Step 5

(75.0g 0.13mol) is dissolved in tetrahydrofuran (THF) (580ml) with the compound that derives from step 4.Under nitrogen gas stream, add two (dibenzalacetones) close palladium (0) (2.99g, 5.20mmol) and three (2-furyl) phosphine (2.41g, 10.38mmol), and in 60 ℃ of tetrahydrofuran solutions that drip 3-chloro-2-luorobenzyl bromination zinc (0.17mol) down.After being added dropwise to complete, with reaction mixture reflux 2 hours.After treating this mixture cooling, ethyl acetate (75ml) and saturated aqueous ammonium chloride solution (38ml) are added in the reaction soln.This mixture was at room temperature stirred 30 minutes and distribution.Organic layer water (75ml) washed twice is used saturated brine (200ml) washing then, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 2 to 1: 1), obtain target product (66.80g, yield 73%), it is brown amorphous substance.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：-0.10(3H，s)，-0.01(3H，s)，0.64(9H，s)，1.06(9H，s)，1.40(3H，t，J＝7.1Hz)，4.04-4.15(4H，m)，4.35-4.46(3H，m)，6.95-7.03(2H，m)，7.24-7.31(2H，m)，8.38(1H，d，J＝8.8Hz)，8.66(1H，s)

Step 6

With derive from step 5 compound (2.41g 4.07mmol) is dissolved in methyl alcohol (20ml), and add 28% methanol solution of sodium methylate (8.4ml, 40.70mmol) and water (0.15ml, 8.14mmol).With reaction mixture reflux 18 hours.Add water (1.4ml) to reaction soln, and this mixture was at room temperature stirred 1.5 hours, and filter by Sai Lite diatomite.Under reduced pressure concentrated filtrate adds water (25ml) and 2N hydrochloric acid (20ml) to residuum.This mixture was stirred 5 minutes and use ethyl acetate extraction.Organic layer water and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure.Residuum carries out ultrasonication with hexane (20ml), after leaving standstill, removes hexane by decantation.Repeat this operation three times.(30ml) is added in the residuum with ether, and this mixture is carried out ultrasonication.By solid collected by filtration, and by the heating gained solid is dissolved in ethyl acetate (15ml).Add hexane (15ml) and carry out recrystallization, obtain target product (1.21g, yield 64%), it is a white solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.99(9H，s)，3.99-4.11(7H，m)，5.11-5.20(2H，m)，7.19-7.25(2H，m)，7.49-7.52(2H，m)，8.03(1H，s)，8.78(1H，s)，15.39(1H，s)

MS(ESI)：M+462

Embodiment 4-37

Step 1

With 3-methoxyl group-2-nitrobenzoic acid (20.00g 0.10mol) is dissolved in dimethyl formamide (100ml), and add salt of wormwood (28.10g, 0.20mol) and methyl iodide (7.60ml, 0.12mol).This mixture was at room temperature stirred 1 hour.Reaction mixture is added in the water (300ml), and stirs this mixture.By filtering collecting precipitation, water (200ml) washing and vacuum-drying obtain thick target product (23.90g), and it is a white solid.

Step 2

The crude product (23.90g) that derives from step 1 is suspended in the mixture of tetrahydrofuran (THF) (150ml) and methyl alcohol (50ml), and adds palladium-carbon (wet) of 5% (2.30g).This mixture was stirred 19.5 hours under nitrogen atmosphere and room temperature.Add ethyl acetate (200ml) to reaction mixture, and by this mixture of Sai Lite diatomite filtration.Concentrated filtrate under reduced pressure, and, obtain crude product (18.80g) by using the methylbenzene azeotropic dephlegmate, it is a brown oil.

Step 3

The crude product (18.80g) that derives from step 2 is dissolved in dimethyl formamide (200ml), and add a N-bromine succinimide (17.98g, 0.10mol). with under 5 ℃, pursuing partAfter being added dropwise to complete, this mixture was stirred 30 minutes under uniform temp.Reaction mixture is poured in the water (500ml) also with ethyl acetate (300ml) extracting twice.Organic layer is water (300ml) successively, and saturated sodium bicarbonate aqueous solution and saturated brine wash, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying (chloroform) through silica gel chromatography, obtains target product (25.11g, yield 95%), and it is a yellow oil.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm?3.86(6H，s)，6.02(2H，brs)，6.90(1H，s)，7.60(1H，s)

Step 4

(25.11g 96.54mmol) is suspended in the water (50ml) and adds concentrated hydrochloric acid (25ml) with the compound that derives from step 3.Drip Sodium Nitrite (7.33g, aqueous solution 106.22mmol) (100ml) down at 5 ℃.After being added dropwise to complete, this mixture was stirred 5 minutes under uniform temp.Under the room temperature, this reaction soln is added drop-wise to cuprous chloride (I), and (9.55g is 96.47mmol) in the solution in concentrated hydrochloric acid (75ml).After being added dropwise to complete, this mixture was at room temperature stirred 13 hours.Add water (200ml) to reaction soln, and extract with ethyl acetate (400ml).Organic layer is water (400ml) and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains target product (15.18g, yield 56%), and it is an orange solids.

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：3.92(3H，s)，3.93(3H，s)，7.16(1H，d，J＝2.1Hz)，7.49(1H，d，J＝2.2Hz)

Step 5

With derive from step 4 compound (74.80g 0.27mol) is dissolved in methylene dichloride (300ml), and under 10 ℃ or lower temperature, drip 1M boron tribromide/dichloromethane solution (700ml, 0.70mol).After being added dropwise to complete, this mixture was at room temperature stirred 1.5 hours.Reaction mixture is added in the frozen water (1500ml), and filters the solid of collecting precipitation.Distribute filtrate, water layer extracts with ethyl acetate (200ml).Merge organic layer and concentrating under reduced pressure.Be dissolved in ether (1000ml) with filtering solid and the residuum collected, and adding 1N aqueous sodium hydroxide solution (1000ml) extracts.Add 2N hydrochloric acid (500ml) to water layer.Stir this mixture and use ethyl acetate (800ml) extraction.Distribute this mixture, organic layer is water and saturated brine washing successively, uses dried over sodium sulfate, filter, and concentrating under reduced pressure, obtaining target product (63.83g, yield 95%), it is a beige solid.

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：7.23(1H，d，J＝2.4Hz)，7.28(1H，d，J＝2.4Hz)，10.99(1H，s)，13.55(1H，brs)

Step 6

With derive from step 5 compound (63.83g 0.25mol) is dissolved in dimethyl formamide (400ml), and add salt of wormwood (87.70g, 0.64mol) and iodoethane (81.20ml, 1.02mol).Mixture was stirred 3 hours under 50 ℃ of heating, and saturated aqueous ammonium chloride solution (600ml) and ethyl acetate (400ml) are added in the reaction mixture.Distribute this mixture, water layer extracts with ethyl acetate (400ml).Merge organic layer, and use salt solution (3 times) and saturated brine washing successively, use dried over sodium sulfate, filter, and concentrating under reduced pressure, obtaining target product (76.38g, yield 98%), it is a brown solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.39(3H，t，J＝7.2Hz)，1.48(3H，t)，4.11(2H，q)，4.38(2H，q，J＝7.2Hz)，7.12(1H，d，J＝2.0Hz)，7.42(1H，d，J＝2.0Hz)

Step 7

With derive from step 6 compound (76.38g 0.25mol) is dissolved in ethanol (250ml), and add the 8N aqueous sodium hydroxide solution (62.00ml, 0.50mol).Mixture was stirred 30 minutes under 50 ℃ of heating.Under cooling, (250ml) is added in the reaction soln with 2N hydrochloric acid, stirs this mixture, and with ethyl acetate (350ml) extracting twice.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains target product (68.79g, yield 99%), and it is the light brown solid.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：1.50(3H，t，J＝6.8Hz)，4.12(2H，q，J＝6.8Hz)，7.19(1H，d，J＝2.4Hz)，7.65(1H，d，J＝2.4Hz)

Step 8

With derive from step 7 compound (85.17g 0.31mol) is dissolved in toluene (450ml), and add thionyl chloride (44.40ml, 0.61mol) and dimethyl formamide (catalytic amount).This mixture was stirred 1 hour down at 90 ℃.After treating this mixture cooling, this reaction soln of concentrating under reduced pressure.Treat residuum is dissolved in after the toluene, with this mixture concentrating under reduced pressure.This operation repeats twice or repeatedly.Residuum is dissolved in tetrahydrofuran (THF) (250ml), and the gained drips of solution is added to 3,3-dimethylamino ethyl propenoate (43.60g, 0.31mol) and triethylamine (50.90ml is in tetrahydrofuran (THF) 0.37mol) (200ml) solution.With reaction mixture reflux 15 hours.After treating this mixture cooling, water (300ml) and ethyl acetate (500ml) are added in the reaction mixture.Stir this mixture and distribution.Organic layer is water (300ml) and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains thick target product (124.80g), and it is a brown oil.

Step 9

The crude product (124.80g) that derives from step 8 is dissolved in tetrahydrofuran (THF) (500ml), and add (S)-(+)-uncle's leucinol hydrochloride (46.80g, 0.31mol) and triethylamine (42.50ml, 0.31mol).This mixture was at room temperature stirred 40 minutes.After the filter reaction mixture, concentrated filtrate under reduced pressure.The gained residuum is dissolved in ethyl acetate (800ml), washes twice with water, carry out drying then with the saturated brine washing, and by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains thick target product (131.30g), and it is a brown oil.

Step 10

The crude product (131.30g) that derives from step 9 is dissolved in dimethyl formamide (400ml), and add imidazoles (27.00g, 0.40mol) and tert-butyldimethylsilyl chloride (41.30g, 0.27mol).This mixture was at room temperature stirred 14 hours.Add water to reaction soln, and extract this mixture twice with ethyl acetate (500ml).Organic layer washes with water three times, carries out drying then with the saturated brine washing, and by sodium sulfate.After the filtration, under reduced pressure concentrated filtrate obtains target product (159.80g), and it is a brown oil.

Step 11

The crude product (159.80g) that derives from step 10 is dissolved in toluene (1100ml), and the adding sodium hydride (15.80g, 0.40mol).Mixture was stirred 14 hours under 100 ℃ of heating.In reaction soln, add 1N hydrochloric acid (400ml) down ice-cooled, stir this mixture and distribution.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and the gained residuum is dissolved in dimethyl formamide (500ml).Add salt of wormwood (42.10g, 0.31mol) and iodoethane (24.40ml 0.31mol), and stirs mixture 1.5 hours under 50 ℃ of heating.Down in reaction soln, add saturated aqueous ammonium chloride solution (400ml) ice-cooled, stir this mixture, and with twice of ethyl acetate extraction.Organic layer washes with water successively, with salt solution and saturated brine washed twice, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 3 to 2: 3), obtain target product (76.50g, yield 45%), it is a brown oil.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.05(3H，s)，0.01(3H，s)，0.73(9H，s)，0.98(9H，s)，1.40(3H，t)，1.53-1.59(3H，m)，4.10-4.24(4H，m)，4.34-4.44(2H，m)，6.10-6.14(1H，m)，7.22(1H，s)，8.32(1H，t，J＝2.4Hz)，8.70(1H，s)

Step 12

With derive from step 11 compound (76.50g 0.14mol) is dissolved in tetrahydrofuran (THF) (500ml), and under nitrogen gas stream, add two (dibenzalacetones) close palladium (0) (3.17g, 5.51mmol) and three (2-furyl) phosphine (2.56g, 11.03mmol).Under 60 ℃, drip the tetrahydrofuran solution of 3-chloro-2-luorobenzyl bromination zinc (0.28mol).After being added dropwise to complete, with reaction mixture reflux 2.5 hours.After treating this mixture cooling, (600ml) is added in the reaction soln with saturated aqueous ammonium chloride solution.This mixture is at room temperature stirred 1 hour, and use the Sai Lite diatomite filtration.Distribute after this mixture twice of ethyl acetate extraction of water layer.On the other hand, the concentrating under reduced pressure organic layer, and residuum is dissolved in ethyl acetate.Merge all ethyl acetate layers, and, carry out drying by sodium sulfate successively with 1N hydrochloric acid and saturated brine washing.After the filtration, concentrated filtrate under reduced pressure.The gained residuum is dissolved in dimethyl formamide (400ml), and add salt of wormwood (19.00g, 0.14mol) and iodoethane (11.00ml, 0.14mol).This mixture was stirred 1.5 hours under 50 ℃ of heating.Down saturated aqueous ammonium chloride solution (400ml) is added in the reaction mixture ice-cooled, stirs this mixture and use ethyl acetate (500ml) extraction.Organic layer water, salt solution (twice) and saturated brine wash, and carry out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, the gained residuum carries out purifying through silica gel chromatography, and (ethyl acetate: hexane=1: 2 to 1: 1), obtain target product (72.10g, yield 85%), it is a brown oil.

¹H?NMR(CDCl ₃?400MHz)(δ)ppm：-0.07(3H，s)，0.00(3H，s)，0.70(9H，s)，1.24(9H，s)，1.39(3H，t，J＝7.2Hz)，1.51-1.54(3H，m)，4.05(2H，s)，4.07-4.19(4H，m)，4.33-4.45(2H，m)，6.12-6.15(1H，m)，6.99-7.02(2H，m)，7.04-7.09(1H，m)，7.19-7.25(1H，m)，8.06(1H，d，J＝2.4Hz)，8.69(1H，s)

Step 13

With derive from step 12 compound (65.80g, 0.11mol) be dissolved in ethanol (200ml) and add the 1N aqueous sodium hydroxide solution (640ml, 0.64mol).With reaction mixture reflux 2 hours.Down 2N hydrochloric acid (350ml) is added in the reaction soln ice-cooled, stirs this mixture, and with twice of ethyl acetate extraction.Organic layer is water and saturated brine washing successively, and carries out drying by sodium sulfate.After the filtration, concentrated filtrate under reduced pressure, and in residuum, add ether (500ml).With this mixture of ultrasonication, and filter and collect the gained solid.Collected solid is added in the ethyl acetate (250ml), and passes through heating for dissolving.Add hexane (50ml), filter the solid of collecting precipitation, and vacuum-drying, obtaining target product (41.10g, yield 81%), it is a white solid.

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.93(9H，s)，1.49(3H，t，J＝6.9Hz)，4.00(2H，t，J＝6.4Hz)，4.20(2H，s)，4.22-4.33(2H，m)，5.12(1H，t)，6.36(1H，t，J＝6.8Hz)，7.21(1H，m)，7.39-7.48(2H，m)，7.54(1H，s)，7.79(1H，s)，8.79(1H，s)，15.04(1H，s)

MS(ESI)：M+476

Embodiment 1-3～1-102,2-1～2-8,3-1～3-86,4-1～4-54

According to embodiment 1-1 and 1-2 and the identical method of the foregoing description, obtain embodiment 1-3～1-102,2-1～2-8, the compound of 3-1～3-86 and 4-1～4-54.Its chemical structure is shown in table 1, in 2,3 and 4.

EXPERIMENTAL EXAMPLE

The hiv integrase of estimating compound of the present invention for explanation suppresses active method below.

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

With hiv integrase full-length gene (J.Virol., 67,425-437 (1993)) the 185th phenylalanine replaced with Histidine, and 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.Collect flaky recombination bacillus coli by centrifugation, and in-80 ℃ of following preservations.

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 dilution integrase protein that contains the 1M sodium chloride.

The integrase protein solution that dilutes is put on Superdex 75 (Pharmacia Corporation) pillar carry out gel-filtration.Protein dilutes with the lysis buffer that contains the 1M sodium chloride.

Collect gained integrase protein cut, and in-80 ℃ of following preservations.

The (iii) preparation of dna solution

Be dissolved in TE damping fluid (10mM Tris-hydrochloric acid (pH8.0), 1mM EDTA) with following by Greiner synthetic DNA, and and donor dna, target dna, each complementary strand (+and-chain) is mixed to 1 μ M.This mixture 95 ℃ of heating 5 minutes, 80 ℃ of heating 10 minutes, was added 10 minutes at 70 ℃,,,, and, obtain the double-stranded DNA that is used to test in 25 ℃ of following preservations 40 ℃ of heating 10 minutes 50 ℃ of heating 10 minutes 60 ℃ of heating 10 minutes.

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

Donor+chain: 5 '-vitamin H-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 AAA G-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 ID NO:3)

Target-chain: 5 '-AGT GAA TTA GCC CTT GGT CA-Dig-3 ' (SEQ ID NO:4)

(iv) enzyme (hiv integrase) suppresses active mensuration

Donor dna is diluted to 10nM with the TE damping fluid, gets 50 μ l and be added in each hole of the droplet plate (Roche) that scribbles streptavidin, and make it to adsorb 60 minutes down at 37 ℃.(Dulbecco PBS, Sanko Junyaku Co. is Ltd.) with the phosphate buffered saline buffer washing with the phosphate buffered saline buffer that contains 0.1% polysorbas20 for this DNA.Then, will have the reaction mixture (70 μ l) of following composition, and be added in each hole with the substances (10 μ l) of reaction mixture dilution and the integrase protein (10 μ l) of 100 μ g/ml, and reacted 60 minutes down in 37 ℃.

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

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

Add peroxidase chromophoric solution (Bio Rad, 100 μ l), make it at room temperature to react 4 minutes.By adding the reaction of 1N sulfuric acid (100 μ l) color development stopping.Measure 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).The results are shown in table 5, in 6 and 7.

