CN109803951A

CN109803951A - Sulfamide compound as cccDNA inhibitor

Info

Publication number: CN109803951A
Application number: CN201780064019.4A
Authority: CN
Inventors: 付志飞; 张杨; 罗妙荣; 陈曙辉; 黎健; 徐宏江; 杨玲; 张喜全
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Medshine Discovery Inc
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Medshine Discovery Inc
Priority date: 2016-11-08
Filing date: 2017-11-08
Publication date: 2019-05-24
Anticipated expiration: 2037-11-08
Also published as: CN109803951B; WO2018086531A1

Abstract

This application discloses a series of sulfamide compound, its tautomer or the pharmaceutically acceptable salts indicated by general formula (I) and general formula (II) as cccDNA inhibitor.

Description

Sulfamide compound as cccDNA inhibitor

Cross reference to related applications

This application claims submitted on November 08th, 2016 to Intellectual Property Right Bureau of the RPC application No. is the equity of the Chinese invention patent application of CN201610979725.9, entire contents are integrally incorporated in a manner of quoting herein herein.

Technical field

This application involves a series of sulfamide compounds and its pharmaceutical composition as cccDNA inhibitor.

Background technique

Virus B hepatitis (hepatitis B, HB) is caused by hepatitis type B virus (hepatitis B virus, HBV).The infection of HBV can not only lead to acute chronic viral hepatitis and principal characteristic hepatitis, but also with cirrhosis (liver cirrhosis, LC) and the generation of hepatocellular carcinoma (hepatocellular carcinoma, HCC), development it is closely related.The Chronic Hepatitis B of 20 ﹪ will develop into cirrhosis, and the risk that the people of HBV chronic infection suffers from HCC is 100 times of normal person.HBV cccDNA is present in liver cell nuclear, is that mark and the chronic hepatitis B of virus success infected liver cell are persistently existing crucial, the stabilization of cccDNA plays a decisive role to the Long-term Infection state for maintaining cell.

Up to the present, obtain U.S. Food and Drug Administration (Food and Drug Administration, FDA) ratify and there are two major classes in the Anti-HBV drugs of clinical application: interferon and nucleoside analog, their representative drug is alpha interferon (interferon-a respectively,) and Lamivudine (Lamivudine, 3CT) IFN-a.It is generally acknowledged that alpha interferon and Lamivudine are unable to the HBV cccDNA in scavenger-cell, HBV still has the ability to infect new liver cell during the treatment of antiviral drugs, it is invalid to cccDNA, recurrence is easy after drug withdrawal, thus slow hepatitis B patient needs that antiviral treatment is used for a long time.

Therefore, it needs new to treat virus B hepatitis, particularly to the effective therapeutic agent of HBV cccDNA.

Summary of the invention

On the one hand, this application provides compound, its tautomer or pharmaceutically acceptable salt shown in general formula (I) and general formula (II),

Wherein,

R⁹Selected from hydrogen or methyl；

R¹Selected from hydrogen,

R²Selected from hydrogen or C₁-C₆Alkyl；

Structural unitIt is selected from

M is selected from 1,2,3,4 or 5；

Each R³Separately it is selected from hydrogen, halogen, C₁-C₆Alkoxy ,-NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂, 3~6 yuan of naphthenic base or 3~6 membered heterocycloalkyls；

Structural unitIt is selected from

Each R⁵Independently selected from hydrogen or methyl；

Each R⁸Independently selected from hydrogen, halogen or C₁-C₆Alkyl；

Each W is independently selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or C₁-C₆Alkyl；

T^a、T^bAnd T^cSeparately it is selected from -CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from hydroxyl, C₁-C₆Alkyloxycarbonyl amino or C₁-C₆Alkyloxycarbonyl amino methyl；Or T^a、T^bAnd T^cSeparately it is selected from-C (R^h)₂, and two R^h4~6 membered heterocycloalkyls are formed together with the C being connected with them, described 4~6 Membered heterocycloalkyl is optionally independently selected by one or more from=O or C₁-C₆The group of alkyloxycarbonyl replaces；

Ring Z¹For 3~5 membered heterocycloalkyls；

Ring Z²For 3~6 membered heterocycloalkyls, 5~6 unit's heteroaryls or phenyl；

Each R^bSeparately it is selected from halogen ,=O, cyano, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls；

P is selected from 0,1,2,3 or 4；

Each R^cWith each R^dSeparately it is selected from hydrogen, halogen, C_1-6The C that alkyl or halogen replace_1-6Alkyl；

Each R^gIndependently selected from-C (O)-NH (C₁-C₆Alkyl), 6-10 member aryl or 5~10 unit's heteroaryls, wherein 6~10 yuan of aryl and 5~10 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；

Ring Z³For 3~5 membered heterocycloalkyls；

Each R^eSeparately it is selected from halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls；

Q is selected from 0,1,2,3 or 4；

Structural unitSelected from following radicals: 3~6 membered heterocycloalkyl methyl, 5~9 unit's heteroaryl methyl ,-CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, wherein 3~6 membered heterocycloalkyl methyl and 5~9 unit's heteroaryl methyl are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；

R⁴Selected from hydrogen, cyano, hydroxyl, C_1-6Alkyl, C_2-6Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls, wherein C_1-6Alkyl and C_2-6The group that alkenyl is independently selected by one or more from halogen, hydroxyl, cyano ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls each independently optionally replaces, wherein 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl and 5~9 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；

L⁵Selected from-CH₂-；

R⁶Selected from C_1-6Alkyl or 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group to form 3~8 member rings；

R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, wherein the pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl and thiazolyl are independently selected by one or more from halogen ,-R each independently^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；

R^fSelected from C_1-6Alkyl, 3~6 yuan of naphthenic base, 5~10 unit's heteroaryls or 6~10 yuan of aryl, wherein the C_1-6The group that alkyl is independently selected by one or more from halogen, hydroxyl, amino, cyano, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；

Condition is: working as R¹Selected from hydrogen orOr structural unitIt is selected fromWhen, structural unitForFor-CH₂NHC (=O) NHR⁴, and R⁴It is not aryl or heteroaryl.

On the other hand, this application provides pharmaceutical compositions, it contains compound, its tautomer or pharmaceutically acceptable salt shown in general formula (I) and general formula (II) as active constituent and one or more pharmaceutically acceptable carriers, excipient or medium.

Another further aspect, this application provides the methods for the disease for the treatment of mammal mediated by cccDNA, including to the mammal for needing the treatment, it is preferred that the mankind, apply compound, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition shown in the general formula (I) and general formula (II) of therapeutically effective amount.

In another aspect, the purposes in the drug of the disease this application provides compound, its tautomer or its pharmaceutically acceptable salt shown in general formula (I) and general formula (II) or its pharmaceutical composition in preparation for preventing or treating cccDNA mediation.

Also on the one hand, this application provides compound, its tautomer or its pharmaceutically acceptable salts shown in general formula (I) and general formula (II) or its pharmaceutical composition to prevent or treat the purposes in the disease that cccDNA is mediated.

Also on the one hand, this application provides compound, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical compositions shown in the general formula (I) and general formula (II) of the disease for preventing or treating cccDNA mediation.

Detailed description of the invention

In the following description, including certain concrete details are to be fully understood by each disclosed embodiment offer.However, those skilled in the relevant art are not, it will be recognized that use one or more of these concrete details, and embodiment can be achieved in the case where using other methods, component, material etc..

Unless required in addition of the application, in the whole instruction and thereafter in claims, word " including (comprise) " and its English variant for example should be interpreted that meaning open, including formula " including (comprises) " and " including (comprising) ", i.e., " including but not limited to ".

" embodiment " mentioned in entire this specification or " embodiment " or " in another embodiment " or mean " in certain embodiments " include in an at least embodiment and relevant specific reference elements, structures, or characteristics described in the embodiment.Therefore, the phrase " in one embodiment " or " in embodiments " or " in another embodiment " or " in certain embodiments " that different location occurs throughout the specification need not all refer to same embodiment.In addition, key element, structure or feature can combine in one or more embodiments in any suitable manner.

It should be appreciated that the article " one " (correspond to English " a ", " an " and " the ") for the singular used in present specification and appended claims includes the object of plural number, unless it is other in text it is manifestly intended that.Thus, for example the reaction including " catalyst " mentioned includes a kind of catalyst or two or more catalyst.It is also understood that term "or" is usually with it includes the meaning of "and/or" and uses, unless in text in addition it is manifestly intended that.

On the one hand, this application provides general formula (I) and general formula (II) compound represented, its tautomer or pharmaceutically acceptable salt,

Wherein,

R⁹Selected from hydrogen or methyl；

R¹Selected from hydrogen,

R²Selected from hydrogen or C₁-C₆Alkyl；

Structural unitIt is selected from

M is selected from 1,2,3,4 or 5；

Structural unitIt is selected from

Each R⁵Independently selected from hydrogen or methyl；

Each R⁸Independently selected from hydrogen, halogen or C₁-C₆Alkyl；

T^a、T^bAnd T^cSeparately it is selected from -CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from hydroxyl, C₁-C₆Alkyloxycarbonyl amino or C₁-C₆Alkyloxycarbonyl amino methyl；Or T^a、T^bAnd T^cSeparately it is selected from-C (R^h)₂, and two R^h4~6 membered heterocycloalkyls are formed together with the C being connected with them, 4~6 membered heterocycloalkyl is optionally independently selected by one or more from=O or C₁-C₆The group of alkyloxycarbonyl replaces；

Ring Z¹For 3~5 membered heterocycloalkyls；

Ring Z²For 3~6 membered heterocycloalkyls, 5~6 unit's heteroaryls or phenyl；

P is selected from 0,1,2,3 or 4；

Ring Z³For 3~5 membered heterocycloalkyls；

Q is selected from 0,1,2,3 or 4；

Structural unitSelected from following radicals: 3~6 membered heterocycloalkyl methyl, 5~9 unit's heteroaryl methyl ,-CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, wherein 3~6 membered heterocycloalkyl methyl and 5~9 unit's heteroaryl methyl are respectively independent Ground is independently selected by one or more from halogen, hydroxyl, cyano, C_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；

L⁵Selected from-CH₂-；

R^fSelected from C_1-6Alkyl, 3~6 yuan of naphthenic base, 5~10 unit's heteroaryls or 6~10 yuan of aryl, wherein C_1-6The group that alkyl is independently selected by one or more from halogen, hydroxyl, amino, cyano, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；

In some embodiments of the application, compound shown in general formula (I) is general formula (I -1) compound represented:

Wherein, R¹、R³、m、R⁴、R⁹WithAs defined in general formula (I).

In some embodiments of the application, compound shown in general formula (I -1) is general formula (I -2) compound represented:

Wherein, R¹、R³、m、R⁹WithAs defined in general formula (I).

On the other hand, this application provides general formula (III) and general formula (IV) compound represented, its tautomer or pharmaceutically acceptable salt,

Wherein,

R₁Selected from H or

N is selected from 1,2,3,4 or 5；

Ring Y is selected from optionally by 1,2 or 3 R, 6~9 yuan of aryl replaced or heteroaryl；

R₂Separately it is selected from H, halogen, CN, Me, CF₃、OMe、OH、NH₂、NH(Me)、N(Me)₂With

Ring X is selected from the following substituent groups optionally replaced by 1,2 or 3 R: 6~9 yuan of aryl or heteroaryl and 3~6 yuan of naphthenic base or Heterocyclylalkyl；

M is selected from 1,2,3,4 or 5；

R₃Separately it is selected from H, halogen, CN, Me, CF₃、OMe、OH、NH₂、NH(Me)、N(Me)₂With

R₅Selected from H, halogen, CN, Me, CF₃、OMe、OH、NH₂、NH(Me)、NH(Me)₂、With 5~6 yuan of aryl or heteroaryl；

R₆Selected from the following substituent groups optionally replaced by 1,2 or 3 R: C_1-6Alkyl, C_1-6Miscellaneous alkyl, 3~6 yuan of naphthenic base and 3~6 membered heterocycloalkyls；

R₄Selected from H, halogen and CN, or selected from the following substituent groups optionally replaced by 1,2 or 3 R: OH, NH₂、C_1-6Alkyl, C_1-6Miscellaneous alkyl, C_2-6Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 5~6 yuan of aryl, 5~6 unit's heteroaryls ,-C_1-6Alkyl -3~6 yuan naphthenic base, -C_1-6Alkyl -3~6 membered heterocycloalkyls,-C_1-6Alkyl -5~6 yuan aryl,-C_1-6Alkyl -5~6 unit's heteroaryls,With-CH=NH；

L₄Selected from singly-bound or optionally by following substituent groups of 1,2 or 3 R ' substitution: CH₂、NH、CH₂NH、CH₂O, C (=O), CH₂CH₂C (=O), C (=O) O, C (=O) NH, CH₂NHC (=O), CH₂NHC (=O) O, CH₂OC (=O) NH, CH₂CH₂NHC (=O) O, CH₂NHC (=O) NH, CH (CH₃) NHC (=O) NH, CH₂N(CH₃) C (=O) NH and CH₂NHC (=O) N (CH₃)；

L₇Selected from CH₂, CHR ' and C (R ')₂, wherein R ' can be same or different；

R₇Selected from the following substituent groups optionally replaced by 1,2 or 3-L-R: 3~5 yuan of naphthenic base, 3~6 membered heterocycloalkyls and 5~6 unit's heteroaryls；

L is selected from singly-bound, C (=O), C (=O) O and C (=O) NH；

R₈Selected from H, halogen, CN, Me, CF₃、OMe、OH、NH₂, NH (Me) and N (Me)₂；

A is selected from singly-bound, O, NR and CRR, and wherein the R in CRR can be same or different；

D and E are separately selected from: CRR, C (=O) and singly-bound, wherein the R in CRR can be same or different；

G is selected from CH₂, CHR ' and C (R ')₂, wherein R ' can be same or different；

R is selected from H, halogen, OH, NH₂And CN, or selected from the following substituent groups optionally replaced by 1,2 or 3 R ': C_1-6Alkyl, C_1-6Heterocycle, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 5~6 yuan of aryl and 5~6 unit's heteroaryls；

R ' is selected from halogen, CN, Me, CF₃、OMe、OH、NH₂、NH(Me)、NH(Me)₂And Boc；

Optionally, when A is selected from CRR, two R therein can be connected with each other or be commonly connected on same group, form 4~6 member rings optionally replaced by 1,2 or 3 R '；

Optionally, D, E or A and R₄It can be connected with each other or be commonly connected on same group, form 3~6 member rings optionally replaced by 1,2 or 3 R, the ring is formed together 6-9 member fused rings with the ring where N, D, E and A；Optionally, R₅It can be connected with each other or be commonly connected on same group with E, form 3~8 member rings optionally replaced by 1,2 or 3 R；

Optionally, G and R₆It can be connected with each other or be commonly connected on same group, form 3~8 member rings optionally replaced by 1,2 or 3 R.

In some embodiments of the application, above-mentioned R is selected from H, halogen, OH, NH₂And CN, or selected from the following substituent groups optionally replaced by 1,2 or 3 R ': C_1-4Alkyl, C_1-4Miscellaneous alkyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl, pyridyl group, pyrimidine radicals, imidazole radicals, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl.In some embodiments of the application, above-mentioned R is selected from H, halogen, OH, NH₂And CN, or selected from the following substituent groups optionally replaced by 1,2 or 3 R ': n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, C_1-4Miscellaneous alkyl, 3~6 yuan of naphthenic base and 3~6 membered heterocycloalkyls, pyridyl group, pyrimidine radicals, imidazole radicals, pyrazolyl, oxazolyl, thiazolyl and isoxazolyl；Or selected from by Cl, Br, I, CN, Me, CF₃、OH、NH₂、NH(Me)、N(Me)₂The phenyl replaced with Boc；And the ring where N, E, D and A is not unsubstituted

In some embodiments of the application, above-mentioned R is selected from H, halogen, OH, NH₂And CN, or selected from the following substituent groups optionally replaced by 1,2 or 3 R ': n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, C_1-4Miscellaneous alkyl, 3~6 yuan of naphthenic base and 3~6 membered heterocycloalkyls, pyridyl group, pyrimidine radicals, imidazole radicals, pyrazolyl, oxazolyl, thiazolyl and isoxazolyl；Or selected from by Cl, Br, I, CN, Me、CF₃、OH、NH₂、NH(Me)、N(Me)₂The phenyl replaced with Boc；And the ring where N, E, D and A is not unsubstituted、

In some embodiments of the application, above-mentioned R is selected from: H, F, Cl, Br, I, OH, CN, NH₂、Me、Et、CH₂F、CHF₂、CF₃、OMe、OEt、NHCH₃、

In some embodiments of the application, above-mentioned R is selected from: H, OH,

In some embodiments of the application, above-mentioned ring Y is selected from the following substituent groups optionally replaced by 1,2 or 3 R: phenyl, pyridyl group, pyrimidine radicals, benzothiazolyl, naphthalene and thienyl.In some embodiments of the application, above-mentioned ring X is selected from the following substituent groups optionally replaced by 1,2 or 3 R: phenyl, naphthalene, cyclopropyl, pyridyl group, thienyl, pyrimidine radicals and benzothiazolyl.