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 evaluation of antiviral activity

Unite and use the effect of compound of the present invention and known anti-HIV medicament can measure as follows.

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

In addition, also can estimate associating use-testing substance A, zidovudine and lamivudine, perhaps the effect of three kinds of medicaments such as substances A, tynofovir and lamivudine.

Before the associating use-testing, measure the independent IC of each medicament ₅₀And CC ₅₀Unite the combination of the medicament B of medicament A that the Evaluation on effect basis of using two kinds of medicaments is 5 kinds of concentration and 9 kinds of concentration, it is measured according to The above results.For the use of uniting of three kinds of medicaments, the medicament B of high density is mixed with medicament C, and with each the concentration thing that obtained and the medicament A combination of different concns, to estimate.

By Prichard and Shipman MacSynergy II version 2.01 and Delta graphversion 1.5d programs, analyze and to use separately and unite substances and the experimental data of uniting the medicament of use under the service condition.With the confidence level of 95% (or 68%, 99%), by the inhibition percentage ratio under each combination medicament concentration (it is that experiment by triplicate obtains), the drawing three-dimensional graphic representation, and according to the μ M that therefrom calculates ²The numerical value of %, the effect of evaluation associating use.The standard of estimating is as follows.

Interactional definition μ M ²%

High Collaboration＞100

Slight collaborative+51～+ 100

Additive properties+50～-50

Slight antagonism-51～-100

Height antagonism＜-100

Table 1

Table 2

Table 3

Table 4

Table 5

Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)
Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)	????1-1	????0.029	????1-2	????0.033
????1-3	????0.36	????1-4	????0.24	????1-1	????0.029	????1-2	????0.033
????1-3	????0.36	????1-4	????0.24	????1-6	????0.14	????1-7	????0.067
????1-8	????0.046	????1-9	????0.017	????1-6	????0.14	????1-7	????0.067
????1-8	????0.046	????1-9	????0.017	????1-10	????0.072	????1-11	????0.18
????1-12	????0.71	????1-13	????0.14	????1-10	????0.072	????1-11	????0.18
????1-12	????0.71	????1-13	????0.14	????1-14	????0.075	????1-15	????0.23
????1-16	????0.032	????1-17	????0.084	????1-14	????0.075	????1-15	????0.23
????1-16	????0.032	????1-17	????0.084	????1-18	????0.12	????1-19	????0.081
????1-20	????0.69	????1-21	????0.074	????1-18	????0.12	????1-19	????0.081
????1-20	????0.69	????1-21	????0.074	????1-22	????0.11	????1-23	????0.19
????1-24	????0.29	????1-25	????0.16	????1-22	????0.11	????1-23	????0.19
????1-24	????0.29	????1-25	????0.16	????1-26	????0.18	????1-27	????0.076
????1-28	????0.059	????1-29	????0.24	????1-26	????0.18	????1-27	????0.076
????1-28	????0.059	????1-29	????0.24	????1-30	????0.14	????1-31	????0.17
????1-32	????0.068	????1-33	????0.14	????1-30	????0.14	????1-31	????0.17
????1-32	????0.068	????1-33	????0.14	????1-34	????0.35	????1-36	????0.18
????1-37	????0.11	????1-38	????0.17	????1-34	????0.35	????1-36	????0.18
????1-37	????0.11	????1-38	????0.17	????1-39	????0.18	????1-40	????0.11
????1-41	????0.21	????1-42	????0.13	????1-39	????0.18	????1-40	????0.11
????1-41	????0.21	????1-42	????0.13	????1-43	????0.024	????1-44	????0.051

????1-45	????0.21	????1-46	????0.42
????1-45	????0.21	????1-46	????0.42	????1-47	????0.098	????1-48	????0.38
????1-49	????0.053	????1-50	????0.11	????1-47	????0.098	????1-48	????0.38
????1-49	????0.053	????1-50	????0.11	????1-51	????0.18	????1-63	????0.02
????1-64	????0.056	????1-65	????0.12	????1-51	????0.18	????1-63	????0.02
????1-64	????0.056	????1-65	????0.12	????1-66	????0.049	????1-67	????0.79
????1-68	????0.049	????1-69	????0.074	????1-66	????0.049	????1-67	????0.79
????1-68	????0.049	????1-69	????0.074	????1-70	????0.082	????1-71	????0.013
????1-72	????0.025	????1-73	????0.031	????1-70	????0.082	????1-71	????0.013
????1-72	????0.025	????1-73	????0.031	????1-74	????0.098	????1-75	????0.016
????1-76	????0.028	????1-77	????0.063	????1-74	????0.098	????1-75	????0.016
????1-76	????0.028	????1-77	????0.063	????1-78	????0.59	????1-79	????0.077
????1-80	????0.35	????1-86	????0.15	????1-78	????0.59	????1-79	????0.077
????1-80	????0.35	????1-86	????0.15	????1-87	????0.14	????1-88	????0.45
????1-92	????0.28	????1-93	????0.37	????1-87	????0.14	????1-88	????0.45
????1-92	????0.28	????1-93	????0.37	????1-96	????0.23	????1-97	????0.13
????2-1	????0.17	????2-2	????0.18	????1-96	????0.23	????1-97	????0.13
????2-1	????0.17	????2-2	????0.18	????2-3	????0.11	????2-4	????0.018
????2-5	????0.30	????2-6	????0.092	????2-3	????0.11	????2-4	????0.018
????2-5	????0.30	????2-6	????0.092	????2-7	????0.079	????2-8	????0.085

Table 6

Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)
Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)	????3-1	????0.47	????3-2	????0.2
????3-3	????0.19	????3-4	????0.011	????3-1	????0.47	????3-2	????0.2
????3-3	????0.19	????3-4	????0.011	????3-5	????0.024	????3-6	????0.011
????3-8	????0.34	????3-9	????0.084	????3-5	????0.024	????3-6	????0.011
????3-8	????0.34	????3-9	????0.084	????3-10	????0.018	????3-12	????0.016
????3-13	????0.029	????3-14	????0.014	????3-10	????0.018	????3-12	????0.016
????3-13	????0.029	????3-14	????0.014	????3-17	????0.013	????3-20	????0.01
????3-21	????0.03	????3-22	????0.79	????3-17	????0.013	????3-20	????0.01
????3-21	????0.03	????3-22	????0.79	????3-23	????0.0072	????3-24	????0.039
????3-25	????0.069	????3-26	????0.011	????3-23	????0.0072	????3-24	????0.039
????3-25	????0.069	????3-26	????0.011	????3-27	????0.075	????3-33	????0.0087
????3-34	????0.011	????3-35	????0.011	????3-27	????0.075	????3-33	????0.0087
????3-34	????0.011	????3-35	????0.011	????3-36	????0.051	????3-37	????0.011
????3-38	????0.015	????3-39	????0.049	????3-36	????0.051	????3-37	????0.011
????3-38	????0.015	????3-39	????0.049	????3-42	????0.72	????3-43	????0.018

????3-44	????0.0096	????3-45	????0.015
????3-44	????0.0096	????3-45	????0.015	????3-47	????0.0086	????3-48	????0.021
????3-49	????0.0079	????3-50	????0.018	????3-47	????0.0086	????3-48	????0.021
????3-49	????0.0079	????3-50	????0.018	????3-52	????0.012	????3-53	????0.0079
????3-54	????0.0064	????3-55	????0.0087	????3-52	????0.012	????3-53	????0.0079
????3-54	????0.0064	????3-55	????0.0087	????3-56	????0.012	????3-57	????0.015
????3-58	????0.008	????3-59	????0.008	????3-56	????0.012	????3-57	????0.015
????3-58	????0.008	????3-59	????0.008	????3-60	????0.0055	????3-61	????0.0076
????3-62	????0.027	????3-63	????0.017	????3-60	????0.0055	????3-61	????0.0076
????3-62	????0.027	????3-63	????0.017	????3-64	????0.018	????3-65	????0.015
????3-66	????0.048	????3-67	????0.0064	????3-64	????0.018	????3-65	????0.015
????3-66	????0.048	????3-67	????0.0064	????3-69	????0.0043	????3-72	????0.0038
????3-73	????0.0033	????3-74	????0.0049	????3-69	????0.0043	????3-72	????0.0038
????3-73	????0.0033	????3-74	????0.0049	????3-76	????0.0085	????3-77	????0.0089
????3-78	????0.016	????3-79	????0.0067	????3-76	????0.0085	????3-77	????0.0089
????3-78	????0.016	????3-79	????0.0067	????3-80	????0.0088	????3-86	????0.14

Table 7

Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)
Embodiment number	Enzymic activity IC ₅₀????(μM)	Embodiment number	Enzymic activity IC ₅₀????(μM)	????4-1	????0.86	????4-4	????0.55
????4-5	????0.13	????4-6	????0.46	????4-1	????0.86	????4-4	????0.55
????4-5	????0.13	????4-6	????0.46	????4-7	????0.13	????4-8	????0.033
????4-9	????0.021	????4-11	????0.22	????4-7	????0.13	????4-8	????0.033
????4-9	????0.021	????4-11	????0.22	????4-12	????0.065	????4-13	????0.30
????4-15	????0.031	????4-16	????0.0071	????4-12	????0.065	????4-13	????0.30
????4-15	????0.031	????4-16	????0.0071	????4-17	????0.0031	????4-18	????0.0020
????4-19	????0.0029	????4-20	????0.0017	????4-17	????0.0031	????4-18	????0.0020
????4-19	????0.0029	????4-20	????0.0017	????4-21	????0.0045	????4-22	????0.0029
????4-23	????0.0038	????4-24	????0.0025	????4-21	????0.0045	????4-22	????0.0029
????4-23	????0.0038	????4-24	????0.0025	????4-25	????0.0019	????4-26	????0.0015
????4-27	????0.0029	????4-28	????0.0027	????4-25	????0.0019	????4-26	????0.0015
????4-27	????0.0029	????4-28	????0.0027	????4-29	????0.0045	????4-30	????0.0029
????4-31	????0.0021	????4-32	????0.0029	????4-29	????0.0045	????4-30	????0.0029
????4-31	????0.0021	????4-32	????0.0029	????4-33	????0.0020	????4-34	????0.0039
????4-35	????0.0043	????4-36	????0.0037	????4-33	????0.0020	????4-34	????0.0039
????4-35	????0.0043	????4-36	????0.0037	????4-37	????0.0019	????4-38	????0.0033
????4-39	????0.0041	????4-40	????0.0043	????4-37	????0.0019	????4-38	????0.0033
????4-39	????0.0041	????4-40	????0.0043	????4-41	????0.0023	????4-42	????0.0023
????4-43	????0.0028	????4-44	????0.0024	????4-41	????0.0023	????4-42	????0.0023
????4-43	????0.0028	????4-44	????0.0024	????4-45	????0.0034	????4-46	????0.0050
????4-47	????0.0023	????4-48	????0.0030	????4-45	????0.0034	????4-46	????0.0050
????4-47	????0.0023	????4-48	????0.0030	????4-49	????0.0057	????4-50	????0.0031

Above-mentioned table 1 is as follows to the NMR and the MS data of the compound of embodiment shown in the table 4.

Embodiment 1-1

MS(ESI)：M+392

Embodiment 1-2

MS(ESI)：M+409

Embodiment 1-3

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.85(3H，s)，3.41(2H，m)，4.37(2H，s)，4.63(2H，t，J＝5.6Hz)，7.25-7.29(1H，m)，7.39(1H，dd，J＝7.8，7.8Hz)，7.47(1H，dd，J＝1.5，7.7Hz)，7.58(1H，dd，J＝1.5，7.8Hz)，7.84(1H，dd，J＝2.0，8.9Hz)，8.00(1H，d，J＝8.9Hz)，8.15(1H，d，J＝1.8Hz)，8.91(1H，s)

MS(ESI)：M+469

Embodiment 1-4

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.38(2H，s)，4.46(2H，t，J＝5.9Hz)，4.90(2H，t，J＝5.9Hz)，6.84(1H，s)，7.14(1H，s)，7.37-7.47(3H，m)，7.59(1H，m)，7.82(1H，m)，8.01(1H，m)，8.15(1H，s)，8.66(1H，s)，14.99(1H，s)

MS(ESI)：M+441

Embodiment 1-5

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.87(3H，s)，3.12(3H，s)，4.35(2H，s)，5.59(2H，s)，7.38-7.45(2H，m)，7.57(1H，m)，7.71-7.76(2H，m)，8.12(1H，s)，8.94(1H，s)

MS(ESI)：M+432

Embodiment 1-6

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.64(3H，d，J＝4.4)，4.35(2H，s)，5.24(2H，s)，7.35-7.47(2H，m)，7.56-7.65(2H，m)，7.80(1H，m)，8.13(1H，s)，8.32(1H，q，J＝4.4Hz)，9.00(1H，s)

MS(ESI)：M+418

Embodiment 1-7

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.36(2H，s)，5.23(2H，s)，7.35-7.45(2H，m)，7.54-7.65(3H，m)，7.83-7.88(2H，m)，8.13(1H，s)，9.01(1H，s)

MS(ESI)：M+404

Embodiment 1-8

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.57(6H，d，J＝6.5Hz)，4.37(2H，s)，5.24(1H，m)，7.38(1H，dd，J＝7.7，7.7Hz)7.46(1H，dd，J＝1.6，7.7Hz)，7.58(1H，dd，J＝1.6，7.7Hz)，7.85(1H，dd，J＝2.1，8.9Hz)，8.15-8.18(2H，m)，8.86(1H，s)

MS(ESI)：M+389

Embodiment 1-9

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.35(2H，s)，5.98(2H，s)，7.37-7.44(4H，m)，7.57(1H，m)，7.83(1H，m)，8.10-8.12(2H，m)，8.99(1H，s)

MS(ESI)：M+440

Embodiment 1-10

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.85(2H，m)，4.36(2H，s)，4.74(2H，m)，7.38-7.46(2H，m)，7.58(1H，m)，7.85(1H，m)，8.00(1H，m)，8.14(1H，s)，9.00(1H，s)

MS(ESI)：M+419

Embodiment 1-11

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.74(2H，dt，J＝4.8，5.6Hz)，4.59(2H，t，J＝4.9Hz)，4.66(2H，s)，4.98(1H，t，J＝5.6Hz)，7.48-7.53(4H，m)，7.85-8.08(5H，m)，8.18(1H，m)，8.83(1H，s)，15.24(1H，brs)

MS(ESI)：M+373

Embodiment 1-12

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70(2H，m)，3.72(3H，s)，4.27(2H，s)，4.38(2H，m)，4.96(1H，br)，7.32-7.41(2H，m)，7.54(1H，dd，J＝1.8，7.3Hz)，7.61(1H，dd，J＝2.2，8.8Hz)，7.76(1H，d，J＝8.8Hz)，8.00(1H，d，J＝2.2Hz)，8.55(1H，s)

MS(ESI)：M+405

Embodiment 1-13

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.67(2H，m)，4.37(2H，s)，4.73(2H，m)，6.97(1H，br)，7.38-7.48(3H，m)，7.58(1H，m)，7.87(1H，m)，8.01(1H，m)，8.15(1H，s)，8.93(1H，s)

MS(ESI)：M+418

Embodiment 1-14

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.30(3H，s)，4.34(2H，s)，5.62(2H，s)，7.37(1H，m)，7.44(1H，m)，7.55(1H，m)，7.72-7.78(2H，m)，8.10(1H，s)，8.90(1H，s)

MS(ESI)：M+403

Embodiment 1-15

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.31(2H，s)，5.84(2H，s)，7.26-7.41(7H，m)，7.55(1H，m)，7.73(1H，m)，7.83(1H，m)，8.13(1H，m)，9.23(1H，s)，15.18(1H，brs)

MS(ESI)：M+437

Embodiment 1-16

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.12(2H，t，J＝7.3Hz)，4.38(2H，s)，4.78(2H，t，J＝7.3Hz)，7.20-7.28(5H，m)，7.37-7.47(3H，m)，7.58(1H，m)，7.85(1H，m)，8.09(1H，m)，8.15(1H，s)，8.79(1H，s)，15.07(1H，brs)

MS(ESI)：M+451

Embodiment 1-17

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.13(2H，tt，J＝7.3，7.6Hz)，2.70(1H，t，J＝7.6Hz)，4.36(2H，s)，4.58(2H，t，J＝7.3Hz)，7.15-7.24(5H，m)，7.38-7.44(3H，m)，7.57(1H，m)，7.82(1H，m)，7.96(1H，m)，8.13(1H，s)，8.98(1H，s)，15.14(1H，brs)

MS(ESI)：M+465

Embodiment 1-18

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.89(6H，d，J＝6.7Hz)，2.16(1H，tq，J＝6.7，7.6Hz)，4.37(2H，s)，4.39(2H，d，J＝7.6Hz)，7.38-7.47(2H，m)，7.58(1H，m)，7.83(1H，dd，J＝2.0，8.9Hz)，8.02(1H，d，J＝8.9Hz)，8.14(1H，d，J＝2.0Hz)，8.97(1H，s)，15.15(1H，brs)

MS(ESI)：M+403

Embodiment 1-19

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.61-1.64(2H，m)，1.76-1.84(2H，m)，2.60(2H，t，J＝7.5Hz)，4.36(2H，s)，4.56(2H，t，J＝7.2Hz)，7.15-7.17(3H，m)，7.22-7.24(2H，m)，7.38-7.40(1H，m)，7.44(1H，m)，7.56-7.59(1H，m)，7.82(1H，d，J＝2Hz)，7.96(1H，d，J＝8.9Hz)，8.14(1H，d，J＝1.8Hz)，9.01(1H，s)，15.15(1H，brs)

MS(ESI)：M+514

Embodiment 1-20

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm?4.28(2H，s)，5.73(2H，s)，7.02(1H，d，J＝7.6Hz)，7.27-7.43(11H，m)，7.55(1H，d，J＝7.6Hz)，7.60-7.62(1H，m)，8.08(1H，d，J＝1.6Hz)，8.92(1H，s)，14.97(1H，brs)

MS(ESI)：M+502

Embodiment 1-21

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.45-1.49(2H，m)，1.81-1.85(2H，m)，3.42(2H，t，J＝6.3Hz)，4.36(2H，s)，4.56(2H，t，J＝7.4Hz)，7.38(1H，dd，J＝7.7，7.8Hz)，7.44-7.46(1H，m)，7.57(1H，dd，J＝1.4，7.8Hz)，7.83(1H，dd，J＝2.0，8.8Hz)，8.0(1H，d，J＝8.9Hz)，8.14(1H，d，J＝1.8Hz)，9.01(1H，s)，15.18(1H，brs)

MS(ESI)：M+420

Embodiment 1-22

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.32(2H，s)，6.16(2H，s)，7.32-7.42(4H，m)，7.51-7.55(2H，m)，7.77-7.89(3H，m)，8.06-8.12(2H，m)，9.31(1H，s)，15.02(1H，brs)

MS(ESI)：M+494

Embodiment 1-23

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.31(2H，s)，5.83(2H，s)，7.19-7.21(1H，m)，7.33-7.43(2H，m)，7.54-7.59(2H，m)，7.68-7.79(3H，m)，8.12(1H，s)，9.25(1H，s)，15.05(1H，brs)

MS(ESI)：M+508

Embodiment 1-24

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.18(6H，s)，2.64(2H，br)，4.36(2H，s)，4.63(2H，br)，7.38-7.40(1H，m)，7.45(1H，d，J＝1.3Hz)，7.56-7.58(1H，m)，7.84(1H，m)，8.00(1H，d，J＝8.9Hz)，8.14(1H，d，J＝1.7Hz)，8.90(1H，s)，15.15(1H，brs)

MS(ESI)：M+419

Embodiment 1-25

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.93-1.98(2H，m)，3.45(2H，t，J＝5.6Hz)，4.36(2H，s)，4.59(2H，t，J＝7.0Hz)，4.68(1H，br)，7.37(1H，dd，J＝7.7，7.8Hz)，7.44-7.468(1H，m)，7.57(1H，d，J＝7.8Hz)，7.83-7.99(1H，m)，8.00(1H，d，J＝8.9Hz)，8.14(1H，s)，8.96(1H，s)，15.16(1H，brs)

MS(ESI)：M+406

Embodiment 1-26

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.21(3H，s)，3.70(2H，t，J＝4.8Hz)，4.36(2H，s)，4.75(2H，t，J＝4.8Hz)，7.38(1H，dd，J＝7.7，7.7Hz)，7.44-7.47(1H，m)，7.58(1H，dd，J＝1.6，7.8Hz)，7.83(1H，dd，J＝2.1，8.9Hz)，8.04(1H，d，J＝8.9Hz)，8.14(1H，d，J＝2.0Hz)，8.89(1H，s)，15.14(1H，brs)

MS(ESI)：M+406

Embodiment 1-27

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm?4.36(2H，s)，5.68(2H，q，J＝8.7Hz)，7.38(1H，dd，J＝7.7，7.7Hz)，7.46(1H，dd，J＝1.7，7.7Hz)，7.89(1H，dd，J＝2.1，8.9Hz)，8.13-8.16(2H，m)，9.11(1H，s)，14.71(1H，brs)

MS(ESI)：M+430

Embodiment 1-28

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.34(2H，s)，4.78(2H，s)，7.34-7.44(2H，m)，7.55-7.57(1H，m)，7.69(1H，d，J＝8.7Hz)，7.76(1H，d，J＝9.0Hz)，8.09(1H，s)，8.85(1H，s)，15.37(1H，brs)

MS(ESI)：M+406

Embodiment 1-29

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.04(3H，s)，3.27-3.38(2H，m)，4.37(2H，s)，4.78(2H，t，J＝6.8Hz)，7.37-7.39(1H，m)，7.45-7.47(1H，m)，7.58-7.61(1H，m)，7.85-7.87(1H，m)，8.03-8.05(1H，m)，8.15(1H，s)，8.73(1H，s)，8.81(1H，s)

MS(ESI)：M+473

Embodiment 1-30

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.20(3H，d，J＝6.2Hz)，3.96(1H，br)，4.15-4.23(1H，m)，4.36(2H，s)，4.65-4.69(1H，m)，5.02(1H，br)，7.37(1H，dd，J＝7.7，8.0Hz)，7.45(1H，d，J＝6.6Hz)，7.57(1H，d，J＝8.1Hz)，7.81(1H，d，J＝8.8Hz)，8.03(1H，d，J＝9.1Hz)，8.13(1H，s)，8.84(1H，s)

MS(ESI)：M+406

Embodiment 1-31

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.19(2H，s)，4.61(2H，m)，5.00(1H，br)，7.27-7.40(4H，m)，7.86(1H，m)，8.02(1H，m)，8.26(1H，m)，8.86(1H，s)，15.29(1H，s)

MS(ESI)：M+357

Embodiment 1-32

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.10(3H，s)，2.95(2H，t，J＝6.6Hz)，4.37(2H，s)，4.76(2H，t，J＝6.6Hz)，7.38(1H，dd，J＝7.7，7.8Hz)，7.45-7.47(1H，m)，7.58(1H，dd，J＝1.5，7.9Hz)，7.90(1H，dd，J＝2.0，8.9Hz)，8.00(1H，d，J＝8.9Hz)，8.15(1H，d，J＝1.8Hz)，9.02(1H，s)，15.12(1H，brs)

MS(ESI)：M+422

Embodiment 1-33

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(2H，s)，4.33(2H，s)，4.60(2H，t，J＝4.8Hz)，4.98(1H，br)，7.30-7.33(1H，m)，7.39-7.42(2H，m)，7.80(1H，dd，J＝1.7，8.9Hz)，8.02(1H，d，J＝8.9Hz)，8.09(1H，s)，8.85(1H，s)，15，14(1H，brs)

MS(ESI)：M+375

Embodiment 1-34

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.33-1.44(4H，m)，1.75-1.81(2H，m)，3.36-3.38(2H，m)，4.54(2H，t，J＝7.2Hz)，7.38(1H，dd，J＝7.7，7.7Hz)，7.46(1H，d，J＝6.1Hz)，7.57(1H，d，J＝7.8Hz)，7.83(1H，d，J＝8.7Hz)，8.00(1H，d，J＝8.9Hz)，8.14(1H，s)，9.01(1H，s)，15.19(1H，brs)

MS(ESI)：M+434

Embodiment 1-35

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.33-2.45(4H，br)，2.64(2H，t，J＝6.2Hz)，3.52(2H，t，J＝4.4Hz)，4.27(2H，s)，4.40(2H，br)，7.34-7.42(2H，m)，7.55-7.60(2H，m)，7.71(1H，d，J＝8.6Hz)，8.04(1H，s)，8.57(1H，s)

MS(ESI)：M+461

Embodiment 1-36

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.08(3H，s)，4.37(2H，s)，7.37(1H，dd，J＝7.7，7.7Hz)，7.44-7.46(1H，m)，7.57(1H，dd，J＝1.7，7.8Hz)，7.84-7.87(1H，m)，7.92(1H，d，J＝8.8Hz)，8.12(1H，s)，9.01(1H，s)，15.20(1H，brs)

MS(ESI)：M+362

Embodiment 1-37

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.41(3H，t，J＝7.1Hz)，4.36(2H，s)，4.58(2H，q，J＝7.1Hz)，7.38(1H，dd，J＝7.8，7.7Hz)，7.44-7.46(1H，m)，7.57(1H，dd，J＝1.5，7.9Hz)，7.83(1H，dd，J＝2.1，8.8Hz)，8.01(1H，d，J＝8.8Hz)，8.14(1H，s)，9.02(1H，s)，15.18(1H，brs)

MS(ESI)：M+376

Embodiment 1-38

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.90(3H，t，J＝7.3Hz)，1.77-1.85(2H，m)，4.36(2H，s)，4.51(2H，t，J＝7.3Hz)，7.38(1H，dd，J＝7.8，7.6Hz)，7.44-7.46(1H，m)，7.58(1H，dd，J＝1.7，7.8Hz)，7.83(1H，dd，J＝2.1，8.8Hz)，8.02(1H，d，J＝8.9Hz)，8.14(1H，d，J＝2.0Hz)，9.02(1H，s)，15.18(1H，brs)

MS(ESI)：M+390

Embodiment 1-39

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.90(3H，t，J＝7.3Hz)，1.30-1.37(2H，m)，1.74-1.79(2H，m)，4.36(2H，s)，4.54(2H，t，J＝7.3Hz)，7.38(1H，dd，J＝7.6，7.8Hz)，7.46(1H，dd，J＝1.7，7.6Hz)，7.58(1H，dd，J＝1.7，7.8Hz)，7.83(1H，dd，J＝2.1，8.9Hz)，8.00(1H，d，J＝8.9Hz)，8.14(1H，d，J＝2.0Hz)，9.01(1H，s)，15.18(1H，brs)

MS(ESI)：M+404

Embodiment 1-40

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.27-1.29(2H，m)，1.47-1.50(2H，m)，1.59-1.66(4H，m)，2.31-2.40(1H，m)，4.36(2H，s)，4.51(2H，d，J＝7.6Hz)，7.38-7.47(2H，m)，7.57(1H，dd，J＝1.5，7.8Hz)，7.82(1H，dd，J＝2.0，8.8Hz)，8.05(1H，d，J＝8.9Hz)，8.14(1H，d，J＝1.8Hz)，9.028(1H，s)，15.16(1H，brs)

MS(ESI)：M+430

Embodiment 1-41

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.11(3H，s)，3.77(2H，t)，4，37(2H，s)，4.99(2H，t)，7.35-7.41(1H，m)，7.47(1H，d)，7.58(1H，d，J＝7.8Hz)，7.83-7.92(2H，m)，8.16(1H，s)，9.05(1H，s)

MS(ESI)：M+454

Embodiment 1-42

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.10(4H，br)，1.54-1.65(4H，br)，1.83(1H，br)，4.36(2H，s)，4.40(2H，d，J＝7.4Hz)，7.38(1H，dd，J＝7.7，7.8Hz)，7.45-7.48(1H，m)，7.58(1H，dd，J＝1.6，7.8Hz)，7.81-7.84(1H，m)，8.02(1H，d，J＝8.9Hz)，8.13(1H，s)，8.93(1H，s)，15.17(1H，brs)

MS(ESI)：M+444

Embodiment 1-43

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.37(2H，s)，4.49-4.56(1H，m)，4.77-4.82(1H，m)，4.91-4.97(1H，m)，5.81(1H，d，J＝4.7Hz)，7.30-760(8H，m)，7.81(1H，d，J＝11.0Hz)，8.08(1H，d，J＝8.9Hz)，8.17(1H，d)，8.93(1H，s)，15.19(1H，brs)

MS(ESI)：M+468

Embodiment 1-44

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.37(2H，s)，4.72-4.76(1H，m)，4.92(2H，t，J＝4.6Hz)，4.98-5.01(1H，m)，7.38(1H，dd，J＝7.8，8.1Hz)，7.44-7.46(1H，m)，7.58(1H，dd，J＝1.6，7.9Hz)，7.84(1H，dd，J＝2.1，9.0Hz)，8.03(1H，d，J＝9.3Hz)，8.15(1H，d，J＝1.8Hz)，8.78(1H，s)，8.98(1H，s)

MS(ESI)：M+394

Embodiment 1-45

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.21(2H，br)，4.27(2H，s)，4.65(2H，br)，7.20-7.28(2H，m)，7.33-7.41(2H，m)，7.54-7.70(5H，m)，7.77(1H，d，J＝8.7Hz)，8.05(1H，s)，8.50(1H，s)，8.52(1H，s)

MS(ESI)：M+453

Embodiment 1-46

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.93(2H，t)，4.35(2H，s)，4.48(2H，s)，7.38(1H，dd，J＝7.7，7.7Hz)，7.45(1H，d，J＝6.2Hz)，7.57(1H，d，J＝7.7Hz)，7.82(1H，d)，8.02(1H，d，J＝9.1Hz)，8.13(1H，s)，8.92(1H，s)

MS(ESI)：M+391

Embodiment 1-47

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.13(6H，s)，4.35(2H，s)，4.50(2H，s)，4.90(1H，brs)，7.35-7.46(2H，m)，7.57(1H，d，J＝7.7Hz)，7.78(1H，d，J＝7.1Hz)，8.10(1H，s)，8.19(1H，d，J＝9.0Hz)，8.88(1H，s)，15.22(1H，brs)

MS(ESI)：M+420

Embodiment 1-48

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.68(3H，s)，3.46(2H，br)，4.36(2H，s)，4.56(2H，br)，7.38-7.60(3H，m)，7.81-8.13(4H，m)，8.80(1H，s)

MS(ESI)：M+433

Embodiment 1-49

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.00(3H，t，J＝7.0Hz)，3.41(2H，br)，3.82(2H，q)，4.36(2H，s)，4.57(2H，br)，7.24(1H，m)，7.38(1H，m)，7.46(1H，m)，7.58(1H，m)，7.83(1H，m)，8.03(1H，m)，8.13(1H，s)，8.82(1H，s)

MS(ESI)：M+463

Embodiment 1-50

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.26(2H，s)，4.61(2H，t，J＝4.8Hz)，5.00(1H，br)，7.17-7.36(3H，m)，7.83(1H，dd，J＝2.0，8.8Hz)，8.03(1H，d，J＝8.9Hz)，8.21(1H，s)，8.87(1H，s)，15.22(1H，brs)

MS(ESI)：M+360

Embodiment 1-51

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.28(2H，s)，4.61(2H，t，J＝4.8Hz)，5.00(1H，br)，7.24-7.28(1H，m)，7.44-7.55(2H，m)，7.80(1H，dd，J＝2.1，8.8Hz)，8.02(1H，d，J＝8.9Hz)，8.13(1H，d，J＝1.9Hz)，8.86(1H，s)，15.22(1H，s)

MS(ESI)：M+376

Embodiment 1-52

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：1.42(3H，t，J＝7.1Hz)，4.05(2H，s)，4.40(2H，q，J＝7.1Hz)，5.35(2H，s)，7.13-7.28(8H，m)，7.33-7.35(2H，m)，8.41(1H，d，J＝2.0Hz)，8.58(1H，s)

MS(ESI)：M+398

Embodiment 1-53

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：4.10(2H，s)，5.48(2H，s)，7.13-7.50(12H，m)，8.41(1H，d，J＝1.9Hz)，8.87(1H，s)，14.96(1H，brs)

MS(ESI)：M+370

Embodiment 1-54

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.16(2H，s)，5.44(2H，s)，7.19-7.34(5H，m)，7.74(1H，d，J＝8.8Hz)，7.83(1H，dd，J＝2.0，8.9Hz)，8.22(1H，d，J＝1.9Hz)，9.08(1H，s)，13.58(1H，brs)，15.13(1H，brs)

MS(ESI)：M+338

Embodiment 1-55

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.89(3H，t，J＝7.3Hz)，1.25-1.35(5H，m)，1.66-1.76(2H，m)，4.09(2H，s)，4.21(2H，q，J＝7.1Hz)，4.34(2H，t，J＝7.2Hz)，7.20-7.33(5H，m)，7.66(1H，dd，J＝2.1，8.7Hz)，7.74(1H，d，J＝8.7Hz)，8.06(1H，d，J＝1.9Hz)，8.64(1H，s)

MS(ESI)：M+364

Embodiment 1-56

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：0.99(3H，t，J＝7.3Hz)，1.43(2H，m)，1.84-1.94(2H，m)，4.15(2H，s)，4.28(2H，t，J＝7.4Hz)，7.20-7.34(5H，m)，7.52(1H，d，J＝8.8Hz)，7.65(1H，dd，J＝2.1，8.8Hz)，8.42(1H，d，J＝1.9Hz)，8.72(1H，s)，15.04(1H，brs)

MS(ESI)：M+336

Embodiment 1-57

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：1.41(3H，t，J＝7.2Hz)，3.85(3H，s)，4.11(2H，s)，4.39(2H，q，J＝7.2Hz)，7.17-7.35(6H，m)，7.51(1H，dd，J＝2.4，8.4Hz)，8.42(1H，d，J＝1.8Hz)，8.45(1H，s)

MS(ESI)：M+322

Embodiment 1-58

¹H?NMR(CDCl ₃?300MHz)(δ)ppm：3.99(3H，s)，4.16(2H，s)，7.19-7.33(5H，m)，7.52(1H，d，J＝8.7Hz)，7.68(1H，dd，J＝2.0，8.7Hz)，8.41(1H，s)，8.72(1H，s)

MS(ESI)：M+294

Embodiment 1-59

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.08-2.15(2H，m)，2.69(2H，t，J＝7.8Hz)，4.16(2H，s)，4.57(2H，t，J＝7.3Hz)，7.15-7.31(10H，m)，7.81(1H，dd，J＝2.0，8.8Hz)，7.92(1H，d，J＝8.8Hz)，8.20(1H，d，J＝1.9Hz)，8.96(1H，s)，15.21(1H，brs)