In some embodiments of the application, above-mentioned R₁Selected from hydrogen, or it is selected from following substituent groups:

In some embodiments of the application, R²Selected from C₁-C₆Alkyl, preferably C₁-C₄Alkyl, more preferably methyl.

In some embodiments of the application, above-mentioned R₁Or R¹Selected from following radicals: hydrogen, Preferably More preferably

In some embodiments of the application, above structure unitIt is selected from

Structural unit in some embodiments of the application, in above-mentioned general formula (I) or general formula (II) compoundOr the structural unit of general formula (III) or general formula (IV) compoundSelected from following radicals: Preferably More preferably

In some embodiments of the application, the structural unit of above-mentioned general formula (I) or general formula (II) compoundOr the structural unit of general formula (III) or general formula (IV) compoundSelected from following radicals: Preferably More preferably

In some embodiments of the application, compound shown in general formula (III) and general formula (IV) is respectively general formula (V) and general formula (VI) compound represented:

Wherein R₃Selected from H, F, Cl, Br and I, preferably H and Cl.In some embodiments of the application, above-mentioned R₄Selected from H, or selected from optionally being replaced by 1,2 or 3 R: OH, NH₂、C_1-4Alkyl, C_1-4Miscellaneous alkyl, C_2-4Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl, pyridyl group, imidazole radicals, oxazolyl, isoxazolyl, 1,2,4- oxadiazoles base ,-C_1-3Alkyl -3~6 yuan naphthenic base,-C_1-3Alkyl -5~6 unit's heteroaryls,With-CH=NH.

In some embodiments of the application, compound shown in general formula (I) and general formula (II) is respectively general formula (VII) and (VIII) compound represented:

Wherein R³、R⁵、L⁵、R⁶、R⁷、R⁹And structural unitAs hereinbefore defined.

In some embodiments of the application, compound shown in general formula (VII) is respectively general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7) or general formula (VII -8) compound represented:

In some embodiments of the application, compound shown in general formula (III) or general formula (V) is not the compound with flowering structure:

Structure fragment in other embodiments of the application, in compound shown in general formula (III) or general formula (V)It is not following structure fragment:

In some embodiments of the application, the R³Separately it is selected from hydrogen, halogen, C₁-C₆Alkoxy ,-N (C₁-C₆Alkyl)₂Or 3~6 yuan of naphthenic base, preferably hydrogen, halogen, C₁-C₄Alkoxy ,-N (C₁-C₄Alkyl)₂Or 3~6 yuan of naphthenic base, more preferably hydrogen, halogen, methoxyl group, dimethylamino or cyclopropyl, most preferably hydrogen, chlorine, bromine, methoxyl group, dimethylamino or cyclopropyl.

In some embodiments of the application, W is selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or C₁-C₄Alkyl.

In the certain preferred embodiments of the application, W is selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or methyl.

In some more preferreds of the application, W is selected from-O- ,-N (CH₃)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or methyl.

In some most preferred embodiments of the application, W is selected from-O- ,-N (CH₃)-、-CH₂-、-CH(CH₃)-or-CF₂-。

In some embodiments of the application, structural unitIt is selected from Preferably More preferably

In some embodiments of the application, each R^cWith each R^dSeparately it is selected from hydrogen or C_1-6Alkyl, preferably hydrogen or C_1-4Alkyl, more preferably hydrogen or methyl.

In some embodiments of the application, structural unitIt is selected from Preferably More preferably Most preferably

In some embodiments of the application, above-mentioned R⁸Independently selected from hydrogen, halogen or C₁-C₄Alkyl, preferably hydrogen, fluorine, chlorine or C₁-C₄Alkyl, more preferably hydrogen, fluorine or methyl.

In some embodiments of the application, T^a、T^bAnd T^cSeparately it is selected from -CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from hydroxyl, C₁-C₄Alkyloxycarbonyl amino or C rise¹Shape C⁴At the miscellaneous carbonyl ring group alkylamino base of 4~base of alkane, 6 oxygen member base, first institute base is stated；4~or 6 member T are miscellaneous^a, ring T alkane^bBase and T^cChoosing point is stood alone by other one or ground multiselect is from the vertical (R of only-C^h)₂Choosing-, oneself and=O two or a CR₁ ^h- C with₄With one, the base substitution of the base C of alkane its bases oxygen Xiang Jilian carbonyl.

In the certain preferred embodiments of the application, T^aIt is selected from Or T^aSelected from-C (R^h)₂, and two R^hIt is formed together with the C being connected with them and is optionally independently selected by one or more from=O or C₁-C₆The 4-5 membered heterocycloalkyl that the group of alkyloxycarbonyl replaces, preferably optionally by the nitrogenous Heterocyclylalkyl of the 1 or 2=O 4-5 replaced member, the imidazoles more preferably optionally replaced by 1 or 2=O Alkyl.

In the certain preferred embodiments of the application, T^aIt is selected from Or optionally replaced by 1 or 2=O

In some more preferreds of the application, T^aIt is selected from

In the certain preferred embodiments of the application, T^bAnd T^cIt is separately-CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from C₁-C₆Alkyloxycarbonyl amino；Or two R^hIt is formed together with the C being connected with them by 1,2 or 3 C₁-C₆The nitrogenous 4-5 membered heterocycloalkyl that alkyloxycarbonyl replaces；Preferably, T^bAnd T^cIt is separately-CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from C₁-C₄Alkyloxycarbonyl amino；Or T^bAnd T^cSeparately for optionally by 1,2 or 3 C₁-C₆The azetidinyl that alkyloxycarbonyl replaces；It is highly preferred that T^bAnd T^cIt is separately-CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from C₁-C₄Alkyloxycarbonyl amino；Or T^bAnd T^cSeparately for optionally by 1,2 or 3 C₁-C₆What alkyloxycarbonyl replacedIt is further preferred that T^bAnd T^cIt is separately optionally to be replaced by 1,2 or 3 tert-butoxycarbonylMost preferably, T^bAnd T^cSeparately it is

In some embodiments of the application, ring Z¹For 5 membered heterocycloalkyls, preferably nitrogenous and oxygen atom 5 membered heterocycloalkyls are more preferably disliked Oxazolidinyl, most preferably

In some embodiments of the application, ring Z²For 5~6 membered heterocycloalkyls, 6 unit's heteroaryls or phenyl, preferably phenyl, 6 nitrogenous unit's heteroaryls or 5~6 nitrogenous membered heterocycloalkyls, more preferably phenyl, pyridyl group, pyrrolidinyl or piperidyl, most preferably

In some embodiments of the application, structural unitForPreferably

In some embodiments of the application, p is selected from 0 or 1.

In some embodiments of the application, structural unitFor

In some embodiments of the application, R^bSelected from halogen ,=O, cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls, preferably=O or C_1-4Alkyloxycarbonyl, more preferably=O or tert-butoxycarbonyl.

In some embodiments of the application, structural unitFor

In some embodiments of the application, ring Z³For 5 membered heterocycloalkyls, preferably 5 yuan of nitrogenous Heterocyclylalkyls, more preferably pyrrolidinyl, most preferably

In some embodiments of the application, structural unitForPreferablyMore preferably

In some embodiments of the application, q is selected from 1.

In some embodiments of the application, R^eSelected from C_1-6Alkyloxycarbonyl, preferably C_1-4Alkyloxycarbonyl, more preferably tertbutyloxycarbonyl.

In some embodiments of the application, R^gSelected from-C (O)-NH (C₁-C₄Alkyl), phenyl or 5~6 unit's heteroaryls, wherein phenyl and 5~6 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；Preferably, R^gSelected from tert-butylamino carbonyl, phenyl or pyridyl group, wherein phenyl and pyridyl group are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, cyclopropyl or 5~6 unit's heteroaryls optionally replaces；It is highly preferred that R^gSelected from tert-butylamino carbonyl, phenyl,

In some embodiments of the application, structural unitSelected from 5 membered heterocycloalkyl methyl, 5~6 unit's heteroaryl methyl ,-CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, wherein 5 membered heterocycloalkyl methyl and 5~6 unit's heteroaryl methyl are independently selected by one or more from C each independently_1-6The group of alkyl, 3~6 yuan of naphthenic base or=O optionally replaces.

In some embodiments of the application, structural unitThe methyl,-CH that methyl, pyrimidine -2,4 (1H, the 3H)-diketo that methyl, the 1,3,4- oxadiazoles base replaced selected from pyrrolidinylmethyl, oxazolidine -2- ketone group replaces replace₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or -CH₂NHC (=O) NHC (=O) R⁴, wherein the methyl that 1,3,4- oxadiazoles base replaces is optionally by C_1-4Alkyl or 3~6 yuan of naphthenic base replace.

In some embodiments of the application, structural unitIt is selected from-CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, whereinOptionally replaced by methyl or cyclopropyl.

In some embodiments of the application, structural unitSelected from-CH₂NHR⁴、-CH₂OR⁴,-C (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴Or-CH₂NHC (=O) NHR⁴。

In some embodiments of the application, above-mentioned R⁴Selected from hydrogen, cyano, hydroxyl, C_1-4Alkyl, C_2-4Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl or 5~9 unit's heteroaryls, wherein C_1-4Alkyl and C_2-4Alkenyl is optionally replaced by 1,2 or 3 group independently selected from halogen, hydroxyl, cyano ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls each independently, wherein 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl and 5~9 unit's heteroaryls are each independently by 1,2 or 3 independently selected from halogen, hydroxyl, cyano, C_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace.

In some preferred embodiments of the application, above-mentioned R⁴Selected from hydrogen, cyano, hydroxyl, methyl, ethyl, tert-butyl, isopropyl, vinyl, cyclopropyl, phenyl, pyridyl group, pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, isothiazolyl or azetidinyl, wherein methyl, ethyl, tert-butyl, isopropyl and vinyl are each independently by 1, 2 or 3 independently selected from halogen, hydroxyl, cyano, the group of cyclopropyl or pyridyl group optionally replaces, wherein cyclopropyl, phenyl, pyridyl group, pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, isothiazolyl and azetidinyl are each independently by 1, 2 or 3 independently selected from halogen, hydroxyl, cyano, methyl, the methyl that halogen replaces,=O or the group of cyclopropyl optionally replace.

In some more preferable schemes of the application, above-mentioned R⁴Selected from hydrogen, cyano, hydroxyl, methyl, the methyl that pyridine replaces, cyano methyl, cyclopropyl methyl, ethyl, fluorine-substituted ethyl, tert-butyl, isopropyl, vinyl, cyclopropyl, fluorine-substituted cyclopropyl, the cyclopropyl that cyano replaces, methyl substituted cyclopropyl, the cyclopropyl that 1- methyl fluoride replaces, phenyl, p-fluorophenyl, rubigan, pyridyl group, fluorine-substituted pyridyl group, pyrimidine radicals, methyl substituted pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, azetidinyl, the azetidinyl that hydroxyl replaces, fluorine-substituted azetidinyl or methyl substituted azetidinyl.

In some more preferable schemes of the application, above-mentioned R⁴Selected from hydrogen, cyano, hydroxyl, methyl,Ethyl, Tert-butyl, isopropyl, vinyl, cyclopropyl,Phenyl, p-fluorophenyl, rubigan,

In some embodiments of the application, above-mentioned R₄Selected from hydrogen, or selected from optionally replaced by 1,2 or 3 R hydroxyl, amino, methyl, ethyl, - CH=NH or

In some embodiments of the application, above-mentioned R₄Selected from hydrogen, hydroxyl, amino methyl, ethyl,

In some embodiments of the application, above-mentioned R⁴Selected from hydrogen, cyano, hydroxyl, amino methyl, ethyl,

In some embodiments of the application, structural unitOrSelected from following substituent groups:

In some specific embodiments of the application, structural unitIt is selected from

In some embodiments of the application, above-mentioned D, E are separately selected from singly-bound ,-CH₂,-CH (Me)-,-CH (Et)-and-C (=O)-.

In some embodiments of the application, above-mentioned A is selected from singly-bound ,-O- ,-NH- ,-CH₂-、-CF₂,-CH (Me)-,-CH (Et)-,-N (Me)-and-N (Et)-.

In some embodiments of the application, above-mentioned A is selected from CRR, and two R therein may be connected on same group, forms following substituent groups optionally replaced by 1,2 or 3 R ': 4~6 yuan of naphthenic base and 4~6 membered heterocycloalkyls.

In some embodiments of the application, above-mentioned A is selected from CRR, and two R are connected with each other or are commonly connected on same group, forms the following substituent groups optionally replaced by 1,2 or 3 R ': azetidinyl, pyrrolidinyl, piperidyl and

In some embodiments of the application, the structural unit of above-mentioned general formula (III) compound or general formula (V) compoundFor structural unitMore specifically, selected from the following substituent groups optionally replaced by 1,2 or 3 R ': In some embodiments of the application, the structural unit of above-mentioned general formula (III) compound or general formula (V) compound For structural unitMore specifically, it is selected from

In some embodiments of the application, above-mentioned D, E or A and R₄It is connected with each other or is commonly connected on same group, the following substituent groups optionally replaced by 1,2 or 3 R: 5~6 yuan of naphthenic base, 5~6 membered heterocycloalkyls, 5~6 yuan of aryl and 5~6 unit's heteroaryls are formed, the substituent group is formed together the fused rings of 6-9 member with the ring where N, D, E and A.

In some embodiments of the application, above-mentioned D, E or A and R₄It is connected on same group, forms the following substituent groups optionally replaced by 1,2 or 3 R: pyrrolidinyl, piperidyl, phenyl and pyridyl group, the substituent group is formed together the fused rings of 6-9 member with the ring where N, D, E and A.

In some embodiments of the application, above-mentioned D, E or A and R₄It is connected on same group, structural unitSelected from the following substituent groups optionally replaced by 1,2 or 3 R:

In some embodiments of the application, above-mentioned D, E or A and R₄It is connected on same group, structural unitIt is selected from

In some embodiments of the application, above-mentioned R₅It is connected with each other or is commonly connected on same group with E, the nitrogen-atoms adjacent with E is formed together 4~6 membered heterocycloalkyls optionally replaced by 1,2 or 3 R.

In some embodiments of the application, above-mentioned R₅It is connected on same group with E, forms the following substituent groups optionally replaced by 1,2 or 3 R: pyrrolidinyl and piperidyl.In some embodiments of the application, above-mentioned R₅It is connected on same group with E, so that structure list MemberIt is selected fromMore specifically, making structural unitIt is selected from

In some embodiments of the application, above-mentioned R⁶Selected from C_1-6Alkyl and 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group to form 5 member rings.

In some embodiments of the application, above-mentioned R⁶Selected from C_1-4Alkyl and 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group, so that structural unitFor structural unit

In some embodiments of the application, R⁶Selected from methyl, ethyl, propyl, isopropyl and cyclopropyl or R⁶With L⁵It is commonly connected on same group, so that structural unitFor structural unit

In some embodiments of the application, above-mentioned R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, the pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl and thiazolyl are each independently by 1,2,3,4 or 5 independently selected from halogen ,-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；Preferably, above-mentioned R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, the pyrrolidinyl and piperidyl are each independently by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace, the pyridyl group optionally by halogen (preferably chlorine) replace；It is highly preferred that above-mentioned R⁷Selected from piperidyl, the piperidyl is optionally by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup replace；It is more preferred still that above-mentioned R⁷Selected from piperidyl, the piperidyl is optionally selected from-R by 1^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup replace.

In some embodiments of the application, above-mentioned R⁷It is selected from It is describedEach independently by 1,2,3,4 or 5 independently selected from halogen ,-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；Preferably, above-mentioned R⁷It is selected fromIt is described Each independently by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace, it is describedOptionally replaced by halogen (preferably chlorine)；It is highly preferred that above-mentioned R⁷It is selected fromIt is described Each independently by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；It is more preferred still that above-mentioned R⁷It is selected fromThe piperidyl is optionally selected from-R by 1^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup replace.

In some embodiments of the application, R^fSelected from C_1-6Alkyl, 3~6 yuan of naphthenic base, 5~6 unit's heteroaryls or phenyl, the C_1-6Alkyl is optionally replaced by one or more cyano.

In some embodiments of the application, R^fMethyl, pyrimidine radicals or the phenyl replaced selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, imidazole radicals, oxazolyl, isoxazolyl, cyano.

In some embodiments of the application, R^fSelected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, phenyl,

In some embodiments of the application, halogen ,-R^f,-C (=O) R^f,-C (=O) OR^fWith-C (=O) NHR^fSelected from following group: methyl, ethyl, isopropyl, cyclopropyl, fluorine, chlorine,

In some embodiments of the application, above-mentioned R₆Selected from the following substituent groups optionally replaced by 1,2 or 3 R: Me, Et,

In some embodiments of the application, above-mentioned G and R₆It is connected with each other or is commonly connected on same group, form 4~6 membered heterocycloalkyls optionally replaced by 1,2 or 3 R.

In some embodiments of the application, the structural unit of above-mentioned general formula (II) compound or general formula (IV) compoundSelected from what is optionally replaced by 1,2 or 3 R

In some embodiments of the application, above-mentioned R₇Selected from the following substituent groups optionally replaced by 1,2 or 3-L-R: pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl and thiazolyl.

In some embodiments of the application, above-mentioned R₇Selected from what is optionally replaced by 1,2 or 3-L-R:

In some embodiments of the application, above-mentioned R₇Or R⁷It is selected from:

In some embodiments of the application, the compound is selected from:

Its tautomer or its pharmaceutically acceptable salt.

In some embodiments of the application,Including two isomers, respectivelyIncluding two A isomers, respectively Including two isomers, respectively Including four isomers, respectively

Present invention also provides the methods for preparing herein described compound, including following synthetic schemes:

Synthetic schemes 1-1:

Wherein X¹And X²Separately it is selected from halogen, preferably Cl and Br；And Z₁Selected from C₁-C₄Alkyl, preferably methyl and ethyl.Synthetic schemes 1-2:

Wherein X₁And X₂Separately it is selected from halogen, preferably Cl and Br；Z₁Selected from C₁-C₄Alkyl, preferably methyl and ethyl；R₁And R₃R can be replaced with respectively¹And R³。

Synthetic schemes 2:

Wherein X₁And X₂Separately it is selected from halogen, preferably Cl and Br；Z₁Selected from C₁-C₄Alkyl, preferably methyl and ethyl.Synthetic schemes 3:

Wherein R₆And R₇R can be replaced with respectively⁶And R⁷。

Synthetic schemes 4:

Wherein R₁、R₃、R₆And R₇R can be replaced with respectively¹、R³、R⁶And R⁷。

Synthetic schemes 5-1:

Synthetic schemes 5-2:

Synthetic schemes 6-1:

It can be by structural unitIt replaces withAnd it carries out corresponding reaction and obtains corresponding target product.

Synthetic schemes 6-2:

Synthetic schemes 7-1:

Synthetic schemes 7-2:

Synthetic schemes 8-1:

Synthetic schemes 8-2:

Synthetic schemes 9-1:

Synthetic schemes 9-2:

Synthetic schemes 10-1:

Synthetic schemes 10-2:

Synthetic schemes 11-1:

Wherein in R⁴The atom being connected directly in-H with H is N.

Synthetic schemes 11-2:

Wherein in R₄The atom being connected directly in-H with H is N.

Synthetic schemes 12-1:

Synthetic schemes 12-2:

Synthetic schemes 13-1:

Synthetic schemes 13-2:

Synthetic schemes 14-1:

Synthetic schemes 14-2:

Synthetic schemes 15-1:

It can be by structural unitIt replaces with And it carries out corresponding reaction and obtains corresponding target product.

Synthetic schemes 15-2:

Synthetic schemes 16-1:

Wherein X³Selected from F, Cl, Br and I, preferably Cl and Br.

Synthetic schemes 16-2:

Wherein X₃Selected from F, Cl, Br and I, preferably Cl and Br.

Synthetic schemes 17-1:

R₁₁And R₂₂Separately it is selected from H and C₁-C₄Alkyl.

Synthetic schemes 17-2:

R₁₁And R₂₂Separately it is selected from H and C₁-C₄Alkyl.

Synthetic schemes 18-1:

Synthetic schemes 18-2:

Synthetic schemes 19-1:

Wherein X⁴Selected from F, Cl, Br and I, preferably Cl and Br.

Synthetic schemes 19-2:

Wherein X₄Selected from F, Cl, Br and I, preferably Cl and Br.

On the other hand the application provides a kind of pharmaceutical composition, contain general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-mentioned specific Compound, its tautomer or pharmaceutically acceptable salt are as active constituent.

On the other hand, the application provides a kind of pharmaceutical composition, it contains general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-mentioned particular compound, its tautomer or pharmaceutically acceptable salt are as active constituent, and one or more pharmaceutically acceptable carriers.

The pharmaceutical composition of the application can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, pill, capsule, pulvis, granule, pastille, paste, syrup, emulsion, suspending agent, solution, suppository, injection, inhalant, gelling agent, microballoon and aerosol.

The classical pathway for applying herein described compound, its tautomer, its pharmaceutically acceptable salt or its pharmaceutical composition includes but is not limited to oral, rectum, saturating mucous membrane, through enteral administration, or part, percutaneous, sucking, parenteral, sublingual, intravaginal, it is intranasal, intraocularly, peritonaeum is interior, intramuscular, subcutaneous, intravenous administration.Preferred administration route is oral administration.

The pharmaceutical composition of the application can be prepared using method well known in the art, such as conventional mixing method, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying.

The pharmaceutical composition of the application can be oral form.It, can be by the way that reactive compound be mixed with pharmaceutically acceptable carrier well known in the art or excipient, to prepare the pharmaceutical composition for oral administration.These carriers or excipient can make the compound of the application be formulated into tablet, pulvis, granule, pill, pastille, sugar-coat agent, capsule, liquid, emulsion, gelling agent, slurry agent, suspending agent etc., for patient to be administered orally.

The solid composite medicament for being suitable for oral administration can be prepared by conventional mixing, filling or tabletting method.Such as, it can be obtained by following methods: the reactive compound is mixed with solid excipient or carrier, other suitable auxiliary materials are added in resulting mixture of optionally milling if necessary, then the mixture is processed into particle, obtains the core of tablet or sugar-coat agent.Suitable auxiliary material includes but is not limited to: filler, adhesive, diluent, disintegrating agent, lubricant, glidant, sweetener or corrigent etc., for example, microcrystalline cellulose, glucose solution, mucialga of arabic gummy, gelatin solution, sucrose and gelatinized corn starch；Talcum, starch, magnesium stearate, calcium stearate or stearic acid；Lactose, sucrose, starch, mannitol, D-sorbite or Dicalcium Phosphate；Silica；Croscarmellose sodium, pregelatinized starch, primojel, alginic acid, cornstarch, potato starch, methylcellulose, agar, carboxymethyl cellulose, crosslinked polyvinylpyrrolidone etc..Optionally the core of sugar-coat agent can be coated according to method well known in usual pharmaceutical practice, especially use enteric coating.

The pharmaceutical composition of the application could be applicable to parenteral administration, such as sterile solution agent, emulsion, suspension or the freeze-drying prods of suitable unit dosage forms.It is able to use excipient appropriate, such as filler, buffer or surfactant.

On the other hand, this application provides the methods for treating disease relevant to cccDNA, including by the cccDNA and general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, or its pharmaceutically acceptable salt, its stereoisomer, its enantiomter, the mixture of its stereoisomer or its pharmaceutical composition thereof.

On the other hand, this application provides the methods for the disease for the treatment of mammal mediated by cccDNA, including to the mammal for needing the treatment, it is preferred that the mankind, apply the general formula (I) of therapeutically effective amount, general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) or above-described particular compound, its tautomer or its pharmaceutically acceptable salt Or its pharmaceutical composition.The disease includes virus B hepatitis.

Also on the one hand, this application provides general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, or its pharmaceutically acceptable salt, its stereoisomer, its enantiomter, the mixture of its stereoisomer or its pharmaceutical composition are preparing the purposes in the drug for treating and/or preventing disease relevant to cccDNA, the disease includes virus B hepatitis.

On the other hand, this application provides general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition are being prepared for preventing and/or treating the purposes in the drug by the cccDNA disease mediated.The disease includes virus B hepatitis.

Also on the one hand, this application provides general formula (I), general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, the purposes in disease relevant to cccDNA is being treated and/or prevented to its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition.The disease includes virus B hepatitis.

Also on the one hand, this application provides the general formulas (I) for treating and/or preventing disease relevant to cccDNA, general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition.

Also on the one hand, this application provides for treating and/or preventing by the general formula (I) of the cccDNA disease mediated, general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, its tautomer or its pharmaceutically acceptable salt or its pharmaceutical composition.The disease includes virus B hepatitis.

Another further aspect, this application provides treatment and/or the methods of prevention disease relevant to cccDNA, it includes by the general formula (I) of therapeutically effective amount, general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), general formula (VIII) compound or above-described particular compound, or its pharmaceutically acceptable salt, its stereoisomer, its enantiomter, its stereoisomer mixture or its pharmaceutical composition to mammal be administered.The disease includes virus B hepatitis.

Definition

Unless otherwise indicated, following term used herein and phrase are intended to following meanings.One specific term or phrase it is no especially define in the case where should not be considered as uncertain or unclear, and should go to understand according to common meaning.When herein presented trade name, it is intended that refer to its corresponding commodity or its active constituent.

Dotted line (--- -) in structural unit or group herein indicates covalent bond.

In certain structural units herein or group covalent bond (for example,In dotted line (--- -)) when not connect with specific atom, table Show that the covalent bond can be connect with the arbitrary atom in the structural unit or group, without departing from valence link concatenate rule.Thus, for example, structural unitIncluding

C_1-12Selected from C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁And C₁₂；C_3-12Selected from C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁And C₁₂；C_1-6Selected from C₁、C₂、C₃、C₄、C₅And C₆。

C_1-12Alkyl or C_1-12Miscellaneous alkyl, C_3-12Cyclic hydrocarbon radical or C_3-12Heterocyclic hydrocarbyl, by C_3-12Cyclic hydrocarbon radical or C_3-12The C that heterocyclic hydrocarbyl replaces_1-12Alkyl or C_1-12Miscellaneous alkyl includes but is not limited to:

C_1-12Alkyl, C_1-12Alkyl amino ,-N (C_1-12Alkyl)₂、C_1-12Alkoxy, C_1-12Alkanoyl, C_1-12Alkoxy carbonyl group, C_1-12Alkyl sulphonyl, C_1-12Alkyl sulphinyl, C_3-12Naphthenic base, C_3-12Cycloalkyl amino, C_3-12Heterocyclalkylamino, C_3-12Cycloalkyl oxy, C_3-12Cycloalkanoyl, C_3-12Cycloalkyloxycarbonyl, C_3-12Naphthene sulfamide base, C_3-12Cycloalkylsulfinyl, 5~12 yuan of aryl or heteroaryl, 5~12 yuan of aryl alkyls or heteroarylalkyl；

Methyl, ethyl, n-propyl, isopropyl ,-CH₂C(CH₃)(CH₃) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropyl acyl, benzyloxy, trifluoromethyl, aminomethyl, methylol, methoxyl group, formoxyl, methoxycarbonyl group, mesyl, methylsulfinyl, ethyoxyl, acetyl group, ethylsulfonyl, carbethoxyl group, dimethylamino, diethylamino, Dimethylaminocarbonyl, diethylaminocarbonyl；

-N(CH₃)₂,-NH(CH₃),-CH₂CF₃,-CH₂CH₂CF₃,-CH₂CH₂F,-CH₂CH₂S (=O)₂CH₃,-CH₂CH₂CN,-CH₂CH(OH)CH₃,-CH₂CH(F)CH₃,-CH₂CH₂NH₂,-CH₂CH₂OH,-CH₂CH₂OCH₃,-CH₂CH₂CH₂OCH₃,-CH₂CH₂N(CH₃)₂,-S (=O)₂CH₃；With

Phenyl, thiazolyl, xenyl, naphthalene, cyclopenta, furyl, 3- pyrrolinyl, pyrrolidinyl, 1, 3- dioxolanyl, pyrazolyl, 2- pyrazolinyl, pyrazolidinyl, imidazole radicals, oxazolyl, thiazolyl, 1, 2, 3- triazolyl, 1, 2, 4- triazolyl, 1, 3, 4- thiadiazolyl group, 4H- pyranose, pyridyl group, piperidyl, 1, 4- dioxane, morpholinyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperazinyl, 1, 3, 5- trithiane base, 1, 3, 5- triazine radical, benzofuranyl, benzothienyl, indyl, benzimidazolyl, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnoline base or quinoxalinyl.

Terminology employed herein " pharmaceutically acceptable " is for those compounds, material, composition and/or dosage form, they are within the scope of reliable medical judgment, use is contacted suitable for the tissue with human and animal, without excessive toxicity, irritation, allergic reaction or other problems or complication, match with reasonable interests/Hazard ratio.

Term " pharmaceutically acceptable salt " refers to the salt of the application compound, is prepared by the acid or alkali of the compound and relative nontoxic with specified substituent of the application discovery.When in the compound of the application containing relatively acid functional group, base addition salts can be obtained by way of being contacted with the alkali of sufficient amount with this kind of compound.Pharmaceutically acceptable base addition salts include sodium salt, sylvite, calcium salt, ammonium salt, organic ammonium salt, magnesium salts or similar salt.When in the compound of the application containing relatively alkaline functional group, acid-addition salts can be obtained by way of being contacted with the acid of sufficient amount with this kind of compound.The example of pharmaceutically acceptable acid-addition salts includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, one hydrogen radical of phosphoric acid, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include the acid that such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid are similar with methanesulfonic acid；It further include the salt of amino acid (such as arginine), and the salt of such as glucuronic acid organic acid is (referring to Berge et al., " Pharmaceutical Salts ", Journal of Pharmaceutical Science 66:1-19 (1977)).Certain specific compounds of the application contain alkalinity and acid functional group, so as to quilt It is converted into any base addition salts or acid-addition salts.

Preferably, it contacts salt with alkali or acid in a usual manner, then separates parent compound, thus the parent fo of raw compounds again.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as the different solubility in polar solvent.

" pharmaceutically acceptable salt " used herein belongs to the derivative of the application compound, wherein with acid at salt or with alkali at salt by way of modify the parent compound.The example of pharmaceutically acceptable salt includes but is not limited to: the inorganic acid of base such as amine or the alkali metal salt of acylate, acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt includes the quaternary ammonium salt of conventional avirulent salt or parent compound, such as is formed by salt with nontoxic inorganic acid or organic acid.Conventional avirulent salt includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid is selected from Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyl naphthoic acid, isethionic acid, lactic acid, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, Loprazolam, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonase, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannic acid, tartaric acid and p-methyl benzenesulfonic acid.

The pharmaceutically acceptable salt of the application can be synthesized by the parent compound containing acid group or base by conventional chemical processes.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, reacting via free acid or these compounds of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that the non-aqueous medias such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.

In addition to the form of salt, there is also prodrug forms for compound provided herein.Chemical change easily occurs in physiological conditions for the prodrug of compounds described herein to the compound of conversion cost application.In addition, prodrug can be converted into the compound of the application in environment by chemistry or biochemical method in vivo.

Certain compounds of the application can exist with nonsolvated forms or solvation form, including hydrate form.In general, solvation form is suitable with non-solvated form, it is included within scope of the present application.

Word " including (comprise) " or " including (comprise) " and its English variant such as comprises or comprising are interpreted as open, nonexcludability meaning, i.e., " including but not limited to ".

Certain compounds of the application can have asymmetric carbon atom (optical centre) or double bond.Racemic modification, enantiomter, diastereoisomer, geometric isomer and single isomers are included within scope of the present application.Term " tautomer " or " tautomeric forms " refer to can be via the constitutional isomer of the different-energy of low energy barrier interconversion.For example, proton tautomer (also referred to as Prototropic tautomers) includes the interconversion via proton transfer, such as keto-enol and imine-enamine isomerizations.The specific example of proton tautomer is imidazole fragment, and wherein proton can migrate between two ring nitrogen.Valence tautomerism body includes the interconversion by the recombination of some bonding electrons.