MS(ESI)：M+398

Embodiment 1-60

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.11(2H，t，J＝7.3Hz)，4.18(2H，s)，4.77(2H，t，J＝7.4Hz)，7.19-7.35(10H，m)，7.86(1H，d，J＝8.7Hz)，8.06(1H，d，J＝8.8Hz)，8.22(1H，s)，8.76(1H，s)，15.14(1H，brs)

MS(ESI)：M+384

Embodiment 1-61

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.99-2.03(2H，m)，2.37(2H，t，J＝7.1Hz)，4.17(2H，s)，4.54(2H，t，J＝7.3Hz)，7.21-7.34(5H，m)，7.87(1H，dd，J＝2.0，8.8Hz)，8.05(1H，d，J＝8.8Hz)，8.21(1H，d，J＝1.9Hz)，8.98(1H，s)，12.01(1H，brs)，15.28(1H，brs)

MS(ESI)：M+366

Embodiment 1-62

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.15(2H，s)，5.48(2H，s)，7.06-7.10(1H，m)，7.20-7.22(1H，m)，7.28-7.34(6H，m)，7.56-7.58(2H，m)，7.74(1H，d，J＝8.8Hz)，7.848.9Hz)，8.23(1H，s)，9.10(1H，s)，10.63(1H，brs)，15.18(1H，brs)

MS(ESI)：M+413

Embodiment 1-63

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.72(2H，m)，4.26(2H，s)，4.35(2H，m)，5.23(1H，br)，7.32-7.41(2H，m)，7.53-7.58(2H，m)，7.72(1H，m)，8.05(1H，s)，8.63(1H，s)

MS(ESI)：M+391

Embodiment 1-64

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.72(2H，m)，4.23(2H，s)，4.35(2H，m)，5.24(1H，br)，7.25-7.40(3H，m)，7.57(1H，m)，7.72(1H，m)，8.03(1H，s)，8.63(1H，s)

MS(ESI)：M+375

Embodiment 1-65

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.12(2H，t，J＝7.3Hz)，4.31(2H，s)，4.78(2H，t，J＝7.3Hz)，7.20-7.36(7H，m)，7.46-7.48(2H，m)，7.86(1H，m)，8.09(1H，m)，8.15(1H，s)，8.78(1H，s)，15.08(1H，brs)

MS(ESI)：M+417

Embodiment 1-66

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.79(2H，m)，4.39(2H，s)，4.65(2H，m)，5.04(1H，m)，7.31-7.47(3H，m)，7.88(1H，m)，8.07(1H，m)，8.19(1H，m)，8.90(1H，s)，15.25(1H，s)

MS(ESI)：M+375

Embodiment 1-67

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.74(2H，m)，4.35(2H，s)，4.62(2H，m)，5.00(1H，br)，7.62(1H，m)，7.81(1H，m)，7.90(1H，m)，8.02-8.13(2H，m)，8.23(1H，m)，8.32(1H，m)，8.87(1H，s)

MS(ESI)：M+368

Embodiment 1-68

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.09(3H，s)，4.35(2H，s)，5.75(2H，s)，7.37(1H，m)，7.44(1H，m)，7.55(1H，m)，7.83(1H，m)，8.01(1H，m)，8.12(1H，m)，9.10(1H，s)

MS(ESI)：M+407

Embodiment 1-69

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.20(3H，s)，4.36(2H，s)，6.22(2H，s)，7.36-7.47(2H，m)，7.58(1H，m)，7.86(1H，m)，8.12-8.15(2H，m)，9.04(1H，s)

MS(ESI)：M+439

Embodiment 1-70

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.22(9H，s)，4.36(2H，s)，5.99(2H，s)，7.35-7.46(3H，m)，7.58(1H，m)，7.84(1H，m)，8.08-8.11(2H，m)，8.95(1H，s)，14.75(1H，br)

MS(ESI)：M+496

Embodiment 1-71

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.62(3H，d，J＝4.7Hz)，4.36(2H，s)，6.11(2H，s)，7.36-7.47(2H，m)，7.54-7.60(2H，m)，7.84(1H，m)，8.10-8.13(2H，m)，8.98(1H，s)，14.79(1H，br)

MS(ESI)：M+454

Embodiment 1-72

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.77(6H，s)，4.37(2H，s)，6.20(2H，s)，7.39(1H，dd，J＝7.8，7.8Hz)，7.47(1H，dd，J＝1.7，7.8Hz)，7.59(1H，dd，J＝1.7，7.8Hz)，7.89(1H，m)，8.11-8.14(2H，m)，9.04(1H，s)，14.69(1H，br)

MS(ESI)：M+468

Embodiment 1-73

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，br)，4.36(2H，s)，4.60(2H，m)，5.00(1H，br)，7.39-7.49(2H，m)，7.82(1H，m)，8.04(1H，m)，8.11(1H，s)，8.87(1H，s)，15.14(1H，brs)

MS(ESI)：M+393

Embodiment 1-74

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.41(1H，m)，3.51(1H，m)，3.82(1H，m)，4.26(1H，m)，4.36(2H，s)，4.79(1H，m)，4.93(1H，m)，5.19(1H，m)，7.38(1H，m)，7.46(1H，m)，7.58(1H，m)，7.84(1H，m)，7.97(1H，m)，8.15(1H，m)，8.84(1H，s)

MS(ESI)：M+421

Embodiment 1-75

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.32(2H，s)，5.98(2H，s)，7.31-7.43(5H，m)，7.80(1H，m)，8.06(1H，m)，8.12(1H，m)，8.99(1H，m)，14.81(1H，brs)

MS(ESI)：M+424

Embodiment 1-76

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.62(3H，d，J＝4.4Hz)，4.32(2H，s)，6.11(2H，s)，7.30-7.43(3H，m)，7.53(1H，q，J＝4.4Hz)，7.84(1H，m)，8.06(1H，s)，8.12(1H，m)，8.98(1H，m)，14.74(1H，s)

MS(ESI)：M+438

Embodiment 1-77

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.77(6H，s)，4.33(2H，s)，6.19(2H，s)，7.27-7.44(3H，m)，7.89(1H，m)，8.06-8.14(2H，m)，9.03(1H，s)，14.64(1H，s)

MS(ESI)：M+452

Embodiment 1-78

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.74(2H，dt，J＝4.8，5.6Hz)，4.17(2H，s)，4.60(2H，t，J＝4.8Hz)，4.99(1H，t，J＝5.6Hz)，7.20-7.32(5H，m)，7.82(1H，m)，7.99(1H，m)，8.21(1H，m)，8.84(1H，s)，15.27(1H，s)

MS(ESI)：M+323

Embodiment 1-79

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.34(3H，s)，3.75(2H，br)，4.30(2H，s)，4.61(2H，t，J＝4.7Hz)，5.00(1H，br)，7.21-7.31(3H，m)，7.81(1H，dd，J＝2.0，8.9Hz)，8.01(1H，d，J＝8.9Hz)，8.15(1H，d，J＝2.0Hz)，8.86(1H，s)，15.23(1H，s)

MS(ESI)：M+371

Embodiment 1-80

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.76(2H，m)，4.31(2H，s)，4.61(2H，m)，5.01(1H，m)，7.23(1H，m)，7.36-7.47(2H，m)，7.65(1H，m)，7.81(1H，m)，8.02(1H，m)，8.14(1H，m)，8.86(1H，s)

MS(ESI)：M+401

Embodiment 1-81

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.26(3H，s)，3.75(2H，m)，4.12(2H，s)，4.60(2H，m)，4.99(1H，m)，7.10-7.18(4H，m)，7.80(1H，m)，7.99(1H，m)，8.20(1H，m)，8.85(1H，s)，15.29(1H，s)

MS(ESI)：M+337

Embodiment 1-82

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.73(2H，dt，J＝4.8，5.2Hz)，3.84(3H，s)，4.28(2H，s)，4.60(2H，t，J＝4.8Hz)，5.00(1H，t，J＝5.2Hz)，7.04-7.07(2H，m)，7.30(1H，m)，7.79(1H，m)，8.00(1H，m)，8.11(1H，m)，8.84(1H，s)，15.22(1H，s)

MS(ESI)：M+387

Embodiment 1-83

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(2H，m)，4.50(2H，s)，4.62(2H，m)，7.60-8.15(5H，m)，8.35(1H，s)，8.68(1H，m)，8.87(1H，s)，15.25(1H，br)

MS(ESI)：M+324

Embodiment 1-84

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.33(2H，s)，4.62(2H，m)，7.57(2H，d，J＝6.3Hz)，7.89(1H，dd，J＝2.1，8.7Hz)，8.07(1H，d，J＝8.7Hz)，8.32(1H，d，J＝2.1Hz)，8.62(1H，d，J＝6.3Hz)，8.88(2H，s)

MS(ESI)：M+324

Embodiment 1-85

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.21(3H，s)，3.77(2H，m)，4.61(2H，m)，4.66(2H，s)，5.02(1H，m)，7.38(1H，m)，7.55(1H，m)，7.68(1H，m)，7.81(1H，m)，8.00-8.05(2H，m)，8.19(1H，m)，8.87(1H，s)

MS(ESI)：M+401

Embodiment 1-86

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.73(2H，m)，4.15(2H，s)，4.58(2H，m)，5.00(1H，m)，7.23-7.50(10H，m)，7.88-7.92(2H，m)，8.83(1H，s)

MS(ESI)：M+399

Embodiment 1-87

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.30(2H，s)，4.61(2H，m)，5.00(1H，br)，7.26-7.38(2H，m)，7.43-7.49(2H，m)，7.82(1H，m)，8.02(1H，m)，8.14(1H，m)，8.86(1H，s)，15.32(1H，s)

MS(ESI)：M+357

Embodiment 1-88

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.74(2H，m)，4.25(2H，s)，4.60(2H，m)，4.98(1H，br)，7.25-7.53(6H，m)，7.59-7.66(3H，m)，7.87(1H，m)，8.10(1H，m)，8.29(1H，m)，8.85(1H，s)，15.30(1H，s)

MS(ESI)：M+399

Embodiment 1-89

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.79(2H，m)，4.33(2H，s)，4.64(2H，m)，5.03(1H，m)，7.57-7.65(3H，m)，7.76(1H，m)，7.91(1H，m)，8.06(1H，m)，8.32(1H，m)，8.90(1H，s)，15.31(1H，s)

MS(ESI)：M+391

Embodiment 1-90

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.30(3H，t，J＝6.8Hz)，3.74(2H，m)，3.98(2H，q，J＝6.8Hz)，4.12(2H，s)，4.60(2H，m)，5.01(1H，m)，6.76(1H，m)，6.82-6.84(2H，m)，7.20(1H，m)，7.82(1H，m)，7.99(1H，m)，8.22(1H，m)，8.85(1H，s)

MS(ESI)：M+367

Embodiment 1-91

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.25(2H，s)，4.61(2H，m)，7.53(1H，m)，7.66-7.71(2H，m)，7.83-7.89(2H，m)，8.02(1H，m)，8.28(1H，m)，8.87(1H，s)

MS(ESI)：M+348

Embodiment 1-92

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.48(3H，m)，3.74(2H，m)，4.26(2H，s)，4.61(2H，m)，5.09(1H，br)，7.19(1H，m)，7.39(2H，m)，7.82(1H，m)，8.04(1H，m)，8.13(1H，s)，8.85(1H，s)，15.22(1H，s)

MS(ESI)：M+403

Embodiment 1-93

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.24(2H，s)，4.61(2H，m)，5.02(1H，br)，7.38-7.47(4H，m)，7.80(1H，m)，8.03(1H，m)，8.16(1H，m)，8.86(1H，s)，15.23(1H，s)

MS(ESI)：M+407

Embodiment 1-94

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.76(2H，m)，3.99(2H，s)，4.61(2H，m)，5.01(3H，m)，6.41(3H，m)，6.93(1H，m)，7.78(1H，m)，8.00(1H，m)，8.20(1H，m)，8.86(1H，s)

MS(ESI)：M+338

Embodiment 1-95

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.00(3H，s)，3.76(2H，m)，4.13(2H，s)，4.61(2H，m)，5.01(1H，m)，6.98(1H，m)，7.23(1H，m)，7.43(2H，m)，7.81(1H，m)，8.01(1H，m)，8.21(1H，m)，8.86(1H，s)，9.87(1H，s)

MS(ESI)：M+380

Embodiment 1-96

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.73(2H，m)，4.18(2H，s)，4.59(2H，m)，4.98(1H，br)，7.26(1H，s)，7.29(1H，m)，7.39(1H，m)，7.53(1H，m)，7.99(1H，s)，8.24(1H，m)，8.85(1H，s)，15.25(1H，s)

MS(ESI)：M+401

Embodiment 1-97

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.28(3H，s)，3.75(2H，m)，4.25(2H，s)，4.61(2H，m)，5.04(1H，br)，7.13(1H，s)，7.29-7.36(2H，m)，7.81(1H，m)，8.03(1H，m)，8.13(1H，s)，8.86(1H，s)，15.24(1H，s)

MS(ESI)：M+371

Embodiment 1-98

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.59(6H，s)，3.75(2H，m)，4.33(2H，s)，4.61(2H，m)，5.00(1H，m)，7.59-7.64(3H，m)，7.73(1H，m)，7.87(1H，m)，8.03(1H，m)，8.27(1H，s)，8.86(1H，s)，15.27(1H，s)

MS(ESI)：M+430

Embodiment 1-99

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.26(2H，s)，4.61(2H，m)，5.00(1H，br)，7.21(1H，m)，7.38-7.51(2H，m)，7.83(1H，m)，8.03(1H，m)，8.22(1H，s)，8.87(1H，s)

MS(ESI)：M+375

Embodiment 1-100

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.76(2H，m)，4.26(2H，s)，4.61(2H，m)，4.99(1H，m)，7.25(1H，m)，7.61(1H，m)，7.81(1H，m)，8.04(1H，m)，8.16(1H，m)，8.87(1H，s)，15.16(1H，s)

MS(ESI)：M+393

Embodiment 1-101

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.79(2H，m)，4.01(3H，s)，4.19(2H，s)，4.64-4.65(2H，m)，5.02(1H，t，J＝5.5Hz)，7.25(1H，d，J＝1.6Hz)，7.31-7.35(2H，m)，7.56-7.58(1H，m)，7.82(1H，s)，8.78(1H，s)，15.38(1H，brs)

MS(ESI)：M+422

Embodiment 1-102

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.19(2H，m)，1.30(2H，m)，3.83(1H，m)，4.37(2H，s)，7.38(1H，m)，7.46(1H，m)，7.57(1H，m)，7.89(1H，m)，8.12(1H，m)，8.24(1H，m)，8.73(1H，s)，15.05(1H，s)

MS(ESI)：M+387

Embodiment 2-1

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.37(2H，s)，6.88(2H，brs)，7.35-7.47(2H，m)，7.58(1H，m)，7.87(1H，dd，J＝2.1，8.9Hz)，8.08(1H，d，J＝2.1Hz)，8.16(1H，d，J＝8.9Hz)，8.86(1H，s)，15.24(1H，brs)

MS(ESI)：M+362

Embodiment 2-2

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(3H，brs)，4.36(2H，s)，7.35(1H，m)，7.42(1H，m)，7.54(1H，m)，7.72(1H，m)，7.85(1H，m)，8.10(1H，s)，9.03(1H，s)，11.61(1H，brs)

MS(ESI)：M+420

Embodiment 2-3

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.16(3H，s)，4.36(2H，s)，7.35-7.45(2H，m)，7.58(1H，dd，J＝1.8，7.8Hz)，7.76-7.85(2H，m)，8.10(1H，s)，8.96(1H，s)，12.02(1H，brs)，14.77(1H，brs)

MS(ESI)：M+405

Embodiment 2-4

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.32(3H，s)，4.37(2H，s)，7.38(1H，m)，7.46(1H，m)，7.58(1H，m)，7.86(1H，m)，8.06-8.10(2H，m)，8.82(1H，s)，14.60(1H，br)

MS(ESI)：M+440

Embodiment 2-5

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.46(3H，s)，3.53(3H，s)，4.37(2H，s)，7.38(1H，dd，J＝7.8，7.8Hz)，7.47(1H，dd，J＝2.1，7.8Hz)，7.58(1H，dd，J＝2.1，7.8Hz)，7.88(1H，dd，J＝1.8，8.7Hz)，7.97(1H，d，J＝8.7Hz)，8.12(1H，d，J＝1.8Hz)，9.11(1H，s)，15.54(1H，brs)

MS(ESI)：M+454

Embodiment 2-6

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.96(6H，s)，4.36(2H，s)，7.38(1H，dd，J＝7.8，7.8Hz)，7.46(1H，dd，J＝2.0，7.8Hz)，7.57(1H，dd，J＝2.0，7.8Hz)，7.86(1H，dd，J＝2.2，8.8Hz)，8.12(1H，d，J＝2.2Hz)，8.25(1H，d，J＝8.8Hz)，9.25(1H，s)，15.14(1H，brs)

MS(ESI)：M+390

Embodiment 2-7

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.84(3H，d)，4.35(2H，s)，7.19(1H，q)，7.38(1H，m)，7.45(1H，m)，7.55(1H，m)，7.85(1H，m)，8.09-8.11(2H，m)，8.99(1H，m)