The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure herein comes from Maehr, J.Chem.Ed.1985,62:114-120.Unless otherwise indicated, wedge key is usedThe absolute configuration for indicating a Stereocenter, uses waveIndicate one of absolute configuration of a Stereocenter (such asOne of).When compound described herein contains olefinic double bond or other geometry asymmetric centers, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included within scope of the present application.In addition, withAndIndicate the relative configuration of two keys, i.e. cis-trans, such asTable ShowAndKey is in trans position,Indicate twoKey is in cis position,It indicatesAndKey is in trans position.

The compound of the application may exist specific geometric isomer or stereoisomer form.The application imagines all this kind of compounds, including cis and trans isomer, (-)-with (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as the mixture that enantiomter or diastereomer are enriched with, it is all these to belong within scope of the present application.May exist other asymmetric carbon atom in the substituent groups such as alkyl.All these isomers and their mixture are included within scope of the present application.For example,IncludingFor example,Indicate that it isFor another example,Respectively In one, but it is different；For another example,It is identical,It is identical.The compound containing asymmetric carbon atom of the application can be separated with the pure form of optical activity or racemic form.The pure form of optical activity can be obtained by splitting from racemic mixture, or be synthesized by using chiral raw material or chiral reagent.

Optically active (R)-and (S)-isomers and D and L isomers can be prepared by chirality synthesis or chiral reagent or other routine techniques., can be by asymmetric syntheses or prepared by the derivatization with chiral auxiliary if expecting a kind of enantiomer of the application compound, wherein gained non-enantiomer mixture is separated, and auxiliary group splits to provide pure required enantiomter.Or, when containing basic functionality (such as amino) or acidic functionality (such as carboxyl) in molecule, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then diastereoisomer fractionation is carried out by conventional method known in the field, then recycling obtains pure enantiomer.In addition, the separation of enantiomter and diastereoisomer is usually to be completed by using chromatography, the chromatography uses chiral stationary phase, and (such as generating carbaminate by amine) is optionally combined with chemical derivatization.

The compound of the application can include the atom isotope of unnatural proportions on one or more atoms for constituting the compound.For example, radioisotope labeled compound can be used, such as tritium (³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C).The transformation of all isotopics of the compound of the application, no matter radioactivity whether, be included within scope of the present application.

Certain isotope labellings the application compound (such as with³H and¹⁴Those of C flag) it can be used in compound and/or substrate tissue distributional analysis.It is tritiated (i.e.³H) and carbon-14 (i.e.¹⁴C) isotope is since they are easily prepared and detectability is thus especially preferred.Positron emitting isotopes, such as¹⁵O、¹³N、¹¹C and¹⁸F can be used for positron emission computerized tomography (PET) research to measure substrate occupation rate.Usually the reagent without isotope labelling can be replaced by isotope labeling reagent to prepare the application compound of isotope labelling by the program similar with program those of in scheme disclosed below and/or embodiment.

In addition, with higher isotope, (such as deuterium is (i.e.²H it)) carries out replacing and certain treatment advantages (such as increased Half-life in vivo or reduced volume requirements) generated by higher metabolic stability can be provided, it therefore in some cases may be preferred, wherein deuterium substitution can be partially or completely, and deuterium substitution in part refers to that at least one hydrogen is replaced by least one deuterium.

Term " pharmaceutical composition " refers to the compound or its salt of one or more the application and the mixture of pharmaceutically acceptable auxiliary material composition.The purpose of pharmaceutical composition is the compound for being conducive to apply organism the application.

Term " pharmaceutically acceptable carrier ", " pharmaceutically acceptable excipient " any reagent or carrier or medium that either " pharmaceutically acceptable auxiliary material " is a effective amount of active material for referring to delivering the application, does not interfere the bioactivity of the active material and have no toxic side effect to host or patient.Representative carrier includes water, oil and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, Suspending agent, tackifier, transdermal enhancer etc..Their reagent is well known to the technical staff in cosmetic field or topical remedy field.Other information about carrier, Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott can be referred to, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.

Term " excipient " or " auxiliary material " typically refer to carrier, diluent and/or medium required for preparing drug composition effective.

For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to enough dosages of drug that is nontoxic but can achieving the desired results or medicament.For the peroral dosage form in the application, in composition it is a kind of " effective quantity " of active material refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.A effective amount of determination varies with each individual, age and ordinary circumstance depending on receptor, also depends on specific active material, and suitable effective quantity can be determined by those skilled in the art according to routine test in case.

Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can effectively treat disorder, disease or the illness of target.

Term " treatment ", which is meant, to be administered with prevention, improvement by herein described compound or preparation or eliminates disease or one or more symptoms relevant to the disease, and includes:

(i) prevent disease or morbid state occurs in mammals, especially when this kind of mammal is susceptible to the disease or morbid state, but is not yet diagnosed as having suffered from the disease or morbid state；

(ii) inhibit disease or morbid state, that is, contain its development；

(iii) alleviate disease or morbid state, that is, the disease or morbid state is made to subside.

Term " therapeutically effective amount " means that (i) treats or prevents specified disease, morbid state or illness, (ii) mitigation, improvement or the one or more symptoms for eliminating specified disease, morbid state or illness, or (iii) prevent or delay the dosage of the application compound of one or more paresthesia epilepsies of specified disease described herein, morbid state or illness.Constitute the application compound of " therapeutically effective amount " amount depend on the compound, disease, morbid state or illness and its seriousness, administration mode and mammal to be treated age and change, but can be determined by those skilled in the art according to the knowledge and present disclosure of its own to routine.

General formula (I) described herein, general formula (I -1), general formula (I -2), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), logical (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7), general formula (VII -8), in all method of administration of general formula (VIII) or above-described particular compound, the dosage of daily administration is 0.01mg/kg weight to 200mg/kg weight, it is applied in the form of individually dosed or separate doses.

Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, the variant including heavy hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is stable.Term " being optionally substituted " refers to and can be substituted, and can not also be substituted, and unless otherwise prescribed, the type and number of substituent group can be arbitrary on the basis of may be implemented in chemistry.

Term " optional " or " optionally " refer to that the event then described or situation may or may not occur, which includes that the event or situation occurs and the event or situation does not occur.For example, ethyl " optionally " is replaced by fluorine, refer to that ethyl can be unsubstituted (CH₂CH₃), mono-substituted (such as CH₂CH₂F), polysubstituted (such as CHFCH₂F、CH₂CHF₂Deng) or substituted (CF completely₂CF₃).It is understood that for any group comprising one or more substituent groups, will not introduce any can not spatially exist and/or the substitution that cannot be synthesized or substitute mode those skilled in the art.

As any variable (such as R or R³) when occurring more than once in the composition of compound or structure, definition at each occurrence is all independent.Thus, for example, if a group replaced 0-2 R, the group can optionally at most replaced two R, and R in each case has independent option.In addition, the combination of substituent group and/or its variant is only just allowed in the case where such group of credit union generates stable compound.For another example, (R³)_mIndicate group by m R³It is replaced, then each R³There is independent option；Specifically, for example, indicating group by 2 R as m=2³It is replaced, and each R³There is independent option.

When the quantity of linking group is 0, such as-(CRR)₀, indicate that the linking group is singly-bound.

When one of variable is selected from singly-bound, indicate that two groups of its connection are connected directly, for example in A-L-Z, L indicates that the structure is actually A-Z when representing singly-bound.

Unless otherwise prescribed, term " halogenated " or " halogen " itself or as another substituent group a part when indicate fluorine, chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogenated (C₁-C₄) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyl, 4- chlorobutyl and 3- bromopropyl etc..

The example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls." alkoxy " indicates the alkyl with certain number of carbon atom connected by oxygen bridge.C_1-6Alkoxy includes C₁、C₂、C₃、C₄、C₅And C₆Alkoxy.The example of alkoxy includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxy." naphthenic base " includes saturated cyclic group, such as cyclopropyl, cyclobutyl or cyclopenta.3-7 member naphthenic base includes C₃、C₄、C₅、C₆And C₇Naphthenic base." alkenyl " includes the hydrocarbon chain of straight chain or branched chain, wherein there are one or more carbon-to-carbon double bonds, such as vinyl and acrylic on stabilization site any on the chain.

Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.

Term " hydroxyl " refers to-OH group.

Term " cyano " refers to-CN group.

Term " amino " refers to-NH₂Group.

Term " trifluoromethyl " refers to-CF₃Group.

Term " alkoxy " refers to-O- alkyl.

Term " alkyl amino " refers to-NH (alkyl).

Term " dialkyl amido " refers to-N (alkyl)₂。

Term " Boc " or " boc " refer to tertbutyloxycarbonyl.

Term " alkyl " refers to that general formula is C_nH_2n+1Alkyl.The alkyl can be linear chain or branched chain.For example, term " C_1-6Alkyl " refers to the alkyl (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 1- methyl butyl, 2- methyl butyl, 3- methyl butyl, neopentyl, hexyl, 2- methyl amyl etc.) containing 1 to 6 carbon atom.Similarly, the moieties (i.e. alkyl) of alkoxy, alkyl amino, dialkyl amido, alkyl sulphonyl, alkyl sulphinyl and alkylthio group have above-mentioned identical definition.

Term " alkenyl " refers to the unsaturated fatty hydrocarbons base at least one double bond for the linear chain or branched chain being made of carbon atom and hydrogen atom.The non-limiting example of alkenyl includes but is not limited to vinyl, 1- acrylic, 2- acrylic, 1- cyclobutenyl, isobutenyl, 1,3- butadienyl etc..

Term " naphthenic base " refer to it is fully saturated and can in the form of monocycle, bridged ring or loop coil existing for full carbocyclic ring.Unless otherwise directed, which is usually 3 to 10 member rings.The non-limiting example of naphthenic base includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, norborny (bicyclic [2.2.1] heptyl), bicyclic [2.2.2] octyl, adamantyl etc..

Unless otherwise prescribed, " miscellaneous " the expression hetero atom of term or hetero atom group (containing heteroatomic atomic group), including other than carbon (C) and hydrogen (H) atom and contain these heteroatomic atomic groups, for example including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B) ,-O-, - S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O) ,-S (=O)₂, and-C (=O) the N (H)-,-N (H)-,-C (=NH)-,-S (=O) that are optionally substituted₂N (H)-or-S (=O) N (H)-.

Unless otherwise prescribed, " ring " indicates substituted or unsubstituted naphthenic base, Heterocyclylalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocycle, connection ring, loop coil and ring, fused rings or bridged ring.The number of ring atom is generally defined as first number of ring, for example, " 5~7 member ring " refers to around 5~7 atoms of arrangement.Unless otherwise prescribed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 member ring " includes such as phenyl, pyridine and piperidyl；On the other hand, term " 5~7 membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " further includes the ring system containing at least one ring, each of these " ring " independently conforms to above-mentioned definition.Unless otherwise prescribed, term " heterocycle " or " heterocycle " mean the stable monocyclic, bicyclic or tricyclic rolled into a ball containing hetero atom or hetero atom, they can be saturation, part it is unsaturated or unsaturated (aromatics), they include carbon atom and 1,2,3 or 4 hetero atom independently selected from N, O and S, wherein above-mentioned any heterocycle can be fused on a phenyl ring formed it is bicyclic.Nitrogen and sulfur heteroatom are optionally oxidized that (i.e. NO and S (O) p, p are 1 or 2).Nitrogen-atoms can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).The heterocycle can be attached in the side group of any hetero atom or carbon atom to form stable structure.If generate compound be it is stable, the substitution on carbon potential or nitrogen position can occur for heterocycle as described herein.Miscellaneous ring nitrogen is optionally quaternized.One preferred embodiment is that, when the sum of S in heterocycle and O atom is more than 1, these hetero atoms are not adjacent to each other.Another preferred embodiment is that the sum of S and O atom is no more than 1 in heterocycle.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean stable 5,6,7 unit monocycles or bicyclic or 7,8,9 or 10 membered bicyclic heterocycles aromatic rings, it includes carbon atom and 1,2,3 or 4 hetero atom independently selected from N, O and S.Nitrogen-atoms can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).Nitrogen and sulfur heteroatom are optionally oxidized that (i.e. NO and S (O) p, p are 1 or 2).It is worth noting that, the sum of S and O atom is no more than 1 on aromatic heterocycle.Bridged ring is also contained in the definition of heterocycle.Bridged ring is formed when one or more atoms (i.e. C, O, N or S) connects two non-conterminous carbon atoms or nitrogen-atoms.Preferred bridged ring includes but is not limited to: a carbon atom, two carbon atoms, a nitrogen-atoms, two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, monocycle is always converted into tricyclic by a bridge.In bridged ring, the substituent group on ring can also be appeared on bridge.

The example of heterocyclic compound includes but is not limited to: acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzo sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyl, carboline base, chromanyl, chromene base, cinnoline base decahydroquinolyl, 2H, 6H-1, 5, 2- dithiazine base, dihydrofuran simultaneously [2, 3-b] tetrahydrofuran base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyl, indoles alkenyl, indolinyl, indolizine base, indyl, 3H- indyl, isobenzofuran-base, isoindolyl, iso-dihydro-indole-group, isoquinolyl, it is different Thiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinolyl, oxadiazoles base, 1, 2, 3- oxadiazoles base, 1, 2, 4- oxadiazoles base, 1, 2, 5- oxadiazoles base, 1, 3, 4- oxadiazoles base, oxazolidinyl, oxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, phenazinyl, phenothiazinyl, benzo xanthinyl, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone base, piperonyl, pteridyl, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, pyridyl group, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, quinazolyl, quinolyl, 4H- quinazinyl, quinoxalinyl, Kui Peaceful ring group, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiadiazine bases, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1,2,5- thiadiazolyl groups, 1,3,4- thiadiazolyl group, thianthrene group, thiazolyl, isothiazolyl thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine radical, 1,2,3-triazoles base, 1,2,4- triazolyls, 1,2,5- triazolyl, 1,3,4- triazolyls and xanthyl.It further include condensed ring and spiro-compound.

Unless otherwise prescribed, either its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) itself or a part as another substituent group indicate straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof to term " alkyl ", it can be fully saturated, unit or polynary unsaturated, it can be monosubstituted, two substitutions or polysubstituted, it can be monovalence (such as methyl), divalent (such as methylene) or multivalence (such as methine), it may include divalent or polyad group, carbon atom (such as C with specified quantity₁-C₁₀Indicate 1 to 10 carbon)." alkyl " includes but is not limited to aliphatic alkyl and aromatic hydrocarbyl, the aliphatic alkyl includes chain and ring-type, specific example includes but is not limited to alkyl, alkenyl, alkynyl, and the aromatic hydrocarbyl includes but is not limited to aryl radical of 6-12 member, such as benzene, naphthalene etc..In some embodiments, term " alkyl " indicates straight chain or branch atomic group or their combination, can be fully saturated, unit or polynary unsaturated, may include divalent and polyad group.The example of saturated hydrocarbons atomic group includes but is not limited to the homologue or isomers of the atomic groups such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, isobutyl group, sec-butyl, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, n-hexyl, n-heptyl, n-octyl.Unsaturated alkyl has one or more double bonds or three key, the example includes but is not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene group, 2- (butadienyl), 2,4- pentadienyl, 3- (1,4- pentadienyl), acetenyl, 1- propinyl, 3- propinyl, 3- butynyl and more advanced homologue and isomers.

Unless otherwise prescribed, either its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl etc.) itself or while combining with another term, indicate stable, straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof to term " miscellaneous alkyl ", are made of the carbon atom and at least one hetero atom of certain amount.In some instances, term " miscellaneous alkyl " itself or while combining with another term, indicate stable, straight chain, branch, saturation hydrocarbon atomic group or combinations thereof object, are made of the carbon atom and at least one hetero atom of certain amount.In a representative instance, hetero atom is selected from B, O, N and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Hetero atom or hetero atom group can be located at any interior location (position of molecule rest part is attached to including the alkyl) of miscellaneous alkyl.Example includes but is not limited to-CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-CH₂-CH₂-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃,-CH=CH-O-CH₃、-CH₂- CH=N-OCH₃With-CH=CH-N (CH₃)-CH₃.At most two hetero atoms can be continuously, such as-CH₂-NH-OCH₃。

Term " alkoxy ", " alkyl amino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to those of the rest part alkyl group for being connected to molecule by oxygen atom, amino or sulphur atom respectively.

Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocyclic hydrocarbyl " or its subordinate concept (such as aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or while combining with other terms, respectively indicate " alkyl ", " miscellaneous alkyl " of cyclisation.In addition, hetero atom can take up the miscellaneous alkyl or heterocyclic hydrocarbyl is attached to the position of molecule rest part for miscellaneous alkyl or heterocyclic hydrocarbyl (such as miscellaneous alkyl, Heterocyclylalkyl).The example of cyclic hydrocarbon radical includes but is not limited to cyclopenta, cyclohexyl, 1- cyclohexenyl group, 3- cyclohexenyl group, suberyl etc..The non-limiting example of heterocycle includes 1- (1,2,5,6- tetrahydro pyridyl), 1- piperidyl, 2- piperidyl, 3- piperidyl, 4- morpholinyl, morpholinyl, tetrahydrofuran -2- base, tetrahydrofuran indol-3-yl, thiophane -2- base, thiophane -3- base, 1- piperazinyl and 2- piperazinyl.

Term " Heterocyclylalkyl " refer to it is fully saturated and can in the form of monocycle, bicyclic or loop coil existing for cyclic group.Unless otherwise directed, which is usually 3 to 7 member rings containing 1 to 3 hetero atom (preferably 1 or 2 hetero atom) independently selected from sulphur, oxygen and/or nitrogen.The example of 3 membered heterocycloalkyls includes but is not limited to Oxyranyle, thiirane base, azirane base；The non-limiting example of 4 membered heterocycloalkyls includes but is not limited to azete piperidinyl, dislikes fourth ring group, thiophene fourth ring group；The example of 5 membered heterocycloalkyls includes but is not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazole alkyl, thiazolidinyl, imidazolidinyl, tetrahydro-pyrazole base, pyrrolinyl；The example of 6 membered heterocycloalkyls includes but is not limited to piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazinyl, 1,4- thiophene oxane base, 1,4- dioxy Six ring groups, thio-morpholinyl, 1,2- dithianyl, 1,4- dithianyl；The example of 7 membered heterocycloalkyls includes but is not limited to nitrogen heterocyclic heptyl, oxepane alkyl, thia cycloheptyl alkyl.Preferably with the monocyclic heterocycloalkyl of 5 or 6 annular atoms.

Unless otherwise prescribed, term " aryl " indicates the aromatics hydrocarbon substituent of how unsaturated, can be it is monosubstituted, two replace or polysubstituted, can be monovalence, divalent or multivalence, it can be monocycle or polycyclic (such as 1 to 3 ring；Wherein at least one ring is aromatics), they are fused together or are covalently attached.

Term " heteroaryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom is selected from B, N, O and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to the rest part of molecule by hetero atom.

The non-limiting embodiment of aryl or heteroaryl includes but is not limited to phenyl, 1- naphthalene, 2- naphthalene, 4- xenyl, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyl, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyl, 4- oxazolyl, 2- phenyl -4- oxazolyl, 5- oxazolyl, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- benzothiazolyl, purine radicals, 2- benzimidazolyl, 5- indyl, 1- isoquinolyl, 5- isoquinolyl, 2- quinoxalinyl, 5- quinoxalinyl, 3 Quinolyl and 6- quinolyl.Any one above-mentioned aryl and the substituent group of heteroaryl ring system are selected from acceptable substituent group described below.

Unless otherwise prescribed, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) includes aryl and heteroaryl ring as defined above.Therefore, term " aralkyl " is intended to include that aryl is attached to those of alkyl atomic group (such as benzyl, phenethyl etc.), including wherein carbon atom (such as methylene) by those of the replacement of such as oxygen atom alkyl, such as phenoxymethyl, 2- pyridine oxygen methyl 3- (1- naphthoxy) propyl etc..

Term " leaving group ", which refers to, can pass through functional group or atom replaced substitution reaction (such as nucleophilic substitution) by another functional group or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulfonate group, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoroacetyl oxygroup.

Term " protecting group " includes but is not limited to " amino protecting group ", " carboxyl-protecting group " " hydroxyl protection base " or " sulfhydryl protected base ".Term " amino protecting group " refers to the blocking group that side reaction occurs on the nitrogen position for being suitable for preventing amino.Representative amino protecting group includes but is not limited to: formoxyl；Acyl group, such as alkanoyl (such as acetyl group, trichloroacetyl or trifluoroacetyl group)；Alkoxy carbonyl, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyl) methyl；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS).Term " hydroxyl protection base " refers to the protecting group for being suitable for preventing hydroxyl that side reaction occurs.Representative hydroxyl protection base includes but is not limited to: alkyl, such as methyl, ethyl and tert-butyl；Acyl group, such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyl (Fm) and diphenyl methyl (benzhydryl, DPM)；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS).

The compound of the application can be prepared by a variety of synthetic methods well-known to those skilled in the art, it includes but is not limited to embodiments herein that combination including the specific embodiment, itself and other chemical synthesis process that are set forth below, which is formed by embodiment and equivalent replacement mode well-known to those skilled in the art, preferred embodiment,.

Solvent used in this application can be through commercially available acquisition.The application uses following initialisms: aq represents water；HATU represents O- (7- azepine benzo triazol-1-yl)-N, N, N', N'- tetramethylurea hexafluorophosphate；EDC represents N- (3- dimethylaminopropyl)-N'- ethyl-carbodiimide hydrochloride；M-CPBA represents 3- chloroperoxybenzoic acid；CDI represents carbonyl dimidazoles；DCM represents methylene chloride；PE represents petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents N,N-dimethylformamide；DMSO represents dimethyl sulfoxide；EtOAc represents ethyl acetate；EtOH Represent ethyl alcohol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amido protecting group；BOC represents tertbutyloxycarbonyl, is a kind of amido protecting group；HOAc/AcOH represents acetic acid；NaCNBH₃Represent sodium cyanoborohydride；R.t. room temperature is represented；O/N is represented overnight；THF represents tetrahydrofuran；Boc₂O represents di-tert-butyl dicarbonate；TFA represents trifluoroacetic acid；DIPEA/DIEA represents diisopropylethylamine；SOCl₂Represent thionyl chloride；CS₂Represent carbon disulfide；TsOH represents p-methyl benzenesulfonic acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidine-2,5-dione；n-Bu₄NF represents tetrabutyl ammonium fluoride；IPrOH represents 2- propyl alcohol；Mp represents fusing point；LDA represents lithium diisopropylamine；IPA represents isopropanol；DEA represents diethylamine.

" pharmaceutical composition " refers to mixture and the preparation for the carrier that bioactive compound is delivered to organism (such as people) to be combined that usually receives in the art of the compound or its salt of one or more the application, its stereoisomer, its enantiomter, its stereoisomer.The purpose of pharmaceutical composition is the compound for being conducive to apply organism the application.

Term " pharmaceutically acceptable carrier ", which refers to, acts on organism without obvious stimulation, and those of bioactivity and performance that will not damage reactive compound carrier." pharmaceutically acceptable carrier " refers to inert substance being administered together with active ingredient, being conducive to active ingredient administration, including but not limited to acceptable any glidant, sweetener, diluent, preservative, dyestuff/colorant, flavoring reinforcing agent, surfactant, wetting agent, dispersing agent, disintegrating agent, suspending agent, stabilizer, isotonic agent, solvent or the emulsifier for human or animal (such as domestic animal) of State Food and Drug Administration's license.The non-limiting example of the carrier includes calcium carbonate, calcium phosphate, various sugar and each kind of starch, cellulose derivative, gelatin, vegetable oil and polyethylene glycol.

Commercial compound uses supplier's directory name.

Embodiment

In order to which the application is described in more detail, the following example is provided, but scope of the present application is not limited to this.All solvents used in this application are commercially available, and can be used without being further purified.

Combiflash companion instrument model: CombiFlash RF, Teledyne isco

Reference example 1: segment BB-1

Synthetic route:

Step 1: the synthesis of compound BB-1-3

Compound BB-1-1 (11.73g) is dissolved in pyridine (100.00mL) under the conditions of 0 DEG C, compound BB-1-2 (10.60g) is then slowly added dropwise at that same temperature, stirs the reaction solution 5 hours under the conditions of 0 DEG C.The pH value of solution is slowly adjusted under conditions of 0 DEG C with 2N hydrochloric acid to about 4~5.It is extracted, merge organic phase and is washed with water (200mL × 2) with ethyl acetate (300mL × 3), anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, obtains white crude.The crude product through combiflash companion instrument (petroleum ether: ethyl acetate=10:1) purify, obtain target compound BB-1-3 (white solid, 8.50g, yield: 38.40%, purity: 91%).MS (ESI) m/z:336 [M+H]⁺。

Step 2: the synthesis of compound BB-1-5

Compound BB-1-3 (8.50g) is dissolved in anhydrous tetrahydro furan (200.00mL), then by sodium hydride suspension (2.03g under conditions of 0 DEG C, 60% purity) it is added portionwise in above-mentioned reaction solution, the reaction solution is stirred 1 hour under conditions of 0C, then compound BB-1-4 (6.34g) is added in above-mentioned reaction solution, continuation is stirred 17 hours at 25 DEG C.Reaction solution is slowly added into the aqueous ammonium chloride solution (500mL) of saturation, is extracted with ethyl acetate (500mL × 3), organic phase is merged and (200mL × 3) are washed with water, anhydrous sodium sulfate is dry, then it filters, is spin-dried for being concentrated, obtain canescence crude product.The crude product through fast chromatographic instrument (petroleum ether: ethyl acetate=8:1) purify, obtain target compound BB-1-5 (white solid, 6.50g, yield: 57.75%, purity: 94.9%).MS (ESI) m/z:422 [M+H]⁺。

Step 3: the synthesis of compound BB-1

Compound BB-1-5 (6.50g) is dissolved in the in the mixed solvent of dioxane (180.00mL) and water (20.00mL), then a hydronium(ion) lithia (3.23g) is added under conditions of 25 DEG C, 25 DEG C at a temperature of continue stirring 12 hours.Reaction solution is slowly adjusted to acid pH with 2N hydrochloric acid, about 4~5, then ethyl acetate extraction (150mL × 3), merge organic phase, anhydrous sodium sulfate is dry, under reduced pressure concentrated by rotary evaporation, obtain crude product target compound BB-1 (pale solid, 5.00g, yield: 66.75%, purity: 81%) MS (ESI) m/z:394 [M+H]⁺。

Reference example 2: segment BB-2

Synthetic route:

Step 1: the synthesis of compound BB-2-2

Compound BB-1-1 (2.00g) is dissolved in pyridine (20.00mL), then compound BB-2-1 (2.16g) is added at 0 DEG C, the reaction solution is stirred 5 hours under the conditions of 0 DEG C, and is quenched under conditions of 0 DEG C with 2N hydrochloric acid.It is extracted with ethyl acetate (20mL × 3), merges organic phase, and wash (20mL × 2) with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, obtains crude product.The crude product through combiflash companion instrument (petroleum ether: ethyl acetate=20:1) purify, obtain target compound BB-2-2 (yellow solid, 900.00mg, yield: 23.53%, purity: 99%).MS (ESI) m/z:392 [M+Na]⁺。

Step 2: the synthesis of compound BB-2-3

Compound BB-2-2 (900.00mg) is dissolved in anhydrous tetrahydro furan (10.00mL), then by sodium hydride suspension (213.84mg under conditions of 0 DEG C, 60% purity) it is added in above-mentioned reaction solution, the reaction solution stirs 0.5 hour under conditions of 0 DEG C, then compound BB-1-4 (649.30mg) is added in above-mentioned reaction solution, continuation is stirred 12 hours at 25 DEG C.The aqueous ammonium chloride solution (50mL) that reaction solution is saturated is quenched, is extracted with ethyl acetate (20mL × 2), organic phase is merged, (10mL × 2) are washed with saturated common salt, organic phase is dried over anhydrous sodium sulfate, and is then filtered, it is spin-dried for being concentrated, obtains crude product.The crude product through fast chromatographic instrument (petroleum ether: ethyl acetate=10:1) purify, obtain target compound BB-2-3 (white solid, 700.00mg, yield: 61.24%, purity: 97%).MS (ESI) m/z:456 [M+H]⁺。

Step 3: the synthesis of compound BB-2

Compound BB-2-3 (700.00mg) is dissolved in the in the mixed solvent of dioxane (10.00mL) and water (1.00mL), then be added lithium hydroxide (250.00mg), 25 DEG C at a temperature of continue stirring 3 hours.Revolving removes solvent, acid pH is slowly adjusted to 2N hydrochloric acid, about 2, then ethyl acetate extraction (20mL × 3) merges organic phase, anhydrous sodium sulfate is dry, concentrated by rotary evaporation under reduced pressure obtains crude product target compound BB-2 (yellow solid, 600.00mg, yield: 88.83%, purity: 97%) MS (ESI) m/z:450 [M+Na]⁺。

Reference example 3: segment BB-3

Synthetic route:

Step 1: the synthesis of compound BB-3-2

By compound BB-3-1 (500.00mg), triethylamine (308.88mg) and dimethylamino naphthyridine (62.15mg) are dissolved in methylene chloride (5.00mL), it is added dropwise compound BB-1-2 (448.61mg), reaction mixture is heated to 40 DEG C after stirring 2 hours at 20 DEG C, continues stirring 16 hours.Water (10mL) is added into reaction mixture, separate organic layer, it is dried, filtered with anhydrous sodium sulfate, boils off solvent with water pump decompression, purify that (petroleum ether and ethyl acetate are eluant, eluent with flash silica gel chromatography, the content from 0 to 30% of ethyl acetate), obtain target compound BB-3-2 (orange solids, 780mg, yield: 61.72%, purity: 96%) MS (ESI) m/z:477 [M+H]⁺。

Step 2: the synthesis of compound BB-3-3

Compound BB-3-2 (800.00mg) is dissolved in dioxane (10.00mL), the aqueous solution of potassium hydroxide (3M) is added, reaction mixture is heated to 100 DEG C and stirs 1 hour.Water pump decompression boils off solvent, residue is suspended in water (5mL), being neutralized to pH value with 6N aqueous hydrochloric acid solution is 2-3, is filtered under diminished pressure out solid, solid is re-dissolved in ethyl acetate (10mL), it is dried, filtered with anhydrous sodium sulfate, water pump decompression boils off solvent, obtain target compound BB-3-3 (brown oil, 600.00mg, crude product), and directly carry out next step reaction.MS (ESI) m/z:337 [M+H]⁺。

Step 3: the synthesis of compound BB-3-5

Compound BB-3-3 (600.00mg) is dissolved in dimethylformamide (5.00mL), it is cooled to 0 DEG C, sodium hydride (121.04mg is added, 60% purity), reactant is blended at 0 DEG C after 30 points of stirring, it is added compound BB-3-4 (326.74mg), final reaction mixture is risen to 20 DEG C and stirs 6 hours.Saturated aqueous ammonium chloride 10mL is added into reaction mixture, (10mL × 2) are extracted with ethyl acetate, merge organic phase, is washed with water (20mL) and saturated sodium-chloride water solution (20mL), it is dry with anhydrous sodium sulfate, filtering, water pump decompression boils off solvent, obtains target compound BB-3-5 (brown oil, 600mg, crude product), and be directly used in and react in next step.MS (ESI) m/z:409 [M+H]⁺。

Step 5: the synthesis of compound BB-3

Compound BB-3-5 (1.00g) is dissolved in tetrahydrofuran (6.00mL), the in the mixed solvent of methanol (2.00mL) and water (2.00mL), a hydronium(ion) lithia (514.01mg) is added, reaction mixture is stirred 3 hours at 20 DEG C.Water pump decompression boils off solvent, residue is dissolved in water (10mL), and being neutralized to pH value with 6N hydrochloric acid is 3-4, and (10mL × 2) are extracted with ethyl acetate, organic layer is washed with water (10mL) and saturated salt solution (10mL), it is dried, filtered with anhydrous sodium sulfate, water pump decompression boils off solvent, obtain target compound BB-3 (brown oil, 1.00g, crude product), and be directly used in and react in next step.MS (ESI) m/z:395 [M+H]⁺。

Reference example 4: segment BB-4

Synthetic route:

Step 1: the synthesis of compound BB-4-2

Compound BB-4-1 (500.00mg) is dissolved in acetic acid (10.00mL), is slowly added to iron powder (214.81mg), reaction solution stirs 4 hours at 100 DEG C, and reaction solution becomes brown and muddiness.Water (15mL) is added into reaction solution, (10mL × 2) are extracted with dichloromethane, merge organic layer, and successively use saturated aqueous sodium carbonate (20mL), water (20mL) and saturated common salt aqueous solution (20mL) washing, it is dry with anhydrous sodium sulfate, filtering, water pump decompression boils off solvent, residue flash silica gel chromatography purifying (petroleum ether and ethyl acetate are eluant, eluent, the content from 0 to 20% of ethyl acetate), obtains target compound BB-4-2 (light yellow oil, 270.00mg, yield: 61.14%)¹HNMR (400MHz, CDCl₃): δ 7.39 (s, 1H), 7.06 (d, J=4.8Hz, 1H), 4.23 (m, 2H ,-NH₂)。

Step 2: the synthesis of compound BB-4-3

Compound BB-4-2 (100.00mg) is dissolved in pyridine (1.00mL), is added dropwise compound BB-1-2 (76.79mg), reaction solution stirs 5 hours at 20 DEG C.Reaction solution becomes muddy.Water (5mL) is added into reaction solution, (5mL × 3) are extracted with ethyl acetate, merge organic layer, and it is successively washed with water (10mL) and saturated salt solution (10mL), it is dry with anhydrous sodium sulfate, filtering, water pump decompression boils off solvent, (petroleum ether and ethyl acetate are eluant, eluent for obtained residue flash silica gel chromatography separation, the content from 0 to 20% of ethyl acetate), obtain target compound BB-4-3 (light yellow solid, 130.00mg, yield: 57.93%, purity: 71.719%).MS (ESI) m/z:370 [M+H]⁺。

Step 3: the synthesis of compound BB-4-4

Compound BB-4-3 (130.00mg) is dissolved in tetrahydrofuran (3.00mL), sodium hydride (21.07mg is added, 60% purity), after reaction mixture stirs 30 minutes at 20 DEG C, it is added compound BB-3-4 (64.47mg), final reaction mixture stirs 16 hours at 30 DEG C.Reaction mixture is quenched with saturated aqueous ammonium chloride (10mL), organic layer is separated, aqueous layer with ethyl acetate (5mL) extraction is primary, merges organic layer, it is dry with anhydrous sodium sulfate, filtering, water pump decompression boil off solvent, and (petroleum ether and ethyl acetate are eluant, eluent to the separation of obtained residue flash silica gel chromatography, the content from 0 to 10% of ethyl acetate), obtain target compound BB-4-4 (light yellow solid, 150.00mg Yield: 51.73%, purity: 53.56%).MS (ESI) m/z:442 [M+H]⁺。

Step 4: the synthesis of compound BB-4

Compound BB-4-4 (180.00mg) is dissolved in tetrahydrofuran (3.00mL), the in the mixed solvent of methanol (1.00mL) and water (1.00mL), a hydronium(ion) lithia (85.39mg) is added, reaction mixture is stirred 2 hours at 20 DEG C.Water pump decompression boils off solvent, residue is dissolved in water (5mL), water layer is neutralized to pH=2-3 with 2N aqueous hydrochloric acid solution, filtering, white solid is obtained, is dissolved with ethyl acetate (10mL), it is dry with anhydrous sodium sulfate, filtering, water pump decompression boils off solvent, obtains target compound BB-4 (white solid, 90.00mg, crude product) white solid, and be directly used in and react in next step.MS (ESI) m/z:428 [M+H]⁺。

Reference example 5: segment BB-5

Synthetic route:

Step 1: the synthesis of compound BB-5-2

Compound BB-1-1 (2.00g) is dissolved in pyridine (20.00mL), compound BB-5-1 (3.81g) then is added at 0 DEG C, stirs reaction solution 3 hours under conditions of 0 DEG C -25 DEG C.With 2N hydrochloric acid under conditions of 0 DEG C quenching reaction.It is extracted with ethyl acetate (20mL × 3), merges organic phase, and wash (20mL × 2) with saturated common salt, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, obtains crude product.The crude product through combiflash companion instrument (petroleum ether: ethyl acetate=20:1) purify, obtain target compound BB-5-2 (faint yellow solid, 3.50g, yield: 86.06%, purity: 92%).MS (ESI) m/z:388 [M+Na]⁺。

Step 2: the synthesis of compound BB-5-3

Compound BB-5-2 (2.00g) is dissolved in anhydrous tetrahydro furan (20.00mL), then the sodium hydride suspension (481.36mg) of 60% purity is added in above-mentioned reaction solution under conditions of 0 DEG C, the reaction solution is stirred 0.5 hour under conditions of 0 DEG C, then compound BB-1-4 (1.46g) is added in above-mentioned reaction solution, continuation is stirred 12 hours at 25 DEG C.The aqueous ammonium chloride solution (50mL) that reaction solution is saturated is quenched, is extracted with ethyl acetate (40mL × 2), organic phase is merged, and (20mL × 2) are washed with saturated common salt, organic phase is dried over anhydrous sodium sulfate, and is then filtered, it is spin-dried for being concentrated, obtains crude product.The crude product through fast chromatographic instrument (petroleum ether: ethyl acetate=10:1) purify, obtain target compound BB-5-3 (faint yellow solid, 2.20g, yield: 81.00%, purity: 91%).MS (ESI) m/z:452 [M+H]⁺。

Step 3: the synthesis of compound BB-5

Compound BB-5-3 (2.30g) is dissolved in the in the mixed solvent of dioxane (30.00mL) and water (3.00mL), then be added lithium hydroxide (500.00mg), 27 DEG C at a temperature of continue stirring 3 hours.Revolving removes solvent, slowly being adjusted to acid pH with 2N hydrochloric acid is about 2, then it is extracted with ethyl acetate (20mL × 3), merges organic phase, washing, anhydrous sodium sulfate is dry, concentrated by rotary evaporation under reduced pressure obtains crude product target compound BB-5 (faint yellow solid, 1.80g, yield: 75.10%, purity: 90%) MS (ESI) m/z:446 [M+Na]⁺。

Reference example 6: segment BB-6

Synthetic route:

Step 1: the synthesis of compound BB-6-2

Compound BB-6-1 (1.00g) is dissolved in pyridine (10.00mL), compound BB-1-2 (1.01g) then is added, which is stirred into 16h at 25 DEG C.Reaction solution is diluted with 80mL ethyl acetate, is washed with 1N hydrochloric acid (30mL × 3), then washes (20mL) with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration.Obtain crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-6-2 (white solid, 1.40g, yield: 75.13%, purity: 95.6%).MS (ESI) m/z:320 [M+H]⁺。

Step 2: the synthesis of compound BB-6-3

Compound BB-6-2 (500.00mg) is dissolved in N, dinethylformamide (10.00mL), then the sodium hydride suspension (125.60mg) of 60% purity is added at 0 DEG C, compound BB-3-4 (360.24mg) is added after stirring 0.5 hour, which is stirred into 16h at 25 DEG C.Reaction solution is gone out with 2mL water quenching, and 80mL ethyl acetate is added to dilute, then washes (20mL × 3) with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-6-3 (yellow oily, 450.00mg, yield: 56.03%, purity: 76.5%).MS (ESI) m/z:414 [M+Na]⁺。

Step 3: the synthesis of compound BB-6

Compound BB-6-3 (450.00mg) is dissolved in the in the mixed solvent of tetrahydrofuran (5.00mL) and water (3.00mL), then a hydronium(ion) lithia (193.00mg) is added, which is stirred into 2h at 25 DEG C.Reaction solution 3N salt acid for adjusting pH to 1, mixed liquor acetic acid Ethyl ester extracts (50mL × 2), and organic phase washes (25mL) with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains target compound BB-6 (white solid, 410.00mg, crude product).MS (ESI) m/z:400 [M+Na]⁺。

Reference example 7: segment BB-7

Synthetic route:

Step 1: the synthesis of compound BB-7-2

Compound BB-7-1 (1.00g) is dissolved in pyridine (10.00mL), compound BB-1-2 (1.18g) then is added, which is stirred into 16h at 25 DEG C.Reaction solution is diluted with 80mL ethyl acetate, is washed with 1N hydrochloric acid (30mL × 3), then washes (20mL) with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-7-2 (white solid, 1.10g, yield: 52.49%, purity: 91.5%).MS (ESI) m/z:293 [M+H]⁺。

Step 2: the synthesis of compound BB-7-3

Compound BB-7-2 (500.00mg) is dissolved in N, dinethylformamide (10.00mL), then sodium hydride (136.80mg is added at 0 DEG C, 60% purity), compound BB-3-4 (392.37mg) is added after stirring 0.5 hour, which is stirred into 16h at 25 DEG C.Reaction solution is gone out with 2mL water quenching, and 80mL ethyl acetate is added to dilute, then washes (20mL × 3) with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-7-3 (white solid, 430.00mg, yield: 58.59%, purity: 85%).MS (ESI) m/z:387 [M+Na]⁺。

Step 3: the synthesis of compound BB-7

Compound BB-7-3 (430.00mg) is dissolved in the in the mixed solvent of tetrahydrofuran (5.00mL) and water (3.00mL), then a hydronium(ion) lithia (197.84mg) is added, which is stirred into 2h at 25 DEG C.Reaction solution 3N salt acid for adjusting pH to 1, mixed liquor are extracted with ethyl acetate (50mL × 2), and organic phase washes (25mL) with saturated common salt, anhydrous sodium sulfate dries, filters, filtrate concentration, it obtains target compound BB-7 (white solid, 405.00mg, crude product).MS (ESI) m/z:373 [M+Na]⁺。

Reference example 8: segment BB-8

Synthetic route:

Step 1: the synthesis of compound BB-8-2

Compound BB-1-3 (100.00mg) and compound BB-8-1 (107.84mg) are dissolved in n,N-Dimethylformamide (1.00mL), then n,N-diisopropylethylamine (115.49mg) is added in reaction solution.Reaction solution is stirred 16 hours at 80 DEG C.Water (3mL) is slowly instilled in reaction solution, has solid to be precipitated gradually.Filtering, filter cake is dissolved in ethyl acetate (10mL), with anhydrous sodium sulfate it is dry after be spin-dried for, obtain target compound BB-8-2 (brownish black solid, 100.00mg, yield: 67.85%, purity: 88.078%).MS (ESI) m/z:436 [M+H]⁺。

Step 2: the synthesis of compound BB-8

Compound BB-8-2 (100.00mg) is dissolved in methanol (4.00mL) and water (1.00mL), then a hydronium(ion) lithia (48.14mg) is added in reaction solution.Reaction solution stirs 2 hours at 20 DEG C.Methanol is removed from reaction solution, the dilute hydrochloric acid of 2N is slowly instilled in reaction solution, adjusts pH until 3, there is solid precipitation.Filtering, filter cake is dissolved in ethyl acetate (10mL), with anhydrous sodium sulfate it is dry after be spin-dried for, obtain target compound BB-8 (brownish black solid, 80.00mg, yield: 74.10%, purity: 86.665%).MS (ESI) m/z:425 [M+NH₄]⁺。

Reference example 9: segment BB-9

Synthetic route:

Step 1: the synthesis of compound BB-9-2

Compound BB-9-1 (1.00g) is dissolved in pyridine (10.00mL), compound BB-1-2 (1.14g) then is added, which is stirred into 3h at 25 DEG C.Reaction solution is diluted with 80mL ethyl acetate, it is washed with 1N hydrochloric acid (30mL × 3), (20mL) is washed with saturated common salt again, anhydrous sodium sulfate dries, filters, filtrate concentration, obtain target compound BB-9-2 (faint yellow solid, 1.40g, yield: 68.44%, purity: 92.433%) it is directly used in and reacts in next step.MS (ESI) m/z:298 [M+H]⁺。

Step 2: the synthesis of compound BB-9-3

Compound BB-9-2 (500.00mg) is dissolved in tetrahydrofuran (5.00mL), then sodium hydride (134.34mg) is added at 0 DEG C, compound BB-3-4 (385.30mg) is added after stirring 0.5 hour, which is stirred into 16h at 25 DEG C.Reaction solution is gone out with 2mL water quenching, and 80mL ethyl acetate is added to dilute, then washes (20mL × 3) with saturated common salt, and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-9-3 (white solid, 310.00mg, yield: 42.53%, purity: 85.24%).MS (ESI) m/z:392 [M+Na]⁺。

Step 3: the synthesis of compound BB-9

Compound BB-9-3 (300.00mg) is dissolved in tetrahydrofuran (5.00mL) and water (3.00mL), a hydronium(ion) lithia (136.15mg) is then added, which is stirred into 2h at 25 DEG C.Reaction solution 3N hydrochloric acid tune pH to 1, mixed liquor are extracted with ethyl acetate (50mL × 2), and organic phase washes (25mL) with saturated common salt, anhydrous sodium sulfate dries, filters, filtrate concentration, it obtains target compound BB-9 (white solid, 250.00mg, crude product).MS (ESI) m/z:378 [M+Na]⁺。

Reference example 10: segment BB-10

Synthetic route:

Step 1: the synthesis of compound BB-10-2

Compound BB-10-1 (3.00g) is dissolved in pyridine (25.00mL), compound BB-1-2 (3.74g) is then slowly added dropwise.Then it is stirred at 20 DEG C 1 hour, reaction solution is in pale yellow cloudy liquid at this time.Reaction solution is filtered, filtrate is poured into 50mL ethyl acetate, is then washed with the dilute hydrochloric acid of 3M (20mL × 5).Organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains crude product.Solid crude product is beaten purifying with (20mL × 2) petrol ether/ethyl acetate (petroleum ether: ethyl acetate=10:1).Filtering collects filtrate, is spin-dried for, obtains target compound BB-10-2 (light red solid, 5.70g, yield: 95.47%, purity: 100%) MS (ESI) m/z:282 [M+H]⁺。

Step 2: the synthesis of compound BB-10-3

Compound BB-10-2 (1.00g) is dissolved in N, in dinethylformamide (10.00mL), then potassium carbonate (981.29mg) and compound BB-1-4 (1.19g) is added, which is stirred 1.5 hours at 60 DEG C.The reaction solution is poured into 50mL ethyl acetate, and is washed with water (20mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains crude product.The crude product isolates and purifies (petroleum ether: ethyl acetate=5:1) by combiflash companion instrument, obtain target compound BB-10-3 (Off-white solid, 1.30g, yield: 99.55%, purity: 100%) MS (ESI) m/z:390 [M+Na]⁺。

Step 3: the synthesis of compound BB-10

Compound BB-10-3 (1.30g) is dissolved in tetrahydrofuran (5.00mL), a hydronium(ion) lithia (444.36mg) and water (5.00mL) is then added, which is stirred 2 hours at 20 DEG C.The reaction solution is concentrated to remove organic solvent, remaining water phase is adjusted to pH=2 with the dilute hydrochloric acid of 3M, there is white solid precipitation at this time.The solid product being collected by filtration is washed with water (10mL × 2), solid is spin-dried for, obtain target compound BB-10 (white solid, 1.10g, yield: 91.71%, purity: 100%).MS (ESI) m/z:340 [M+H]⁺。

Reference example 11: segment BB-11

Synthetic route:

Step 1: the synthesis of compound BB-11-2

Compound BB-1-1 (1.00g) is dissolved in pyridine (10.00mL), compound BB-11-1 (1.21g) then is added, which is stirred into 16h at 25 DEG C.Reaction solution 80mL ethyl acetate is diluted, is washed with 1N hydrochloric acid (30mL × 3), then washes (20mL) with saturated common salt, anhydrous sodium sulfate dries, filters, and filtrate concentration obtains crude product.The crude product with combiflash companion instrument separate (0-40% ethyl acetate is dissolved in petroleum ether), obtain target compound BB-11-2 (colorless oil, 520.00mg, yield: 25.36%, purity: 98.638%).MS (ESI) m/z:396 [M+H]⁺。

Step 2: the synthesis of compound BB-11-3

Compound BB-11-2 (120.00mg) (crude product) is dissolved in N, in dinethylformamide (3.00mL), then potassium carbonate (83.81mg) and compound BB-3-4 (69.57mg) is added, which is stirred into 5h at 60 DEG C.Reaction solution adds 80mL ethyl acetate to dilute, then washes (20mL × 3) with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, obtains target compound BB-11-3 (yellow oily, 120.00mg, crude product) and is directly used in and reacts in next step.MS (ESI) m/z:468 [M+H]⁺。