MS(ESI)：M+376

Embodiment 2-8

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.09(3H，t，J＝7.1Hz)，3.13(2H，dq，J＝6.1，7.1Hz)，4.36(2H，s)，7.19(1H，t，J＝6.1Hz)，7.38(1H，dd，J＝7.7，7.7Hz)，7.46(1H，dd，J＝1.7，7.7Hz)，7.58(1H，dd，J＝1.7，7.8Hz)，7.85(1H，dd，J＝2.1，8.8Hz)，8.10(1H，d，J＝2.1Hz)，8.15(1H，d，J＝8.8Hz)，8.99(1H，s)，15.14(1H，brs)

MS(ESI)：M+390

Embodiment 3-1

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，3.79(3H，s)，4.28(2H，s)，4.57(2H，m)，5.02(1H，m)，7.17(1H，m)，7.32(1H，m)，7.57(2H，m)，7.76(1H，m)，8.83(1H，m)，15.75(1H，s)

MS(ESI)：M+421

Embodiment 3-2

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.24(3H，s)，3.77(2H，dd，J＝5.2，5.6Hz)，4.27(2H，s)，4.61(2H，t，J＝5.2Hz)，5.05(1H，t，J＝5.6Hz)，7.23(2H，m)，7.34(1H，m)，7.76(1H，m)，8.03(1H，m)，8.08(1H，m)，8.86(1H，s)，15.23(1H，s)

MS(ESI)：M+371

Embodiment 3-3

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.73(5H，s)，4.21(2H，s)，4.61(2H，t，J＝4.8Hz)，5.01(1H，t，J＝5.2Hz)，5.02(1H，m)，7.12(1H，m)，7.25(1H，m)，7.37(1H，m)，7.81(1H，m)，8.01(1H，m)，8.19(1H，m)，8.86(1H，s)，15.26(1H，s)

MS(ESI)：M+387

Embodiment 3-4

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.80(2H，m)，4.01(3H，s)，4.12(2H，s)，4.65(2H，m)，5.02(1H，m)，7.17-7.50(4H，m)，8.03(1H，s)，8.81(1H，s)，15.45(1H，s)

MS(ESI)：M+405

Embodiment 3-5

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.74(2H，t)，4.17(2H，s)，4.56(2H，t)，5.02(1H，br)，7.20(1H，m)，7.31(1H，m)，7.38(1H，m)，7.52-7.56(2H，m)，8.86(1H，s)，13.63(1H，s)

MS(ESI)：M+407

Embodiment 3-6

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.78(2H，t)，4.18(2H，s)，4.44-4.49(2H，m)，5.08(1H，t)，7.20-7.25(2H，m)，7.34-7.40(1H，m)，7.56(1H，d)，7.82(1H，s)，8.77(1H，s)，11.10-11.30(1H，br)，15.49(1H，s)

MS(ESI)：M+408

Embodiment 3-7

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.68(3H，d，J＝4.4Hz)，3.74(2H，t，J＝4.8Hz)，4.04(2H，s)，4.60(2H，t，J＝4.8Hz)，5.01(1H，t)，5.27(1H，q，J＝5.2Hz)，6.51-6.56(2H，m)，6.95(1H，d)，7.07-7.09(1H，m)，7.78(1H，d，J＝9.2Hz)，7.98(1H，d，J＝8.8Hz)，8.21(1H，s)，8.84(1H，s)，15.33(1H，s)

MS(ESI)：M+353

Embodiment 3-8

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.62(6H，s)，3.74(2H，t)，4.24(2H，s)，4.60(2H，t，J＝4.8Hz)，5.01(1H，t)，6.97-7.05(2H，m)，7.21(2H，m)，7.77(1H，d，J＝11.2Hz)，7.97(1H，d)，8.16(1H，s)，8.85(1H，s)，15.29(1H，s)

MS(ESI)：M+367

Embodiment 3-9

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：4.35(2H，s)，7.11(1H，d，J＝8.8Hz)，7.37-7.40(1H，m)，7.44(1H，d)，7.56(1H，d)，7.69-7.74(6H，m)，8.19(1H，s)，8.68(1H，s)，14.99(1H，s)

MS(ESI)：M+424

Embodiment 3-10

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.84-3.95(4H，m)，4.36(2H，s)，5.11-5.19(3H，m)，7.38(1H，m)，7.45(1H，d)，7.57(1H，d)，7.82(1H，d，J＝9.2Hz)，8.15(1H，d，J＝8.8Hz)，8.90(1H，s)，15.21(1H，s)

MS(ESI)：M+422

Embodiment 3-11

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.76(2H，t)，4.05(2H，s)，4.59(2H，t)，5.00(1H，t)，6.61(1H，d)，6.64(1H，s)，6.70(1H，d，J＝8.0Hz)，7.09-7.11(1H，m)，7.81(1H，d，J＝8.8Hz)，8.00(1H，d，J＝8.8Hz)，8.21(1H，s)，8.86(1H，s)，9.30(1H，s)，15.30(1H，s)

MS(ESI)：M+340

Embodiment 3-12

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.80-1.90(2H，m)，2.45-2.50(2H，m)，2.60-2.70(2H，m)，4.36(2H，s)，5.11-5.16(1H，m)，7.38-7.40(1H，m)，7.45(1H，d)，7.57(1H，d)，7.81(1H，d，J＝8.8Hz)，7.93(1H，d)，8.14(1H，s)，8.68(1H，s)，15.16(1H，s)

MS(ESI)：M+402

Embodiment 3-13

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.70-1.90(4H，m)，1.91-2.00(2H，m)，2.20-2.30(2H，m)，4.37(2H，s)，5.20-5.30(1H，m)，7.38-7.40(1H，m)，7.45(1H，d)，7.57(1H，d)，7.86(1H，d)，8.16(1H，d)，8.19(1H，s)，8.75(1H，s)，15.16(1H，s)

MS(ESI)：M+416

Embodiment 3-14

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.80(2H，m)，3.96(3H，s)，4.32(2H，s)，4.81(2H，t)，4.90(1H，t)，7.35-7.43(2H，m)，7.54-7.59(2H，m)，7.69(1H，s)，8.69(1H，s)，15.16(1H，s)

MS(ESI)：M+422

Embodiment 3-15

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.88(3H，s)，2.95(3H，s)，3.70-3.80(2H，m)，4.21(2H，s)，4.61(2H，t)，4.99(1H，t)，7.20-7.23(1H，m)，7.33(1H，s)，7.37-7.38(2H，dx2)，7.86(1H，d)，8.02(1H，d，J＝8.8Hz)，8.26(1H，s)，8.86(1H，s)，15.30(1H，s)

MS(ESI)：M+395

Embodiment 3-16

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.71(6H，s)，3.70-3.76(2H，m)，4.58(2H，s)，4.60(2H，t，J＝5.2Hz)，5.02(1H，t)，7.42(1H，d)，7.51(1H，m)，7.64(1H，m)，7.80(1H，d)，7.84(1H，d)，8.01(1H，d，J＝8.8Hz)，8.11(1H，s)，8.86(1H，s)，15.25(1H，s)

MS(ESI)：M+431

Embodiment 3-17

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.73-3.75(2H，m)，4.24(2H，s)，4.61(2H，t)，5.00(1H，t，J＝5.6Hz)，7.31(1H，m)，7.48-7.51(1H，m)，7.84(1H，d)，8.02(1H，d)，8.21(1H，s)，8.87(1H，s)，15.22(1H，s)

MS(ESI)：M+394

Embodiment 3-18

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.80(2H，m)，4.56(2H，s)，4.60(2H，t)，5.00(1H，t)，7.38-7.43(2H，m)，7.52-7.54(1H，m)，7.78(1H，d)，7.87(1H，d，J＝7.8Hz)，7.98(1H，d，J＝8.9Hz)，8.11(1H，s)，8.84(1H，s)，12.60-13.00(1H，br)，15.29(1H，s)

MS(ESI)：M+368

Embodiment 3-19

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.74-3.77(2H，m)，4.58(2H，s)，4.61(2H，t)，5.02(1H，t，J＝5.6Hz)，7.29(1H，d)，7.46(1H，m)，7.56(1H，m)，7.70(1H，m)，7.81(1H，d)，7.87(1H，d)，8.01(1H，s)，8.18(1H，s)，8.86(1H，s)，15.27(1H，s)

MS(ESI)：M+417

Embodiment 3-20

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.37(3H，t，J＝6.9Hz)，3.70-3.80(2H，m)，4.22(2H，s)，4.28(2H，q，J＝6.9Hz)，4.65(2H，t)，5.00(1H，t)，7.30-7.34(3H，m)，7.60(1H，d)，7.92(1H，s)，8.80(1H，s)，15.44(1H，s)

MS(ESI)：M+436

Embodiment 3-21

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.76(2H，m)，4.40(2H，s)，4.63(2H，t，J＝5.1Hz)，5.02(1H，t，J＝5.6Hz)，7.20(1H，d，J＝6.3Hz)，7.35-7.39(1H，m)，7.62(1H，d，J＝6.3Hz)，8.00(1H，s)，8.32(1H，s)，8.89(1H，s)，15.87(1H，s)

MS(ESI)：M+426

Embodiment 3-22

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.80(2H，t，J＝5.3Hz)，4.48(2H，s)，4.75(2H，t，J＝4.6Hz)，5.06(1H，t，J＝5.6Hz)，7.24(1H，d，J＝6.3Hz)，7.39-7.42(1H，m)，7.65(1H，d，J＝6.7Hz)，7.95(1H，s)，8.40(1H，s)，9.00(1H，s)，14.62(1H，s)

MS(ESI)：M+460

Embodiment 3-23

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.53(3H，d，J＝6.4Hz)，3.76-3.83(2H，m)，4.26(2H，s)，5.19-5.23(2H，m)，7.20-7.22(1H，m)，7.41-7.49(2H，m)，7.86(1H，d)，8.17(1H，d，J＝8.8Hz)，8.24(1H，s)，8.88(1H，s)

MS(ESI)：M+390

Embodiment 3-24

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.53(3H，d，J＝6.8Hz)，3.76-3.82(2H，m)，4.26(2H，s)，5.19-5.23(2H，m)，7.22-7.24(1H，m)，7.41-7.49(2H，m)，7.86(1H，d)，8.17(1H，d，J＝9.2Hz)，8.24(1H，s)，8.88(1H，s)

MS(ESI)：M+390

Embodiment 3-25

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.40-3.50(2H，m)，4.34(2H，s)，4.57(2H，t)，4.89(1H，t)，7.24-7.27(1H，m)，7.45-7.51(2H，m)，8.35(1H，s)，8.45(1H，s)，9.00(1H，s)，14.30-14.40(1H，br)

MS(ESI)：M+444

Embodiment 3-26

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.84-3.96(4H，m)，4.26(2H，s)，5.13-5.18(3H，m)，7.19-7.21(1H，m)，7.40-7.48(2H，m)，7.84(1H，d，J＝9.2Hz)，8.15(1H，d，J＝8.8Hz)，8.23(1H，s)，8.90(1H，s)，15.24(1H，s)

MS(ESI)：M+406

Embodiment 3-27

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.77(2H，t，J＝5.2Hz)，4.53(2H，s)，4.68(2H，t，J＝4.8Hz)，5.01(1H，t，J＝5.6Hz)，7.32(1H，d，J＝6.0Hz)，7.39-7.43(1H，m)，7.64(1H，d，J＝6.4Hz)，8.07(1H，s)，8.79(1H，s)，8.96(1H，s)，14.61(1H，s)

MS(ESI)：M+417

Embodiment 3-28

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.97(3H，t，J＝7.2Hz)，2.58(3H，s)，2.84(2H，q，J＝7.2Hz)，3.77(2H，t)，4.21(2H，s)，4.60(2H，t)，5.00(1H，t)，7.00-7.02(1H，m)，7.12(1H，d)，7.20-7.24(2H，m)，7.78(1H，d，J＝8.8Hz)，7.98(1H，d，J＝8.8Hz)，8.17(1H，s)，8.84(1H，s)，15.31(1H，s)

MS(ESI)：M+381

Embodiment 3-29

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.78(3H，t，J＝7.2Hz)，1.42(2H，m)，2.56(3H，s)，2.76(2H，t，J＝6.8Hz)，3.74(2H，t)，4.23(2H，s)，4.60(2H，t，J＝4.8Hz)，5.02(1H，t，J＝5.6Hz)，7.00-7.03(1H，m)，7.09(1H，d)，7.20-7.21(2H，m)，7.77(1H，d，J＝9.2Hz)，7.99(1H，d，J＝8.8Hz)，8.15(1H，s)，8.85(1H，s)，15.30(1H，s)

MS(ESI)：M+395

Embodiment 3-30

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.52(3H，s)，3.77(2H，t，J＝4.8Hz)，4.01(2H，s)，4.30(2H，s)，4.61(2H，t)，4.90-5.10(1H，br)，7.03-7.09(2H，m)，7.20-7.26(7H，m)，7.76(1H，d)，7.98(1H，d)，8.17(1H，s)，8.85(1H，s)，15.30(1H，s)

MS(ESI)：M+443

Embodiment 3-31

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.94(3H，s)，3.09(3H，s)，3.75(2H，m)，4.13-4.18(1H，m)，4.44-4.48(1H，m)，4.61(2H，t)，5.02(1H，t，J＝5.6Hz)，7.33-7.37(3H，m)，7.52(1H，d，J＝9.2Hz)，7.81(1H，d)，8.01(1H，d，J＝8.8Hz)，8.15(1H，s)，8.86(1H，s)，15.27(1H，s)

MS(ESI)：M+431

Embodiment 3-32

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.01(6H，d)，2.52(3H，s)，3.12-3.19(1H，m)，3.73-3.75(2H，m)，4.20(2H，s)，4.60(2H，t)，5.02(1H，t)，7.00-7.02(1H，m)，7.11(1H，d)，7.19-7.22(2H，m)，7.77(1H，d，J＝8.8Hz)，7.98(1H，d，J＝9.2Hz)，8.18(1H，s)，8.84(1H，s)，15.31(1H，s)

MS(ESI)：M+395

Embodiment 3-33

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.86(9H，s)，4.26(2H，s)，7.22-7.24(1H，m)，7.42-7.49(2H，m)，7.79(1H，d，J＝9.2Hz)，8.28(1H，s)，8.39(1H，d，J＝8.8Hz)，8.98(1H，s)，15.16(1H，s)

MS(ESI)：M+388

Embodiment 3-34

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.71(2H，m)，3.96(3H，s)，4.21(2H，s)，4.81(2H，t)，4.89(1H，t)，7.19-7.24(1H，m)，7.40-7.52(3H，m)，7.77(1H，s)，8.68(1H，s)，15.17(1H，s)

MS(ESI)：M+406

Embodiment 3-35

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.09(2H，s)，4.83(2H，t)，5.33(1H，t)，5.81(2H，s)，7.15(1H，s)，7.15-7.24(1H，m)，7.36(1H，m)，7.48(1H，m)，7.57(1H，s)，8.77(1H，s)，15.37(1H，s)

MS(ESI)：M+391

Embodiment 3-36

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.79(2H，t)，4.60(2H，s)，4.68(2H，t)，5.05(1H，t)，7.11(1H，d，J＝6.0Hz)，7.30-7.34(1H，m)，7.57(1H，d，J＝6.8Hz)，8.02(1H，s)，8.38(1H，s)，8.95(1H，s)，13.60-14.00(1H，br)，14.88(1H，s)

MS(ESI)：M+436

Embodiment 3-37

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.72(2H，m)，4.98(3H，s)，4.23(2H，s)，4.81(2H，t)，4.89(1H，t)，7.20-7.26(1H，m)，7.50(1H，s)，7.62-7.67(2H，m)，8.68(1H，s)，15.10(1H，s)

MS(ESI)：M+424

Embodiment 3-38

MS(ESI)：M+419

Embodiment 3-39

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.10(3H，s)，4.50-4.60(2H，m)，4.23(2H，s)，4.65(2H，t)，5.00(1H，t)，7.20-7.30(1H，m)，7.40-7.50(2H，m)，7.65(1H，s)，8.20(1H，s)，8.83(1H，s)，10.20(1H，s)，15.00(1H，s)

MS(ESI)：M+433

Embodiment 3-40

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.74-3.75(2H，m)，4.55(2H，s)，4.65(2H，t)，5.00(1H，t)，7.17(1H，d，J＝6.3Hz)，7.34-7.39(1H，m)，7.62(1H，d，J＝6.6Hz)，7.73(1H，d，J＝9.3Hz)，8.34(1H，d，J＝9.3Hz)，8.97(1H，s)，14.62(1H，s)

MS(ESI)：M+417

Embodiment 3-41

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.45(3H，s)，2.97(3H，s)，3.74-3.76(2H，m)，4.12(2H，s)，4.61(2H，m)，5.03(1H，t，J＝5.6Hz)，7.24-7.30(1H，m)，7.30-7.39(3H，m)，7.76(1H，d)，8.01(1H，d，J＝8.8Hz)，8.13(1H，s)，8.87(1H，s)，15.23(1H，s)

MS(ESI)：M+395

Embodiment 3-42

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.88(6H，t，J＝7.2Hz)，2.91(4H，q，J＝6.8Hz)，3.75(2H，m)，4.23(2H，s)，4.60(2H，t)，5.02(1H，t，J＝5.6Hz)，7.00-7.06(1H，m)，7.14-7.25(3H，m)，7.77(1H，d)，7.98(1H，d，J＝8.8Hz)，8.16(1H，s)，8.84(1H，s)，15.32(1H，s)

MS(ESI)：M+395

Embodiment 3-43

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.78(6H，s)，3.99(2H，s)，4.25(2H，s)，4.23(2H，s)，5.52(1H，br)，7.20-7.22(1H，m)，7.42-7.49(2H，m)，7.76(1H，d，J＝9.2Hz)，8.27(1H，s)，8.34(1H，d，J＝9.2Hz)，9.05(1H，s)

MS(ESI)：M+404

Embodiment 3-44

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.36(3H，t，J＝6.9Hz)，3.70-3.80(2H，m)，4.12(2H，s)，4.24(2H，q，J＝7.0Hz)，4.62(2H，t)，5.00(1H，t)，7.16-7.27(3H，m)，7.40-7.50(1H，m)，8.12(1H，s)，8.80(1H，s)，15.50(1H，s)

MS(ESI)：M+420

Embodiment 3-45

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.80(2H，m)，3.84(3H，s)，3.85(3H，s)，4.19(2H，s)，4.75(2H，t)，4.92(1H，t，J＝5.6Hz)，7.21-7.28(2H，m)，7.45-7.50(1H，m)，7.95(1H，s)，8.75(1H，s)，15.09(1H，s)

MS(ESI)：M+436

Embodiment 3-46

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.62(3H，s)，3.74(2H，m)，4.02(2H，s)，4.61(2H，t)，5.01(1H，t)，5.50-5.60(1H，m)，6.30-6.43(3H，m)，6.95-7.01(1H，m)，7.82(1H，d)，7.99(1H，d，J＝8.8Hz)，8.21(1H，s)，8.85(1H，s)，15.33(1H，s)

MS(ESI)：M+353

Embodiment 3-47

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.42(3H，t，J＝6.8Hz)，3.70-3.80(2H，m)，4.20-4.23(4H，m)，4.84-5.00(3H，m)，7.20-7.30(1H，m)，7.40-7.49(3H，m)，7.77(1H，s)，8.67(1H，s)

MS(ESI)：M+420

Embodiment 3-48

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.78(3H，s)，3.60-3.70(2H，m)，4.16(2H，s)，4.75-4.79(2H，m)，5.38(1H，t)，6.20-6.27(1H，m)，7.07(1H，s)，7.20-7.23(1H，m)，7.39-7.49(3H，m)，8.80(1H，s)，15.32(1H，s)

MS(ESI)：M+405

Embodiment 3-49

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.94(3H，t，J＝7.2Hz)，1.72-1.78(2H，m)，3.77(2H，m)，4.13-4.14(4H，m)，4.62(2H，t)，5.00(1H，br)，7.12-7.18(2H，m)，7.26(1H，s)，7.44-7.46(1H，m)，8.13(1H，s)，8.79(1H，s)，15.49(1H，s)

MS(ESI)：M+434

Embodiment 3-50

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.00(3H，s)，3.08(3H，s)，3.75-3.77(2H，m)，4.16(2H，s)，4.57(2H，t)，5.00(1H，t，J＝5.6Hz)，7.09-7.18(2H，m)，7.24(1H，s)，7.40-7.41(1H，m)，7.85(1H，s)，8.01(1H，s)，8.72(1H，s)，15.67(1H，s)

MS(ESI)：M+446

Embodiment 3-51

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.72(3H，s)，3.72-3.80(2H，m)，3.95(3H，s)，4.06(2H，s)，4.40-4.50(2H，m)，5.00(1H，t)，7.12(1H，s)，7.15-7.19(2H，m)，7.40-7.45(1H，m)，7.88(1H，s)，8.51(1H，s)

MS(ESI)：M+420

Embodiment 3-52

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.77(2H，m)，4.17(2H，s)，4.72(2H，t，J＝4.8Hz)，4.97(1H，t，J＝5.6Hz)，7.08(2H，d，J＝7.6Hz)，7.09-7.25(2H，m)，7.31-7.36(2H，m)，7.43-7.49(3H，m)，8.04(1H，s)，7.76(1H，s)，15.02(1H，s)

MS(ESI)：M+468

Embodiment 3-53

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.24(6H，d，J＝7.2Hz)，3.75(2H，t)，4.08(2H，s)，4.61(2H，t)，4.99-5.04(2H，m)，7.11-7.20(2H，m)，7.28(1H，s)，7.43-7.45(1H，m)，8.17(1H，s)，8.79(1H，s)，15.52(1H，s)

MS(ESI)：M+434

Embodiment 3-54

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.99(3H，t，J＝7.3Hz)，1.60-1.70(2H，m)，3.00-3.10(2H，m)，3.70-3.80(2H，m)，4.15(2H，s)，4.82(2H，t)，5.50(1H，t)，6.20(1H，t)，7.08(1H，s)，7.10-7.20(1H，m)，7.40-7.51(3H，m)，8.78(1H，s)，15.30-15.40(1H，br)

MS(ESI)：M+433

Embodiment 3-55

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.24(3H，t，J＝6.9Hz)，3.08(2H，m)，3.71-3.80(2H，m)，4.15(2H，s)，4.83(2H，t)，5.43(1H，t)，6.21(1H，t)，7.10(1H，s)，7.17-7.23(1H，m)，7.36-7.52(3H，m)，8.78(1H，s)

MS(ESI)：M+419

Embodiment 3-56

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.53(3H，d，J＝6.8Hz)，3.72(2H，m)，3.99(3H，s)，4.21(2H，s)，5.12(1H，t)，5.70-5.90(1H，m)，7.20-7.21(1H，m)，7.40-7.55(3H，m)，7.76(1H，s)，8.85(1H，s)，15.00-15.20(1H，br)

MS(ESI)：M+420

Embodiment 3-57

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.52(3H，d，J＝6.8Hz)，3.71(2H，t)，4.00(3H，s)，4.23(2H，s)，5.10(1H，t)，5.80-5.90(1H，m)，7.20-7.30(1H，m)，7.51(1H，s)，7.60-7.67(2H，m)，8.85(1H，s)，14.90-15.10(1H，br)

MS(ESI)：M+438

Embodiment 3-58

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.03(3H，d，J＝8.4Hz)，1.78-1.87(2H，m)，3.73-3.75(2H，m)，4.12(2H，t)，4.20(2H，s)，4.85(2H，t)，4.92(1H，t)，7.20(1H，m)，7.39-7.51(3H，m)，7.76(1H，s)，8.68(1H，s)，15.17(1H，s)

MS(ESI)：M+434

Embodiment 3-59

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.35(6H，s)，3.72-3.75(2H，m)，4.20(2H，s)，4.83-4.91(4H，m)，7.20(1H，m)，7.39-7.49(3H，m)，7.74(1H，s)，8.66(1H，s)，15.18(1H，s)

MS(ESI)：M+434

Embodiment 3-60

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.86(3H，t，J＝7.3Hz)，1.80-2.10(2H，m)，3.70-3.90(2H，m)，4.26(2H，s)，5.00-5.10(1H，m)，5.17(1H，t，J＝5.4Hz)，7.19-7.24(1H，m)，7.39-7.51(2H，m)，7.84(1H，d，J＝8.8Hz)，8.20(1H，d，J＝8.8Hz)，8.23(1H，s)，8.86(1H，s)，15.24(1H，s)

MS(ESI)：M+404

Embodiment 3-61

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.36(3H，t，J＝6.9Hz)，1.52(3H，d，J＝6.6Hz)，3.78-3.80(2H，m)，4.12(2H，s)，4.26(2H，q，J＝7.0Hz)，5.21-5.30(2H，m)，7.16-7.24(2H，m)，7.40-7.46(2H，m)，8.14(1H，s)，8.81(1H，s)，15.40-15.60(1H，br)

MS(ESI)：M+434

Embodiment 3-62

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.88(6H，s)，3.70-3.80(2H，m)，4.22(2H，s)，4.60-4.70(2H，m)，5.05(1H，t)，7.20-7.31(3H，m)，7.50-7.60(1H，m)，7.80(1H，s)，8.78(1H，s)，15.30-15.40(1H，br)

MS(ESI)：M+419

Embodiment 3-63

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.90-1.29(5H，m)，1.62-1.80(6H，m)，3.75-3.78(2H，m)，3.96(2H，d，J＝10.8Hz)，4.13(2H，s)，4.60-4.62(2H，m)，5.02(1H，t)，7.06-7.24(2H，m)，7.14(1H，s)，7.42-7.44(1H，m)，8.16(1H，s)，8.79(1H，s)

MS(ESI)：M+488

Embodiment 3-64

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.85-0.89(6H，m)，2.96-3.00(2H，m)，3.10-3.20(2H，m)，3.33-3.40(2H，m)，4.22(2H，s)，4.74(1H，t)，5.09-5.10(2H，m)，7.20(1H，m)，7.38-7.47(2H，m)，7.59(1H，s)，7.89(1H，s)，8.72(1H，s)，15.08(1H，s)

MS(ESI)：M+447

Embodiment 3-65

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.91(3H，d，J＝4.7Hz)，3.75-3.81(2H，m)，4.01(2H，s)，4.50-4.55(2H，m)，5.04(1H，t，J＝5.5Hz)，6.59(1H，s)，6.60-6.68(1H，m)，7.15-7.24(2H，m)，7.51-7.55(1H，m)，7.63(1H，s)，8.65(1H，s)，15.90(1H，s)

MS(ESI)：M+405

Embodiment 3-66

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.91-2.00(4H，m)，3.40-3.50(4H，m)，3.70-3.81，(2H，m)，4.30(2H，s)，4.50-4.55(2H，m)，5.05(1H，t)，6.87(1H，s)，7.10-7.12(1H，m)，7.18-7.21(1H，m)，7.49-7.52(1H，m)，7.72(1H，s)，8.69(1H，s)，15.65(1H，s)

MS(ESI)：M+445

Embodiment 3-67

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.44(3H，t)，1.55(3H，d)，3.70-3.77，(2H，m)，4.19(2H，s)，4.28(2H，q，J＝8.8Hz)，5.14(1H，t)，5.83-5.90(1H，m)，7.20(1H，m)，7.39-7.40(1H，m)，7.48-7.50(2H，m)，7.75(1H，s)，8.86(1H，s)，15.13(1H，s)

MS(ESI)：M+434

Embodiment 3-68

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.86(3H，t，J＝7.3Hz)，1.37(3H，t，J＝6.9Hz)，1.80-2.00，(2H，m)，3.70-3.90(2H，m)，4.12(2H，s)，4.20-4.28(2H，m)，5.00-5.17(2H，m)，7.14-7.30(2H，m)，7.42-7.49(2H，m)，8.14(1H，s)，8.78(1H，s)，15.50(1H，s)

MS(ESI)：M+448

Embodiment 3-69

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.09-1.27(5H，m)，1.68-1.82(6H，m)，3.71-3.73(2H，m)，3.99(2H，d，J＝5.6Hz)，4.20(2H，s)，4.80-4.85(2H，m)，4.92(1H，t，J＝5.6Hz)，7.20(1H，m)，7.38-7.40(1H，m)，7.40-7.53(2H，m)，7.75(1H，s)，8.68(1H，s)，15.16(1H，s)

MS(ESI)：M+488

Embodiment 3-70

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.70(3H，d，J＝6.4Hz)，1.12(3H，d，J＝6.4Hz)，2.30-2.40(1H，m)，3.75-3.78(1H，m)，3.95-4.00(1H，m)，4.25(2H，s)，4.80-4.85(1H，m)，5.18(1H，t)，7.20-7.21(1H，m)，7.41-7.48(2H，m)，7.84(1H，d)，8.21(1H，s)，8.25(1H，d，J＝9.2Hz)，8.92(1H，s)，15.21(1H，s)

MS(ESI)：M+418

Embodiment 3-71

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm?0.85(3H，d)，0.90(3H，d)，1.40-1.50(1H，m)，1.80-1.91(2H，m)，3.71-3.80(2H，m)，4.25(2H，s)，5.15-5.20(2H，m)，7.20-7.21(1H，m)，7.41-7.48(2H，m)，7.84(1H，d，J＝8.8Hz)，8.22(1H，s)，8.24(1H，d，J＝8.8Hz)，8.83(1H，s)，15.20(1H，s)

MS(ESI)：M+432

Embodiment 3-72

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.86(3H，t，J＝7.3Hz)，1.23(6H，m)，1.80-2.00(2H，m)，3.70-3.90(2H，m)，4.09(2H，s)，5.00-5.18(3H，m)，7.12-7.21(2H，m)，7.44-7.47(2H，m)，8.20(1H，s)，8.79(1H，s)，15.54(1H，s)

MS(ESI)：M+462

Embodiment 3-73

MS(ESI)：M+434

Embodiment 3-74

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.23(6H，dx2)，1.51(3H，d，J＝6.6Hz)，3.77(2H，t)，4.09(2H，s)，4.90-5.10(1H，m)，5.19-5.30(2H，m)，7.12-7.21(2H，m)，7.41-7.47(2H，m)，8.20(1H，s)，8.81(1H，s)，15.55(1H，s)

MS(ESI)：M+448

Embodiment 3-75

MS(ESI)：M+432

Embodiment 3-76

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.81(4H，m)，4.15(2H，s)，4.24(2H，t，J＝5.0Hz)，4.60-4.62(2H，m)，5.00-5.02(2H，m)，7.15-7.20(1H，m)，7.32-7.34(2H，m)，7.44-7.49(1H，m)，8.06(1H，s)，8.79(1H，s)，15.48(1H，s)

MS(ESI)：M+436

Embodiment 3-77

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.90-1.92(2H，m)，3.53-3.54(2H，m)，3.70-3.80(2H，m)，4.12(2H，s)，4.20-4.30(2H，m)，4.60-4.70(3H，m)，5.02(1H，t)，7.16-7.22(2H，m)，7.30(1H，s)，7.40-7.50(1H，m)，8.11(1H，s)，8.80(1H，s)

MS(ESI)：M+450

Embodiment 3-78

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm?3.10-3.20(2H，m)，3.60-3.80(4H，m)，4.15(2H，s)，4.78-4.85(3H，m)，5.30-5.40(1H，m)，6.10-6.20(1H，m)，7.15-7.20(2H，m)，7.30-7.52(3H，m)，8.77(1H，s)，15.33(1H，s)

MS(ESI)：M+435

Embodiment 3-79

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.89(3H，t，J＝7.4Hz)，1.90-2.00(2H，m)，3.70-3.80(2H，m)，3.99(3H，s)，4.22(2H，s)，5.15(1H，t，J＝5.4Hz)，5.70-5.80(1H，m)，7.19-7.24(1H，m)，7.38-7.52(2H，m)，7.55(1H，s)，7.77(1H，s)，8.86(1H，s)，15.12(1H，s)

MS(ESI)：M+434

Embodiment 3-80

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.59(3H，d，J＝7.2Hz)，2.61(3H，s)，2.80(3H，s)，4.20(2H，s)，4.96(1H，t，J＝5.6Hz)，6.50-6.60(1H，m)，7.19-7.23(1H，m)，7.40-7.49(2H，m)，7.60(1H，s)，7.80(1H，s)，8.81(1H，s)，15.06(1H，s)

MS(ESI)：M+433

Embodiment 3-81

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：4.10-4.40(4H，m)，5.50-5.60(1H，m)，6.20-6.30(1H，m)，7.19-7.22(1H，m)，7.30-7.40(6H，m)，7.40-7.50(1H，m)，7.77(1H，d)，8.00(1H，d)，8.21(1H，s)，9.03(1H，s)，15.11(1H，s)

MS(ESI)：M+452

Embodiment 3-82

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.86(3H，t)，1.18-1.34(2H，m)，1.87-1.98(2H，m)，3.73-3.84(2H，m)，4.25(2H，s)，5.13-5.17(2H，m)，7.21(1H，m)，7.41-7.48(2H，m)，7.83(1H，d，J＝8.0Hz)，8.19(1H，d)，8.22(1H，s)，8.85(1H，s)，15.22(1H，s)

MS(ESI)：M+418

Embodiment 3-83

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，t，J＝7.3Hz)，0.90-1.20(5H，m)，2.10-2.30(1H，m)，3.70-3.80(1H，m)，3.90-4.10(1H，m)，4.26(2H，s)，4.90-5.00(1H，m)，5.10-5.20(1H，m)，7.20-7.25(1H，m)，7.40-7.52(2H，m)，7.84(1H，d，J＝7.8Hz)，8.23(1H，s)，8.26(1H，d)，8.92(1H，s)，15.22(1H，s)

MS(ESI)：M+432

Embodiment 3-84

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.54(3H，d，J＝6.6Hz)，3.81-3.82(2H，m)，4.02(3H，s)，4.12(2H，s)，5.22(1H，t，J＝5.4Hz)，5.23-5.40(1H，m)，7.15-7.26(2H，m)，7.44-7.50(2H，m)，8.05(1H，s)，8.82(1H，s)，15.46(1H，s)

MS(ESI)：M-418

Embodiment 3-85

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.25-3.38(2H，m)，3.82-3.89(2H，m)，4.21(2H，s)，5.27(1H，t)，5.40-5.50(1H，m)，7.10-7.21(6H，m)，7.30-7.40(1H，m)，7.40-7.50(1H，m)，7.77(1H，d)，8.14(1H，d)，8.14(1H，s)，8.96(1H，s)，15.15(1H，s)

MS(ESI)：M+466

Embodiment 3-86

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.70-3.80(2H，m)，4.42(2H，s)，4.69(2H，t)，4.95(1H，t)，7.37-7.42(1H，m)，7.51(1H，d，J＝6.2Hz)，7.59(1H，d，J＝7.9Hz)，8.48(1H，s)，8.99(1H，s)，9.04(1H，s)，14.68(1H，s)

MS(ESI)：M+393

Embodiment 4-1

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.26(3H，s)，3.74(2H，m)，4.42(2H，s)，4.61(2H，m)，5.09(1H，br)，7.78(1H，m)，7.84(2H，m)，8.04-8.07(2H，m)，8.18(1H，m)，8.86(1H，s)，15.19(1H，s)

MS(ESI)：M+435

Embodiment 4-2

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.73(2H，m)，4.23(2H，s)，4.59(2H，m)，4.99(1H，br)，7.20(1H，m)，7.31-7.34(2H，m)，7.44(1H，m)，7.85(1H，m)，8.01(1H，s)，8.26(1H，m)，8.85(1H，s)，15.27(1H，s)

MS(ESI)：M+407

Embodiment 4-3

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.15(3H，t，J＝7.6Hz)，2.57(2H，q，J＝7.6Hz)，3.73(2H，m)，4.13(2H，s)，4.59(2H，m)，4.99(1H，m)，7.05(2H，m)，7.13(1H，m)，7.20(1H，m)，7.81(1H，m)，7.98(1H，m)，8.21(1H，s)，8.84(1H，s)，15.28(1H，s)

MS(ESI)：M+351

Embodiment 4-4

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：1.07(3H，t，J＝7.53Hz)，2.58(2H，q，J＝7.53Hz)，3.76(2H，m)，4.22(2H，s)，4.61(2H，m)，5.02(1H，m)，7.19-7.23(4H，m)，7.76(1H，m)，8.01(1H，m)，8.09(1H，s)，8.86(1H，s)，15.26(1H，s)

MS(ESI)：M+351

Embodiment 4-5

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：2.28(3H，s)，3.75(2H，m)，4.24(2H，s)，4.61(2H，m)，5.04(1H，br)，7.13(1H，d，J＝8.1Hz)，7.28-7.36(2H，m)，7.81(1H，d，J＝6.7Hz)，8.03(1H，d，J＝8.9Hz)，8.13(1H，s)，8.86(1H，s)，15.24(1H，brs)

MS(ESI)：M+372

Embodiment 4-6

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.29(2H，s)，4.62(2H，m)，5.07(1H，m)，7.19(1H，m)，7.40(1H，m)，7.52(1H，m)，7.84(1H，m)，8.05(1H，m)，8.19(1H，s)，8.87(1H，s)，15.20(1H，s)

MS(ESI)：M+375

Embodiment 4-7

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(2H，m)，4.29(2H，s)，4.61(2H，t，J＝5.0Hz)，5.01(2H，t，J＝5.4Hz)，7.45(1H，d)，7.51(1H，d，J＝11.2Hz)，7.74(1H，d)，7.84(1H，dd)，8.01(1H，d)，8.15(1H，s)，8.86(1H，s)，15.21(1H，brs)

MS(ESI)：M+436

Embodiment 4-8

Embodiment 4-9

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.76(2H，m)，4.34(2H，s)，4.59(2H，m)，5.01(1H，m)，7.37(2H，m)，7.62(1H，m)，8.07(2H，m)，8.88(1H，s)，14.99(1H，s)

MS(ESI)：M+409

Embodiment 4-10

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.20(3H，s)，3.74(2H，m)，4.31(2H，s)，4.61(2H，t)，5.00(1H，t)，7.55-7.66(2H，m)，7.78(1H，d)，7.84-7.89(2H，m)，8.03(1H，d，J＝8.9Hz)，8.30(1H，s)，8.86(1H，s)，15.27(1H，brs)

MS(ESI)：M+402

Embodiment 4-11

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.75(2H，m)，4.18(2H，s)，4.61(2H，m)，5.02(1H，m)，6.69(1H，m)，6.77(1H，m)，7.23(1H，m)，7.80(1H，m)，8.02(1H，m)，8.15(1H，s)，8.86(1H，s)，9.66(1H，s)，15.24(1H，s)

MS(ESI)：M+373

Embodiment 4-12

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：3.75(2H，m)，4.29(2H，s)，4.58(2H，m)，5.00(1H，s)，7.31(1H，m)，7.35(1H，m)，7.58(1H，m)，7.71(1H，m)，7.82(1H，m)，8.86(1H，s)

MS(ESI)：M+409

Embodiment 4-13

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.34(3H，t，J＝6.8Hz)，3.73(2H，m)，4.00(2H，q，J＝6.8Hz)，4.09(2H，s)，4.59(2H，m)，5.00(1H，m)，6.89(1H，m)，6.95(1H，m)，7.19(1H，m)，7.27(1H，m)，7.83(1H，m)，7.97(1H，m)，8.24(1H，s)，8.84(1H，s)，15.33(1H，s)

MS(ESI)：M+367

Embodiment 4-14

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：3.73(2H，m)，4.06(2H，s)，4.60(2H，m)，5.05(1H，m)，6.74(1H，m)，6.85(1H，m)，7.05(1H，m)，7.14(1H，m)，7.82(1H，m)，7.99(1H，m)，8.19(1H，s)，8.84(1H，s)，9.55(1H，s)，15.34(1H，s)

MS(ESI)：M+339

Embodiment 4-15

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：2.49(3H，s)，3.77(2H，m)，4.27(2H，s)，4.60(2H，m)，5.01(1H，s)，7.17(1H，m)，7.35(1H，m)，7.59(1H，m)，7.78(1H，s)，7.95(1H，s)，8.81(1H，s)，15.22(1H，s)

MS(ESI)：M+406

Embodiment 4-16

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：1.35(3H，d)，1.40(3H，d)，1.54(3H，d，J＝6.8Hz)，3.72(2H，m)，4.20(2H，s)，4.86-4.92(1H，m)，5.12(1H，t，J＝5.2Hz)，5.80-5.90(1H，m)，7.20(1H，m)，7.39-7.52(3H，m)，7.74(1H，s)，8.84(1H，s)，15.13(1H，s)

MS(ESI)：M+448

Embodiment 4-17

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，t，J＝7.2Hz)，1.35-1.37(6H，d)，1.88-2.06(2H，m)，3.73-3.79(2H，m)，4.20(2H，s)，4.80-5.00(1H，m)，5.16(1H，t)，5.81-5.84(1H，m)，7.20(1H，m)，7.40-7.53(3H，m)，7.75(1H，s)，8.83(1H，s)，15.09(1H，s)

MS(ESI)：M+462

Embodiment 4-18

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.80-1.40(6H，m)，1.40-1.60(2H，m)，1.70-1.80(1H，m)，1.80-2.10(2H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，4.26(2H，s)，4.80-5.00(1H，m)，5.19(1H，t)，7.22-7.25(1H，m)，7.42-7.49(2H，m)，7.85(1H，d)，8.22(1H，s)，8.26(1H，d，J＝9.1Hz)，8.95(1H，s)

MS(ESI)：M+458

Embodiment 4-19

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.70(3H，d，J＝6.6Hz)，1.14(3H，d，J＝6.4Hz)，1.21-1.24(6H，m)，2.20-2.40(1H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，4.09(2H，s)，4.80-4.90(1H，m)，5.00-5.20(2H，m)，7.12-7.22(2H，m)，7.43-7.47(2H，m)，8.19(1H，s)，8.87(1H，s)，15.51(1H，s)

MS(ESI)：M+476

Embodiment 4-20

MS(ESI)：M+490

Embodiment 4-21

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，t，J＝7.6Hz)，1.44(3H，t)，1.92-2.06(2H，m)，3.78(2H，m)，4.19(2H，s)，4.25(2H，q)，5.17(1H，t，5.6Hz)，5.78-5.83(1H，m)，7.20(1H，m)，7.39-7.51(3H，m)，7.76(1H，s)，8.85(1H，s)，15.11(1H，s)

MS(ESI)：M+448

Embodiment 4-22

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.80-1.30(6H，m)，1.50-1.80(5H，m)，1.80-1.90(2H，m)，3.60-3.80(2H，m)，4.26(2H，s)，5.10-5.20(2H，m)，7.22(1H，m)，7.30-7.50(2H，m)，7.85(1H，d)，8.23(1H，d)，8.23(1H，s)，8.84(1H，s)，15.20(1H，s)

MS(ESI)：M+472

Embodiment 4-23

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.85(3H，d)，0.91(3H，d)，1.24-1.27(6H，m)，1.35-1.43(1H，m)，1.70-1.80(1H，m)，1.91-1.95(1H，m)，3.75-3.80(2H，m)，4.08(2H，s)，5.00-5.10(1H，m)，5.16-5.19(2H，m)，7.14-7.21(2H，m)，7.43-7.44(2H，m)，8.18(1H，s)，8.79(1H，s)

MS(ESI)：M+490

Embodiment 4-24

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.72(3H，d)，1.09(3H，d)，1.37-1.40(6H，m)，2.35-2.38(1H，m)，3.77-3.79(1H，m)，3.91-3.94(1H，m)，4.20(2H，s)，4.92-4.96(1H，m)，5.23(1H，t)，5.74-5.76(1H，m)，7.21(1H，m)，7.40-7.53(3H，m)，7.75(1H，s)，8.88(1H，s)，15.08(1H，s)

MS(ESI)：M+476

Embodiment 4-25

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.84(3H，d，J＝6.8Hz)，0.87(3H，d，J＝6.4Hz)，1.37(3H，d，J＝11.2Hz)，1.42(3H，d，J＝10.8Hz)，1.83-1.87(2H，m)，3.79-3.80(2H，m)，4.20(2H，s)，4.90-4.96(1H，m)，5.20(1H，t)，6.08-6.10(1H，m)，7.21(1H，m)，7.39-7.55(3H，m)，7.75(1H，s)，8.78(1H，s)，15.08(1H，s)

MS(ESI)：M+490

Embodiment 4-26

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.91(9H，s)，1.35(3H，d)，1.44(3H，d)，4.02-4.03(2H，m)，4.20(2H，s)，4.92-4.95(1H，m)，5.15(1H，t)，6.43(1H，t)，7.19-7.21(1H，m)，7.39-7.48(2H，m)，7.55(1H，s)，7.79(1H，s)，8.80(1H，s)，15.05(1H，s)

MS(ESI)：M+490

Embodiment 4-27

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.76(3H，t)，0.97-1.03(2H，m)，1.12(3H，d)，2.10-2.20(1H，m)，3.75-3.80(1H，m)，3.98-4.02(1H，m)，4.02(3H，s)，4.11(2H，s)，4.92-4.95(1H，m)，5.19(1H，t)，7.16-7.25(2H，m)，7.44-7.50(2H，m)，8.02(1H，s)，8.87(1H，s)，15.40(1H，s)

MS(ESI)：M+462

Embodiment 4-28

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.74(3H，t，J＝7.6Hz)，0.99-1.03(2H，m)，1.11(3H，d)，1.37(3H，t，J＝6.8Hz)，2.10-2.20(1H，m)，3.70-3.80(1H，m)，3.96-4.00(1H，m)，4.11(2H，s)，4.26(2H，q，J＝7.2Hz)，4.92-5.00(1H，m)，5.18(1H，t)，7.14-7.18(1H，m)，7.24-7.25(1H，m)，7.40(1H，s)，7.44-7.46(1H，m)，8.12(1H，s)，8.86(1H，s)，15.46(1H，s)

MS(ESI)：M+476

Embodiment 4-29

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.89(3H，t，J＝7.3Hz)，1.98-2.01(2H，m)，2.70(3H，s)，3.80-3.90(2H，m)，4.21(2H，s)，5.10-5.21(2H，m)，7.15-7.22(2H，m)，7.49-7.51(1H，m)，7.65(1H，s)，8.04(1H，s)，8.84(1H，s)，15.25(1H，s)

MS(ESI)：M+450

Embodiment 4-30

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.70(3H，d，J＝6.5Hz)，1.15(3H，d，J＝6.5Hz)，1.37(3H，t，J＝6.9Hz)，2.30-2.40(1H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，4.11(2H，s)，4.20-4.30(2H，m)，4.80-4.90(1H，m)，5.18(1H，t)，7.14-7.20(1H，m)，7.24-7.26(1H，m)，7.43-7.49(2H，m)，8.13(1H，s)，8.87(1H，s)，15.49(1H，s)

MS(ESI)：M+462

Embodiment 4-31

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.97(9H，s)，1.37(3H，t，J＝6.9Hz)，4.02-4.11(4H，m)，4.25-4.31(2H，m)，5.10-5.20(2H，m)，7.14-7.26(2H，m)，7.44-7.49(2H，m)，8.12(1H，s)，8.78(1H，s)，15.43(1H，s)

MS(ESI)：M+476

Embodiment 4-32

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.72(3H，d，J＝6.5Hz)，1.16(3H，d，J＝6.5Hz)，2.30-2.50(1H，m)，3.70-3.90(1H，m)，3.90-4.00(1H，m)，4.03(3H，s)，4.12(2H，s)，4.80-4.90(1H，m)，5.19(1H，t)，7.19-7.25(2H，m)，7.46-7.51(2H，m)，8.04(1H，s)，8.88(1H，s)，15.44(1H，s)

MS(ESI)：M+448

Embodiment 4-33

MS(ESI)：M+462

Embodiment 4-34

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.93(9H，s)，3.90-4.03(5H，m)，4.22(2H，s)，5.10(1H，t)，6.20(1H，t)，7.20-7.30(1H，m)，7.40-7.57(2H，m)，7.60(1H，s)，7.79(1H，s)，8.78(1H，s)，15.05(1H，s)

MS(ESI)：M+462

Embodiment 4-35

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.86(3H，t，J＝7.2Hz)，1.19-1.29(8H，m)，1.90-1.93(2H，m)，3.72-3.80(2H，m)，4.08(2H，s)，5.02-5.04(1H，m)，5.10-5.20(2H，m)，7.11-7.22(2H，m)，7.43-7.46(2H，m)，8.18(1H，s)，8.78(1H，s)，15.51(1H，s)

MS(ESI)：M+476

Embodiment 4-36

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.88(3H，t，J＝7.2Hz)，1.20-1.35(2H，m)，1.36(3H，t，J＝6.8Hz)，1.80-2.00(2H，m)，3.70-3.80(2H，m)，4.11(2H，s)，4.25(2H，q，J＝7.2Hz)，5.17(1H，t，J＝5.6Hz)，7.14-7.18(1H，m)，7.24-7.26(1H，m)，7.41(1H，s)，7.41-7.45(1H，m)，8.13(1H，s)，8.78(1H，s)，15.48(1H，s)

MS(ESI)：M+462

Embodiment 4-37

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.93(9H，s)，1.49(3H，t)，4.00(2H，t，J＝6.4Hz)，4.20(2H，s)，4.22-4.33(2H，m)，5.12(1H，t)，6.36(1H，t，J＝6.8Hz)，7.21(1H，m)，7.39-7.48(2H，m)，7.54(1H，s)，7.79(1H，s)，8.79(1H，s)，15.04(1H，s)

MS(ESI)：M+476

Embodiment 4-38

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，t，J＝8.0Hz)，1.23-1.40(2H，m)，1.80-2.00(2H，m)，3.75-3.90(2H，m)，4.02(3H，s)，4.11(2H，s)，5.10-5.21(2H，m)，7.16-7.24(2H，m)，7.44-7.49(2H，m)，8.03(1H，s)，8.80(1H，s)，15.44(1H，br)

MS(ESI)：M+448

Embodiment 4-39

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.74(3H，t，J＝7.1Hz)，0.84-1.24(11H，m)，2.10-2.30(1H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，4.09(2H，s)，4.80-5.17(3H，m)，7.15-7.22(2H，m)，7.40-7.50(2H，m)，8.19(1H，s)，8.87(1H，s)，15.51(1H，s)

MS(ESI)：M+490

Embodiment 4-40

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.80-0.89(1H，m)，1.04-1.30(11H，m)，1.50-1.60(2H，m)，1.70-1.80(1H，m)，1.93-2.01(2H，m)，3.73-3.76(1H，m)，3.96-4.00(1H，m)，4.07(2H，s)，4.80-4.89(1H，m)，5.00-5.17(2H，m)，7.12-7.21(2H，m)，7.40-7.42(2H，m)，8.17(1H，s)，8.87(1H，s)

MS(ESI)：M+516

Embodiment 4-41

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.80-1.30(6H，m)，1.46(3H，t，J＝6.9Hz)，1.50-1.70(2H，m)，1.70-1.80(1H，m)，1.90-2.10(2H，m)，3.70-3.81(1H，m)，3.92-4.00(1H，m)，4.20(3H，s)，4.23(2H，q，J＝6.6Hz)，5.20(1H，t，J＝4.8Hz)，5.70-5.81(1H，m)，7.19-7.24(1H，m)，7.38-7.51(3H，m)，7.77(1H，s)，8.91(1H，s)，15.11(1H，s)

MS(ESI)：M+502

Embodiment 4-42

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.84-1.30(6H，m)，1.50-1.70(2H，m)，1.70-1.90(1H，m)，1.94-2.10(2H，m)，3.70-3.79(1H，m)，3.90-4.00(1H，m)，4.03(3H，s)，4.10(2H，s)，4.80-5.00(1H，m)，5.19(1H，m)，7.19-7.30(2H，m)，7.43-7.48(2H，m)，8.02(1H，s)，8.87(1H，s)，15.45(1H，s)

MS(ESI)：M+488

Embodiment 4-43

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.80-1.00(1H，m)，1.14-1.28(5H，m)，1.37(3H，t，J＝6.9Hz)，1.50-1.70(2H，m)，1.70-1.80(1H，m)，1.90-2.10(2H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，4.11(2H，s)，4.25(2H，q)，4.80-5.00(1H，m)，5.18(1H，m)，7.17-7.26(2H，m)，7.41-7.47(2H，m)，8.13(1H，s)，8.89(1H，s)

MS(ESI)：M+502

Embodiment 4-44

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.80-1.00(1H，m)，1.00-1.40(5H，m)，1.50-1.70(2H，m)，1.70-1.80(1H，m)，1.90-2.10(2H，m)，3.70-3.80(1H，m)，3.90-4.00(1H，m)，3.98(3H，s)，4.21(2H，s)，5.20(1H，m)，5.60-5.70(1H，m)，7.19-7.25(1H，m)，7.39-7.54(3H，m)，7.77(1H，s)，8.92(1H，s)

MS(ESI)：M+488

Embodiment 4-45

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.74(3H，d，J＝4.0Hz)，1.08(3H，d，J＝8.0Hz)，1.45(3H，t，J＝8.0Hz)，2.36-2.40(2H，m)，3.70-3.80(1H，m)，3.89-3.93(1H，m)，4.19(2H，s)，4.26(2H，q，J＝8.0Hz)，5.20(1H，t，J＝8.0Hz)，5.69-5.73(1H，m)，7.17-7.20(1H，m)，7.39(1H，m)，7.48-7.51(2H，m)，7.76(1H，s)，8.89(1H，s)

MS(ESI)：M+462

Embodiment 4-46

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.73(3H，d，J＝6.8Hz)，1.08(3H，d，J＝6.8Hz)，2.20-2.40(2H，m)，3.81-3.91(1H，m)，3.91-3.99(1H，m)，3.99(3H，s)，4.22(2H，s)，5.20(1H，m)，5.55-5.58(1H，m)，7.10-7.22(1H，m)，7.41-7.55(3H，m)，7.77(1H，s)，8.91(1H，s)，15.09(1H，s)

MS(ESI)：M+448

Embodiment 4-47

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.85(3H，d，J＝7.3Hz)，1.10-1.34(2H，m)，1.33(6H，d，J＝6.0Hz)，1.70-2.00(2H，m)，3.75(2H，m)，4.17(2H，s)，4.80-4.90(1H，m)，5.14(1H，m)，5.80-6.00(1H，m)，7.10-7.20(1H，m)，7.30-7.50(3H，m)，7.72(1H，s)，8.80(1H，s)

MS(ESI)：M+476

Embodiment 4-48

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，t)，1.20-1.40(2H，m)，1.44(3H，t)，1.80-2.00(2H，m)，3.78(2H，m)，4.20(2H，s)，4.23(2H，q，J＝6.8Hz)，5.16(1H，t，J＝5.6Hz)，5.90-5.92(1H，m)，7.15-7.21(1H，m)，7.39-7.52(3H，m)，7.76(1H，s)，8.84(1H，s)，15.10(1H，s)

MS(ESI)：M+462

Embodiment 4-49

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.89(3H，t)，1.23-1.35(2H，m)，1.87-1.96(2H，m)，3.72-3.79(2H，m)，3.98(3H，s)，4.21(2H，s)，5.15(1H，t，J＝5.2Hz)，5.85-5.88(1H，m)，7.15-7.21(1H，m)，7.39-7.48(2H，m)，7.54(1H，s)，7.76(1H，s)，8.85(1H，s)，15.10(1H，s)

MS(ESI)：M+448

Embodiment 4-50

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.80-1.00(1H，m)，1.11-1.20(4H，m)，1.20-1.30(1H，m)，1.35(3H，d)，1.40(3H，d)，1.55-1.70(2H，m)，1.72-1.80(1H，m)，1.95-2.10(2H，m)，3.77-3.79(1H，m)，3.95-3.98(1H，m)，4.20(2H，s)，4.91-4.94(1H，m)，5.24(1H，t)，5.81-5.83(1H，m)，7.15-7.21(1H，m)，7.39-7.50(2H，m)，7.53(1H，s)，7.74(1H，s)，8.89(1H，s)，15.09(1H，s)

MS(ESI)：M+516

Embodiment 4-51

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.91(9H，s)，1.48(3H，t，J＝6.9Hz)，3.90-4.00(2H，m)，4.13(2H，s)，4.22(2H，q，J＝7.0Hz)，4.90-5.00(1H，m)，6.10-6.20(1H，m)，7.17-7.22(1H，m)，7.34-7.36(2H，m)，7.45-7.50(1H，m)，7.77(1H，s)，8.75(1H，s)

MS(ESI)：M+476

Embodiment 4-52

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.93(9H，s)，3.90-4.02(2H，m)，4.15(2H，s)，4.80-4.81(1H，m)，5.05(1H，m)，7.19-7.21(1H，m)，7.35-7.40(1H，m)，7.43-7.45(1H，m)，7.57(1H，d)，8.01-8.03(1H，d，J＝8.8Hz)，8.12(1H，s)，8.76(1H，s)

MS(ESI)：M+432

Embodiment 4-53

¹H?NMR(DMSO-d ₆?400MHz)(δ)ppm：0.81(3H，d)，1.20(3H，d)，2.28-2.41(1H，m)，3.98(3H，s)，4.00-4.05(2H，m)，4.08(2H，s)，4.51-4.60(1H，m)，7.02-7.08(2H，m)，7.19(1H，s)，7.28-7.30(1H，m)，8.15(1H，s)，8.60(1H，s)

MS(ESI)：M+448

Embodiment 4-54

¹H?NMR(DMSO-d ₆?300MHz)(δ)ppm：0.95(9H，s)，3.96(3H，s)，3.96-4.03(4H，m)，4.83(1H，m)，5.17(1H，m)，7.13-7.23(2H，m)，7.28(1H，s)，7.42-7.47(1H，m)，7.80(1H，s)，8.73(1H，s)

MS(ESI)：M+462

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

Industrial applicibility

Can clearly be seen that from The above results compound of the present invention has high hiv integrase and suppresses active.

Therefore, these compounds can be used for prevention or treatment AIDS efficacious agents, suppress active anti-HIV medicament as having hiv integrase.And by uniting use with other anti-HIV medicament such as proteinase inhibitor, reverse transcriptase inhibitors etc., these compounds can become more effective anti-HIV medicament.Because these compounds suppress active for the specificity that intergrase has height, provide the safe very little medicament of side effect so they can be the mankind.

The application's basis is the patent application 2002-336843 that submits in Japan, and 2003-65807 and 2003-139616 number, its content all is incorporated herein by reference.

Sequence table

＜110〉Japan tobacco Inc (Japan Tobacco Inc.)

＜120〉4-oxoquinoline compound and as the purposes of hiv integrase inhibitor

<130>09593

<140>

<141>

<150>JP?2002-336843

<151>2002-11-20

<150>JP?2003-065807

<151>2003-03-11

<150>JP?2003-139616

<151>2003-5-16

<160>4

<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. an anti-HIV medicament comprises the 4-oxoquinoline compound shown in the following formula [I] or its pharmaceutically acceptable salt, as activeconstituents:

In the formula

Ring Cy is for choosing wantonly by 1～5 C that is selected from the substituting group replacement of following A group _3-10Carbocylic radical, or optional by 1～5 heterocyclic radical that is selected from the substituting group replacement of following A group,

Wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom, and the A group is made up of following groups: cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1And-NR ^A2COOR ^A3

R wherein ^A1And R ^A2Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, R ^A3Be C _1-4Alkyl;

R wherein ^A4And R ^A5Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, R ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group;

R ²Be hydrogen atom or C _1-4Alkyl;

X is C-R ³²Or nitrogen-atoms; And

Y is C-R ³³Or nitrogen-atoms

R wherein ³²And R ³³Identical or the different and hydrogen atom of respectively doing for oneself, cyano group, nitro, halogen atom, the optional C that is replaced by 1～5 substituting group that is selected from above-mentioned A group _3-10Carbocylic radical is chosen wantonly by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group, or optional by 1～3 C that is selected from the substituting group replacement of halogen atom and above-mentioned B group _1-10Alkyl,

-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9,-COOR ^A10Or-N=CH-NR ^A10R ^A11,

R wherein ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl, R ^A9Be C _1-4Alkyl, R ^A10And R ^A11Identical or different and respectively do for oneself hydrogen atom or C _1-4Alkyl.

2. according to the anti-HIV medicament of claim 1, wherein X is C-R ³²And Y is C-R ³³

3. according to the anti-HIV medicament of claim 1, wherein encircle Cy and be

In the formula

4. according to the anti-HIV medicament of claim 1, R wherein ²Be hydrogen atom.

5. the 4-oxoquinoline compound shown in the formula [II] or its pharmaceutically acceptable salt below one kind:

In the formula

R ⁴And R ⁶Identical or different and respectively do for oneself and be selected from the substituting group of following A group

Wherein the A group is made up of following groups: cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-COR ^A3,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3,-COOR ^A1And-NR ^A2COOR ^A3

R ⁵For being selected from the substituting group of hydrogen atom and above-mentioned A group, R ⁴And R ⁵Can form condensed ring with the phenyl ring that they replaced;

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, the optional heterocyclic radical that is replaced by 1～5 substituting group that is selected from above-mentioned A group (this heterocyclic radical such as top defined wherein, be saturated or undersaturated ring, it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R ³¹Be hydrogen atom, cyano group, hydroxyl, amino, nitro, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Alkylthio, halo C _1-4Alkyl or halo C _1-4Alkoxyl group; And

6. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of claim 5 ³¹Be hydrogen atom, cyano group, hydroxyl or C _1-4Alkoxyl group.

7. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of claim 6 ³¹Be hydrogen atom.

8. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of claim 5 ³²And R ³³Identical or the different and hydrogen atom of respectively doing for oneself, cyano group, halogen atom, the optional heterocyclic radical that is replaced by 1～5 substituting group that is selected from following A group,

R wherein ^A1And R ^A2Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl,

Optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl, wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional, and R by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group,

-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9,-COOR ^A10Or-N=CH-NR ^A10R ^A11

R wherein ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl, R ^A9Be C _1-4Alkyl, poly-and R ^A10And R ^A11Identical or different and respectively do for oneself hydrogen atom or C _1-4Alkyl.

9. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of claim 5 ³²Be hydrogen atom, cyano group, halogen atom, optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

-OR ^A7,-SR ^A7,-NR ^A7R ^A8,-NR ^A7COR ^A9Or-COOR ^A10

R wherein ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl, R ^A9Be C _1-4Alkyl, and R ^A10Be hydrogen atom or C _1-4Alkyl.

10. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt, the wherein R of claim 9 ³²Be hydrogen atom ,-OR ^A7Or-NR ^A7R ^A8, R here ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl.

11. 4-oxoquinoline compound according to Claim 8 or its pharmaceutically acceptable salt, wherein R ³³Be hydrogen atom, optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group _1-10Alkyl,

Wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6

-OR ^A7Or-NR ^A7R ^A8

R wherein ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl.

12. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of claim 11, wherein

R ³³Be hydrogen atom ,-OR ^A7Or-NR ^A7R ^A8,

R wherein ^A7And R ^A8Identical or the different and hydrogen atom of respectively doing for oneself, B group group or the optional C that is replaced by 1～3 substituting group that is selected from halogen atom and above-mentioned B group _1-10Alkyl.

13. each 4-oxoquinoline compound or its pharmaceutically acceptable salt according to Claim 8～12, wherein

R ^A7And R ^A8Identical or different, and it is optional by 1～3 C that substituting group replaced that is selected from halogen atom or following B group respectively to do for oneself _1-10Alkyl, wherein the B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6,

R wherein ^A4And R ^A5Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional, and R by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group.

14. 4-oxoquinoline compound or its pharmaceutically acceptable salt, wherein R according to claim 5 ⁴And R ⁵Identical or different and respectively do for oneself and be selected from cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A2COOR ^A3And-COOR ^A1Substituting group,

R wherein ^A1And R ^A2Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl or benzyl, and R ^A3Be C _1-4Alkyl.

15. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of claim 14, wherein

R ⁴Be phenyl, halogen atom, C _1-4Alkyl, halo C _1-4Alkoxyl group ,-OR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2,-NR ^A1COR ^A3,-SO ₂R ^A3,-NR ^A1SO ₂R ^A3Or-COOR ^A1,

16. 4-oxoquinoline compound or its pharmaceutically acceptable salt, wherein R according to claim 15 ⁴Be halogen atom.

17. 4-oxoquinoline compound or its pharmaceutically acceptable salt, wherein R according to claim 5 ⁵Be hydrogen atom, cyano group, phenyl, nitro, halogen atom, C _1-4Alkyl, halo C _1-4Alkyl ,-OR ^A1,-SR ^A1,-NR ^A1R ^A2,-CONR ^A1R ^A2,-SO ₂NR ^A1R ^A2Or-NR ^A1COR ^A3,

18. 4-oxoquinoline compound or its pharmaceutically acceptable salt, wherein R according to claim 5 ⁶Be halogen atom.

19. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of claim 5, wherein m is 0 or 1.

20. 4-oxoquinoline compound or its pharmaceutically acceptable salt, wherein R according to claim 5 ¹For choosing wantonly by 1～5 C that is selected from the substituting group replacement of following A group _3-10Carbocylic radical,

Be selected from-NR ^A4R ^A5,-NR ^A4COR ^A6,-NR ^A4SO ₂R ^A6And-NR ^A5COOR ^A6Substituting group,

R wherein ^A4And R ^A5Identical or the different and hydrogen atom of respectively doing for oneself, C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, or optional by 1～5 heterocyclic radical (wherein this heterocyclic radical is saturated or undersaturated ring, and it also comprises the heteroatoms that at least one is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except carbon atom) that is selected from the substituting group replacement of above-mentioned A group, and R ^A6Be C _1-4Alkyl, optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical or the optional heterocyclic radical (define the same) that is replaced by 1～5 substituting group that is selected from above-mentioned A group, perhaps optional by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl wherein B group is made up of following groups: optional by 1～5 C that is selected from the substituting group replacement of above-mentioned A group _3-10Carbocylic radical, optional by 1～5 heterocyclic radical (defining the same) that is selected from the substituting group replacement of above-mentioned A group ,-OR ^A4,-SR ^A4,-NR ^A4R ^A5,-CONR ^A4R ^A5,-SO ₂NR ^A4R ^A5,-COR ^A6,-NR ^A4COR ^A6,-SO ₂R ^A6,-NR ^A4SO ₂R ^A6,-COOR ^A4And-NR ^A5COOR ^A6(R wherein ^A4, R ^A5, R ^A6And the definition of A group is the same).

21. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of claim 20, wherein

R ¹For choosing wantonly by 1～3 C that is selected from the substituting group replacement of halogen atom and following B group _1-10Alkyl,

22. according to 4-oxoquinoline compound or its pharmaceutically acceptable salt of claim 5, it is selected from following compounds:

(S)-and 6-(3-chloro-2-luorobenzyl)-1-[2,2-dimethyl-1-(methylol) propyl group]-7-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (embodiment 4-33),

23. a pharmaceutical composition, it comprises in the claim 5～22 each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

24. an integrase inhibitor, its comprise in the claim 1～22 each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

25. an antiviral agent, its comprise in the claim 5～22 each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

26. an anti-HIV medicament, its comprise in the claim 5～22 each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents.

27. an anti-HIV combination thing, it comprises in the claim 1～22 each 4-oxoquinoline compound or its pharmaceutically acceptable salt, and other one or more anti-HIV active substances are as activeconstituents.

28. an anti-HIV medicament, its comprise in the claim 1～22 each the 4-oxoquinoline compound or its pharmaceutically acceptable salt as activeconstituents, be used for multiple medicines agent conjoint therapy with other anti-HIV medicament.

29. each 4-oxoquinoline compound or its pharmaceutically acceptable salt purposes in preparation anti-HIV medicament in the claim 5～22.

30. each 4-oxoquinoline compound or its pharmaceutically acceptable salt purposes in the preparation integrase inhibitor in the claim 5～22.

31. each 4-oxoquinoline compound or its pharmaceutically acceptable salt purposes in the preparation antiviral agent in the claim 5～22.

32. the method for prevention or treatment HIV transmissible disease comprises significant quantity delivered medicine to Mammals according to each 4-oxoquinoline compound or its pharmaceutically acceptable salt in the claim 5～22.

33., comprise that further at least a different anti-HIV active substance with significant quantity delivers medicine to described Mammals according to the prevention of claim 32 or the method for treatment HIV transmissible disease.

34. a method that suppresses intergrase comprises significant quantity delivered medicine to Mammals according to each 4-oxoquinoline compound or its pharmaceutically acceptable salt in the claim 5～22.

35. the method for prevention or treatment viral infectious comprises significant quantity delivered medicine to Mammals according to each 4-oxoquinoline compound or its pharmaceutically acceptable salt in the claim 5～22.

36. an anti-HIV combination thing comprises in the claim 5～22 each 4-oxoquinoline compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

37. a pharmaceutical composition that suppresses intergrase comprises in the claim 5～22 each 4-oxoquinoline compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

38. an antiviral composition comprises in the claim 5～22 each 4-oxoquinoline compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

39. a commercial cartridge bag, it comprises the composition of claim 36 and associated specification sheets, and described specification sheets explanation said composition can or should be used for prevention or treatment HIV transmissible disease.

40. a commercial cartridge bag, it comprises the composition of claim 37 and associated specification sheets, and described specification sheets explanation said composition can or should be used to suppress intergrase.

41. a commercial cartridge bag, it comprises the composition of claim 38 and associated specification sheets, and described specification sheets explanation said composition can or should be used for prevention or treatment viral infectious.