Step 3: the synthesis of compound BB-11

Compound BB-11-3 (120.00mg) is dissolved in tetrahydrofuran (5.00mL) and water (3.00mL), a hydronium(ion) lithia (43.05mg) is then added, which is stirred into 2h at 25 DEG C.Reaction solution 3N hydrochloric acid tune pH to 1, mixed liquor are extracted with ethyl acetate (50mL × 2), and organic phase washes (25mL) with saturated common salt, anhydrous sodium sulfate dries, filters, filtrate concentration, it obtains target compound BB-11 (white solid, 100.00mg, crude product).MS (ESI) m/z:476 [M+Na]⁺。

Reference example 12: segment BB-12

Synthetic route:

Step 1: the synthesis of compound BB-12-2

Compound BB-1-1 (2.00g) is dissolved in pyridine (20.00mL), system temperature is down to 0 DEG C, compound BB-12-1 (2.61g) is added portionwise in reaction system, is reacted 1 hour at 0 DEG C, reaction system is warming up to 70 DEG C and is reacted 5 hours.Reaction system is added in 2N aqueous hydrochloric acid solution (30mL), ethyl acetate (3 × 30mL) extraction, organic phase is dry with anhydrous sodium sulfate, it is spin-dried for, yellow oil is obtained, crude product obtains target compound BB-12-2 (faint yellow solid through column chromatographic purifying (petroleum ether: ethyl acetate: 3:1), 1.58g, yield: 37.25%)¹HNMR (400MHz, CD₃OD): δ 7.96 (d, J=1.8Hz, 1H), 7.70-7.60 (m, 4H), 7.46-7.41 (m, 1H), 7.39-7.32 (m, 1H), 7.13 (br.s., 1H)

Step 2: the synthesis of compound BB-12-3

Compound BB-12-2 (800.00mg) is dissolved in N, in dinethylformamide (8.00mL), then system temperature is down to 0 DEG C, by sodium hydride (170.00mg, 60% purity) reaction system is added, it stirs 0.5 hour, then at 0 DEG C, reaction system is added in compound BB-3-4 (531.42mg), is reacted 8 hours at 20 DEG C.Reaction system is added in water (15mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for by ethyl acetate (3 × 20mL) extraction, obtain yellow oil.Crude product obtains target chemical combination through column chromatography (petroleum ether: ethyl acetate=4:1) purifying Object BB-12-3 (light yellow oil, 398.00mg, yield: 42.37%).MS (ESI) m/z:488,486 [M+H]⁺。

Step 3: the synthesis of compound BB-12

Compound BB-12-3 (127.00mg) is dissolved in dioxane (1.80mL) and water (200.00 μ L), reaction system then is added in a hydronium(ion) lithia (37.20mg), is reacted 2 hours at 25 DEG C.With 2N hydrochloric acid tune pH to 4-5, ethyl acetate (4 × 10mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, it is spin-dried for, obtains target compound BB-12 (yellow oil, 97.00mg, yield: 79.09%) MS (ESI) m/z:474,472 [M+H]⁺。

Reference example 13: segment BB-13

Synthetic route:

Step 1: the synthesis of compound BB-13-2

Compound BB-1-1 (300.00mg) is dissolved in N, in dinethylformamide (2.00mL), system temperature is down to 0 DEG C, by sodium hydride (79.60mg, 60% purity) reaction system is added, then reaction system is added in compound BB-13-1 (307.40mg) at 0 DEG C, is stirred 2 hours at 20 DEG C.Reaction system is added in water (10mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 15mL) extraction.Crude by column chromatography (petroleum ether: ethyl acetate=4:1) purifying, obtains target compound BB-13-2 (light yellow oil, 215.00mg, yield: 41.12%).

Step 2: the synthesis of compound BB-13-3

Compound BB-13-2 (210.00mg) is dissolved in N, in dinethylformamide (3.00mL), then system temperature is down to 0 DEG C, by sodium hydride (54.07mg, 60% purity) reaction system is added, then reaction system is added in compound BB-3-4 (169.19mg) at 0 DEG C, is reacted 8 hours at 20 DEG C.Reaction system is added in water (10mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 20mL) extraction.Crude product obtains target compound BB-13-3 (light yellow oil, 135.00mg, yield: 53.09%) through column chromatography (petroleum ether: ethyl acetate=4:1) purifying.MS (ESI) m/z:414 [M+H]⁺。

Step 3: the synthesis of compound BB-13

Compound BB-13-3 (130.00mg) is dissolved in Isosorbide-5-Nitrae-dioxane (2.00mL) and water (300.00 μ L), then by a hydrated hydroxide Change lithium (45.14mg) and reaction system is added, it is stirred 3 hours at 20 DEG C, with 2N hydrochloric acid tune pH value to 5-6, ethyl acetate (3 × 10mL) extraction, organic phase is dried, filtered with anhydrous sodium sulfate, it is spin-dried for, obtain target compound BB-13 (yellow solid, 100.00mg, yield: 79.62%).MS (ESI) m/z:400 [M+H]⁺。

Reference example 14: segment BB-14

Synthetic route:

Step 1: the synthesis of compound BB-14-2

Compound BB-1-1 is dissolved in pyridine (5.00mL), reaction system is added portionwise in compound BB-14-1 (431.95mg) at 0 DEG C, after adding, is reacted 1 hour at 0 DEG C.It is added 2N hydrochloric acid (10mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 15mL) extraction.Crude product obtains target compound BB-14-2 (white solid, 330.00mg, yield: 38.28%) through column chromatography (petroleum ether: ethyl acetate=3:1) purifying¹HNMR (400MHz, CD3OD): δ 9.01 (d, J=2.0Hz, 1H), 8.83 (dd, J=1.6,4.8Hz, 1H), 8.08 (td, J=2.0,8.0Hz, 1H), 7.99 (d, J=1.2Hz, 1H), 7.48-7.41 (m, 2H), 7.41-7.36 (m, 1H), 7.22 (s, 1H)

Step 2: the synthesis of compound BB-14-3

Compound BB-14-2 is dissolved in tetrahydrofuran (8.00mL), then system temperature is down to 0 DEG C, by sodium hydride (70.56mg, 60% purity) reaction system is added, stirring 0.5 hour, then reaction system is added in compound BB-3-4 (220.79mg) at 0 DEG C, is reacted 8 hours at 20 DEG C.Reaction system is added in water (15mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 20mL) extraction.Crude product obtains target compound BB-14-3 (light yellow oil, 130.00mg, yield: 39.66%) MS (ESI) m/z:409 [M+H] through column chromatography (petroleum ether: ethyl acetate=3:1) purifying⁺。

Step 3: the synthesis of compound BB-14

Compound BB-14-3 (127.00mg) is dissolved in dioxane (1.80mL) and water (200.00 μ L), reaction system then is added in a hydronium(ion) lithia (37.20mg), is reacted 2 hours at 25 DEG C.With 2N hydrochloric acid tune pH value to 4-5, ethyl acetate (4 × 10mL) extraction will Organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, and target compound BB-14 (yellow oil, 97.00mg, yield: 79.09%) MS (ESI) m/z:395 [M+H] are obtained⁺。

Reference example 15: segment BB-15

Synthetic route:

Step 1: the synthesis of compound BB-15-1

Compound BB-3-1 (500.00mg) is dissolved in pyridine (5.00mL), reaction system is added portionwise in compound BB-14-1 (428.57mg) at 0 DEG C, after adding, is reacted 1 hour at 0 DEG C.Reaction system is added in 6N hydrochloric acid (10mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 25mL) extraction.Yellow oil is through column chromatography for separation (petroleum ether: ethyl acetate=3:1), obtain target compound BB-15-1 (yellow solid, 389.00mg, yield: 18.87%, purity: 59%) MS (ESI) m/z:479 [M+H]⁺

Step 2: the synthesis of compound BB-15-2

Compound BB-15-1 (370.00mg) is dissolved in 1, in 4- dioxane (5.00mL) and water (2.00mL), reaction system is added in potassium hydroxide (346.84mg), reaction mixture is heated to 100 DEG C and stirs 1 hour.Reaction system is added in water (10mL), with 3N hydrochloric acid tune pH value to 5-6, organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 20mL) extraction.Yellow oil is through column chromatography (petroleum ether: ethyl acetate=2:1) purifying, obtain target compound BB-15-2 (yellow solid, 162.00mg, yield: 61.46%, purity: 99%) MS (ESI) m/z:338 [M+H]⁺。

Step 3: the synthesis of compound BB-15-3

Compound BB-15-2 (155.00mg) is dissolved in N, in dinethylformamide (3.00mL), then system temperature is down to 0 DEG C, by sodium hydride (40.40mg, 60% purity) reaction system is added, compound BB-3-4 (126.38mg) is then added reaction system at 0 DEG C, reacted 5 hours at 25 DEG C by stirring 0.5 hour.Reaction system is added in water (15mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 20mL) extraction.Yellow oil obtains target through column chromatographic purifying (petroleum ether: ethyl acetate=2:1) Compound BB-15-3 (light yellow oil, 120.00mg, yield: 52.32%, purity: 82%).MS (ESI) m/z:410 [M+H]⁺。

Step 4: the synthesis of compound BB-15

Compound BB-15-3 (115.00mg) is dissolved in 1, in 4- dioxane (1.80mL) and water (200.00 μ L), then reaction system is added in a hydronium(ion) lithia (58.88mg), is reacted 2 hours at 25 DEG C.(10mL) water is added, it is 5-6 with 3N hydrochloric acid tune pH value, ethyl acetate (3 × 25mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains target compound BB-15 (yellow solid, yield: 81.93%) 91.00mg directly carries out next step reaction.MS (ESI) m/z:396 [M+H]⁺。

Reference example 16: segment BB-16

Synthetic route:

Step 1: the synthesis of compound BB-16-3

Compound BB-16-1 (5.00g) is dissolved in methylene chloride (50.00mL), compound BB-16-2 (2.13g) then is added, which is stirred 2 hours at 20 DEG C.Reaction solution is concentrated, residue is dissolved in 50mL ethyl acetate, and (10mL × 3) are washed with water, organic phase is dried, filtered with anhydrous sodium sulfate, concentration, obtain target compound BB-16-3 (light green oily, 6.90g, yield: 99.45%, purity: 100%) it, without purifying is directly used in next step.MS (ELSD) m/z:298 [M+H]⁺。

Step 2: the synthesis of compound BB-16

Compound BB-16-3 (6.90g) is dissolved in methylene chloride (30.00mL), hydrochloric acid/dioxane (4M, 30.00mL) then is added, which is stirred 1.5 hours at 20 DEG C.The reaction solution is concentrated, obtaining target compound BB-16, (yield: 98.32%) faint yellow oily, 4.50g, are directly used in next step without purifying.MS (ELSD) m/z:198 [M+H]⁺。

Reference example 17: segment BB-17

Synthetic route:

Step 1: the synthesis of compound BB-17

Compound BB-17-1 (1.00g) and acetic acid (281.57mg) are added in dichloroethanes (4.00mL) solution of compound BB-17-2 (321.23mg).The reaction solution is stirred 3 hours at 20 DEG C, sodium cyanoborohydride (441.97mg) then is added.The reaction solution reacts 12 hours at 20 DEG C.The reaction solution is concentrated, is then dissolved in 50mL ethyl acetate, organic phase is washed with water (10mL × 3), and anhydrous sodium sulfate dries, filters, and concentration obtains crude product.The crude product passes through combiflash companion instrument separation (methylene chloride: methanol=10:1) purifying.Obtain target compound BB-17 (colorless oil, 700.00mg, yield: 42.25%, purity: 72%).MS (ELSD) m/z:198.9 [M-tBu+H]⁺。

Reference example 18: segment BB-18

Synthetic route:

Step 1: the synthesis of compound BB-18-2

By compound BB-18-1 (200.00mg), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (567.00mg) and diisopropylethylamine (514.00mg) are dissolved in N, in dinethylformamide (2.00mL), tert-butylamine (109.05mg) then is added, mixture is stirred to react at 25 DEG C 1.5 hours.It after the water quenching reaction of 5mL, is extracted with ethyl acetate (50mL × 2), organic phase is washed with saturated salt solution (20mL × 2), dried, filtered with anhydrous sodium sulfate, is spin-dried for, and crude product is obtained.By crude product it is thick prepare silica gel plate (petrol ether/ethyl acetate=3/1) separation, obtain target compound BB-18-2 (yellow oil product 250.00mg, yield: 98.12%, purity: 100%).MS (ESI) m/z:201 [M+H-tBu]⁺。

Step 2: the synthesis of compound BB-18

Compound BB-18-2 (250.00mg) is dissolved in methylene chloride (3.00mL), HCl/ dioxane (4M, 3.00mL) then is added, is stirred 2 hours at 25 DEG C.Reaction solution is directly depressurized and is spin-dried for, the hydrochloride (yellow oily, 180.00mg, crude product) of target compound BB-18 is obtained.MS (ESI) m/z:157 [M+H]⁺。

Reference example 19: segment BB-19

Synthetic route:

Using compound BB-19-1 as raw material, with reference to the synthesis step 1-2 of segment BB-18 in reference example 18, segment BB-19 is synthesized.MS (ESI) m/z:171 [M+H]⁺。

Reference example 20: segment BB-20

Synthetic route:

Using compound BB-20-1 as raw material, with reference to the synthesis step 1-2 of segment BB-18 in reference example 18, segment BB-20 is synthesized.MS (ESI) m/z:187 [M+H]⁺。

Reference example 21: segment BB-21

Synthetic route:

Step 1: the synthesis of compound BB-21

Compound BB-21-1 (200.00mg) and AcOH (56.32mg) is added in 1,2- dichloroethanes (4.00mL) solution of ethamine (50.73mg).The reaction solution is stirred 1 hour at 15 DEG C, 0 DEG C is then cooled to, is added sodium cyanoborohydride (88.40mg).The reaction solution is reacted 11 hours at 15 DEG C.The reaction solution is poured into 10mL ice water, and is extracted with methylene chloride (20mL × 3).Organic phase is washed with saturated salt solution (10mL × 2), and anhydrous sodium sulfate dries, filters, and concentration obtains crude product.By the crude product by combiflash companion instrument purifying (methylene chloride: methanol=10:1), target compound BB-21 (white oil, 40.00mg, crude product) is obtained.MS (ESI) m/z:243 [M+H]⁺。

Reference example 22: segment BB-22

Synthetic route:

Using compound BB-21-1 and BB-22-1 as raw material, with reference to the synthesis step 1 of segment BB-21 in reference example 21, segment BB-22 is synthesized.MS (ESI) m/z:255 [M+H]⁺。

Reference example 23: segment BB-23

Synthetic route:

Using compound BB-21-1 and BB-23-1 as raw material, with reference to the synthesis step 1 of segment BB-21 in reference example 21, segment BB-23 is synthesized.MS (ESI) m/z:257 [M+H]⁺。

Reference example 24: segment BB-24

Synthetic route:

Using compound BB-21-1 and BB-24-1 as raw material, with reference to segment BB-21 synthesis step 1 in reference example 21, segment BB-24 is synthesized.MS (ESI) m/z:257 [M+H]⁺。

Reference example 25: segment BB-25

Synthetic route:

Step 1: the synthesis of compound BB-25-2

Compound BB-25-1 (5.00g) is added in tetrahydrofuran (5.00mL), borane-dimethyl sulfide (10M) slowly then is added dropwise, is stirred 16 hours at 20 DEG C.Reaction solution is cooled to 0 DEG C, 1N NaOH (5mL) is added to be quenched, then it is extracted with ethyl acetate (20mL × 2), merges organic phase, organic phase washes (20mL) with saturated common salt, it is dry with anhydrous sodium sulfate, filtering, filtrate concentration, obtains target compound BB-25-2 (light yellow oil, 450.00mg, crude product) it is directly used in and reacts in next step.MS (ESI) m/z:174 [M+H-tBu]⁺。

Step 2: the synthesis of compound BB-25

Compound BB-25-2 (5.00g) is added in methylene chloride (2.00mL), hydrochloric acid/dioxane (4M, 5.00mL) then is added, is stirred 1 hour at 20 DEG C.Reaction solution concentration, the hydrochloride (light yellow oil, 325.00mg, crude product) for obtaining target compound BB-25 is directly used in react in next step.MS (ESI) m/z:130 [M+H]⁺。

Reference example 26: segment BB-26

Synthetic route:

Step 1: the synthesis of compound BB-26

Compound BB-26-1 (300.00mg) is dissolved in methylene chloride (5.00mL) and methanol (3.00mL), then ethamine (345.73mg is sequentially added, its hydrochloride) and triethylamine (643.57mg), the reaction solution is stirred into 1h at 25 DEG C, then sodium cyanoborohydride (266.44mg) is added, reaction solution turns yellow.The reaction solution is stirred into 15h at 25 DEG C.Reaction solution adds methylene chloride (40mL) dilution, then washes (20mL × 2) with saturated common salt, dry with anhydrous sodium sulfate, filtering, filtrate concentration, obtains target compound BB-26 (yellow oily, 350.00mg, crude product) it is directly used in and reacts in next step.MS (ESI) m/z:171 [M+H]⁺。

Reference example 27: segment BB-27

Synthetic route:

Using compound BB-27-1 as raw material, with reference to the synthesis step 1 of segment BB-26 in reference example 26, segment BB-27 is synthesized.MS (ESI) m/z:205 [M+H]⁺。

Reference example 28: segment BB-28

Synthetic route:

Step 1: the synthesis of compound BB-28-2

Compound BB-28-1 (2.70g) is dissolved in ethyl alcohol (30.00mL); dry palladium dydroxide (240.00mg) (20%) is added under protection of argon gas, reaction mixture is stirred 20 hours under 30 DEG C, the hydrogen environment of 50psi.Reaction monitors whether fully reacting with nuclear-magnetism.It is filtered with diatomite, filter cake boils off solvent by water pump decompression with ethanol washing (5mL × 3), filtrate, obtains target compound BB-28-2 (colorless oil, 2.80g, crude product) and directly carries out next step reaction.MS (ELSD) m/z:284 [M+H]⁺。

¹HNMR (400MHz, CDCl₃): δ 4.65 (m, 1H), 4.19-4.09 (m, 2H), 2.45-2.40 (m, 1H), 2.10 (m, 1H), 2.0 (m, 1H), 1.95 (m, 3H), 1.70 (m, 4H), 1.41 (m, 9H), 1.28 (t, J=7.2Hz, 3H)

Step 2: the synthesis of compound BB-28-3

Compound BB-28-2 (1.00g) is dissolved in tetrahydrofuran (10.00mL), -10 DEG C is cooled to, Lithium Aluminium Hydride (211.19mg) is added under nitrogen protection, reaction mixture is stirred 45 minutes at -10 DEG C -0 DEG C.15% sodium hydrate aqueous solution (0.25mL) and water (0.25mL) are slowly added dropwise into reaction mixture, filtering, filter cake is washed with ethyl acetate (5mL × 5), organic layer is dry with anhydrous sodium sulfate, filtering, water pump decompression boil off solvent, obtain target compound BB-28-3 (colorless oil, 640.00mg, crude product) and it is directly used in reaction in next step.MS (ELSD) m/z:242 [M+H]⁺。

Step 3: the synthesis of compound BB-28

Compound BB-28-3 (640.00mg) is dissolved in ethyl acetate (3.00mL), is cooled to 0 DEG C, is slowly added to hydrochloric acid-ethyl acetate (4M, 3.00mL), reaction solution is warming up to 20 DEG C, continues stirring 1 hour.Water pump decompression boils off solvent, obtains target compound BB-28 hydrochloride (milky jelly, 470.00mg, crude product), and is directly used in and reacts in next step.MS (ELSD) m/z:142 [M+H]⁺。

¹HNMR (400MHz, CDCl₃): δ 4.08-4.06 (m, 1H), 4.04-4.03 (m, 1H), 3.89-3.87 (m, 1H), 3.82-3.78 (m, 1H), 2.20-2.12 (m, 4H), 1.94-1.67 (m, 5H)

Reference example 29: segment BB-29

Synthetic route:

Step 1: the synthesis of compound BB-29-1

By compound BB-2 (200.00mg), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (266.39mg) and diisopropylethylamine (181.09mg) are dissolved in n,N-Dimethylformamide (2.00mL), which is stirred 1 hour at 20 DEG C, then compound BB-17 (178.21mg) is added, which is stirred 12 hours at 20 DEG C.It by reaction solution to entering in 50mL ethyl acetate, is then washed with water (10mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains crude product.The crude product isolates and purifies (petroleum ether: ethyl acetate=3:1) by combiflash companion instrument, obtain target compound BB-29-1 (colorless oil, 180.00mg, yield: 53.93%, purity: 93%).MS (ESI) m/z:686 [M+Na]⁺。

Step 2: the synthesis of compound BB-29

Compound BB-29-1 (180.00mg) is dissolved in methylene chloride (2.00mL), then hydrochloric acid/dioxane (4M, 5.00mL) is added, the reaction solution is stirred 1.5 hours at 20 DEG C, reaction solution is the emulsion in milk yellow.By the reaction solution concentration be spin-dried for, obtain target compound BB-29 hydrochloride (faint yellow solid, 160.00mg, yield: 95.26%, purity: 96.9%) without purifying be directly used in next step.MS (ESI) m/z:564 [M+H]⁺。

Reference example 30: segment BB-30

Synthetic route:

Step 1: the synthesis of compound BB-30-3

Compound BB-30-1 (120.00mg) is dissolved in N, in dinethylformamide (3.00mL), then compound BB-30-2 (29.29mg) is sequentially added, diisopropylethylamine (180.80mg) and 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (212.77mg), reaction solution turn yellow.The reaction solution is stirred 2 hours at 25 DEG C.Ethyl acetate (50mL) is added in reaction solution, then washes (20mL × 3) with saturated common salt, it is dry with anhydrous sodium sulfate, filtering, filtrate concentration, obtains target compound BB-30-3 (yellow oily, 140.00mg, crude product), it is directly used in and reacts in next step.MS (ESI) m/z:319 [M+Na]⁺。

Step 2: the synthesis of compound BB-30

Compound BB-30-3 (130.00mg) is dissolved in methylene chloride (2.00mL), hydrochloric acid/dioxane (4M) then is added, reaction solution turns yellow.The reaction solution is stirred 2 hours at 25 DEG C.Reaction solution concentration, obtains the hydrochloride (yellow oily, 103.00mg, crude product) of target compound BB-30, is directly used in and reacts in next step.MS (ESI) m/z:197 [M+H]⁺。

Reference example 31: segment BB-31

Synthetic route:

Step 1: the synthesis of compound BB-31-2

Compound BB-31-1 (1.00g) is dissolved in pyridine (25.00mL), compound BB-2-1 (2.30g) is then slowly added dropwise.Then, liquid 5 hours are stirred to react at 20 DEG C, at this time reaction solution gray dirty solution.Reaction solution is poured into 100mL ethyl acetate, is then washed with the dilute hydrochloric acid of 3M (20mL × 5).Organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains faint yellow solid crude product.Solid crude product with petrol ether/ethyl acetate (10:1) be beaten purify, filter, collect, obtain target compound BB-31-2 (brown solid, 2.60g, yield: 89.46%, purity: 100%).MS (ESI) m/z:532 [M+H]⁺。

Step 2: the synthesis of compound BB-31-3

Compound BB-31-2 (500.00mg) is dissolved in dioxane (10.00mL), potassium hydroxide (3M, 2.50mL) aqueous solution is then added, which is stirred 1 hour at 100 DEG C.The reaction solution is concentrated, remaining solid is dissolved in 5mL water, and is adjusted to PH=2 with the dilute hydrochloric acid of 6M, there is solid precipitation at this time, is filtered, and solid product is collected.It is target compound BB-31-3 (brown solid, 200.00mg, crude product) after the concentrated drying of the solid of precipitation, the crude product is pure enough, without purifying, is directly used in next step.MS (ESI) m/z:358 [M+H]⁺。

Step 3: the synthesis of compound BB-31-4

Compound BB-31-3 (200.00mg) is dissolved in N, in dinethylformamide (3.00mL), then potassium carbonate (154.56mg) and compound BB-1-4 (272.67mg) is added, which is stirred 1 hour at 25 DEG C.The reaction solution is poured into 20mL ethyl acetate, is then washed with water (10mL × 2), organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains crude product.The crude product is isolated and purified with combiflash companion instrument (petroleum ether: ethyl acetate=5:1), obtain target compound BB-31-4 (colorless oil, 200.00mg, yield: 80.60%) MS (ESI) m/z:444 [M+H]⁺。

Step 4: the synthesis of compound BB-31

Compound BB-31-4 (200.00mg) is dissolved in tetrahydrofuran (1.00mL), the aqueous solution of a hydronium(ion) lithia (1M, 2.00mL) is then added.The reaction solution is stirred 3 hours at 30 DEG C.The reaction solution is concentrated to remove organic solvent, is then adjusted to PH=2 with the hydrochloric acid of 6M, is then extracted with ethyl acetate (10mL × 3), organic phase is merged, concentration obtains colorless oil crude product.Target compound BB-31 (colorless oil, 150.00mg, crude product) is directly used in next step without purifying.MS (ESI) m/z:416 [M+H]⁺。

Reference example 32: segment BB-32

Synthetic route:

Using compound BB-31-1 and BB-1-2 as raw material, with reference to the synthesis step 1-4 of segment BB-31 in reference example 31, segment BB-32 is synthesized.MS (ESI) m/z:382 [M+H]⁺。

Reference example 33: segment BB-33

Synthetic route:

Using compound BB-33-1 and BB-2-1 as raw material, with reference to the synthesis step 1-3 of segment BB-10 in reference example 10, segment BB-33 is synthesized.MS (ESI) m/z:345 [M+H]⁺。

Reference example 34: segment BB-34

Synthetic route:

Step 1: the synthesis of compound BB-34-2

By compound BB-1 (100.00mg), compound BB-34-1 (36.36mg), 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (115.88mg) and diisopropylethylamine (98.47mg) are blended in n,N-Dimethylformamide (1.00mL), and reaction solution is reacted 3 hours at 15 DEG C.Water (3mL) is added into reaction solution, (5 × 3mL) is extracted with ethyl acetate.Merge organic phase, dried, filtered with anhydrous sodium sulfate, water pump vacuum distillation obtains target compound BB-34-2 (light yellow oil, 150.00mg, crude product), and is directly used in and reacts in next step.MS (ESI) m/z:519 [M+H]⁺。

Step 2: the synthesis of compound BB-34

Compound BB-34-2 (150.00mg) is dissolved in water (2.00mL), the in the mixed solvent of methanol (2.00mL) and tetrahydrofuran (3.00mL), a hydronium(ion) lithia (60.64mg) is added, reaction mixture is reacted 3 hours at 15 DEG C.Water pump decompression boils off solvent, obtains residue, is added water (5mL), is neutralized to pH value 1 or so with 2N aqueous hydrochloric acid solution.There is solid to be constantly precipitated, filter, obtain solid, It is dissolved with ethyl acetate (10mL), is dried, filtered with anhydrous sodium sulfate, water pump vacuum distillation obtains target compound BB-34 (white solid, 120.00mg, crude product), and is directly used in and reacts in next step.MS (ESI) m/z:505 [M+H]⁺。

Reference example 35: segment BB-35

Synthetic route:

Step 1: the synthesis of compound BB-35-2

Compound 0403 (300.00mg) and compound BB-35-1 (120.07mg) are dissolved in tetrahydrofuran (5.00mL), triphenylphosphine (356.75mg) then is added.The reaction solution is stirred 1 hour at nitrogen protection and 20 DEG C, is then slowly added dropwise at 0 DEG C diisopropyl azodiformate (275.04mg).The reaction solution is stirred 12 hours at 20 DEG C.The reaction solution is concentrated, solid crude product is obtained.The crude product is dissolved in 20mL ethyl acetate, and is filtered, filtrate water (5mL × 2) washing.Organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains target compound BB-35-2 (pale brown oil, 300.00mg, crude product), not purified to be directly used in next step.MS (ESI) m/z:702 [M+Na]⁺。

Step 2: the synthesis of compound BB-35

Compound BB-35-2 (300.00mg) and hydrazine hydrate (66.21mg) are dissolved in ethyl alcohol (5.00mL), which stirred 5 hours at 80 DEG C.The reaction solution is concentrated to get crude product.The crude product is isolated and purified by combiflash companion instrument (methylene chloride: methanol=10:1), obtain target compound BB-35 (colorless oil, 160.00mg, yield: 53.41%, purity: 81%) MS (ESI) m/z:550 [M+H]⁺。

Reference example 36: segment BB-36

Synthetic route:

Using compound 0310 and BB-35-1 as raw material, with reference to the synthesis step 1-2 of segment BB-35 in reference example 35, segment BB-36 is synthesized.MS (ESI) m/z:550 [M+H]⁺。

Reference example 37: segment BB-37

Synthetic route:

Using compound 0306 and BB-35-1 as raw material, with reference to the synthesis step 1-2 of segment BB-35 in reference example 35, segment BB-37 is synthesized.MS (ESI) m/z:538 [M+H]⁺。

Reference example 38: segment BB-38

Synthetic route:

Using compound BB-1 and BB-38-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-38 is synthesized.MS (ESI) m/z:504 [M+H]⁺。

Reference example 39: segment BB-39

Synthetic route:

Using compound BB-1 and BB-39-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-39 is synthesized.MS (ESI) m/z:476 [M+H]⁺。

Reference example 40: segment BB-40

Synthetic route:

Using compound BB-40-1 and BB-16-2 as raw material, with reference to the synthesis step 1-2 of segment BB-16 in reference example 16, segment BB-40 is synthesized.MS (ESI) m/z:216 [M+H]⁺。

Reference example 41: segment BB-41

Synthetic route:

Step 2: the synthesis of compound BB-41

Compound BB-1 (600.00mg) and compound BB-41-1 (210.59mg) are dissolved in N, in dinethylformamide (5.00mL), then 2- (7- azo benzotriazole)-N is added, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (869.08mg) and diisopropylethylamine (590.80mg) stir the reaction solution 2 hours at 30 DEG C.The reaction solution is poured into 30mL ethyl acetate, is then washed with water (5mL × 3) and saturated salt solution (10mL).Organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains brown oil crude product.The oily crude product is isolated and purified with combiflash companion instrument (petroleum ether: ethyl acetate=1:1), obtain target compound BB-41 (colorless oil, 700.00mg, yield: 93.81%, purity: 100%) MS (ESI) m/z:491 [M+H]⁺。

Reference example 42: segment BB-42

Synthetic route:

Using compound BB-42-1 and BB-16-2 as raw material, with reference to the synthesis step 1-2 of segment BB-16 in reference example 16, segment BB-42 is synthesized.MS (ESI) m/z:234 [M+H]⁺。

Reference example 43: segment BB-43

Synthetic route:

Using compound BB-2 and BB-43-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-43 is synthesized.MS (ESI) m/z:538 [M+H]⁺。

Reference example 44: segment BB-44

Synthetic route:

Using compound BB-2 and BB-44-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-44 is synthesized.MS (ESI) m/z:538 [M+H]⁺。

Reference example 45: segment BB-45

Synthetic route:

Using compound BB-45-1 and BB-16-2 as raw material, with reference to the synthesis step 1-2 of segment BB-16 in reference example 16, segment BB-45 is synthesized.MS (ESI) m/z:212 [M+H]⁺。

Reference example 46: segment BB-46

Synthetic route:

Step 1: the synthesis of compound BB-46-2

Compound BB-46-1 (400.00mg) is dissolved in tetrahydrofuran (8.00mL), HCHO (460.19mg is then added, 37% purity) aqueous solution, then sodium cyanoborohydride (593.84mg) is added in above-mentioned reaction solution, continues stirring 14 hours.100 milliliters of ethyl acetate is added into reaction solution, then washes (30mL × 3), organic phase is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure under water pump, and colorless oil crude product is obtained.The crude product thick prepare silica gel plate (methanol: ethyl acetate=1:10) purifies, and obtains target compound BB-46-2 (colorless oil, 240.00mg, yield: 52.19%).MS (ESI) m/z:244 [M+H]⁺。

Step 2: the synthesis of compound BB-46-3

Compound BB-46-2 (100.00mg) is dissolved in tetrahydrofuran (3.00mL), borine tetrahydrofuran (35.32mg) is added in above-mentioned reaction solution under conditions of at 0 DEG C, continues stirring 12 hours at 60 DEG C.The methanol that 2mL is added to reaction solution is quenched, it is extracted with ethyl acetate (150mL), it washes (50mL × 3), organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated under reduced pressure with water pump, obtains target compound BB-46-3 (colourless oil liquid, 90.00mg crude product).The crude product is not further purified.MS (ESI) m/z:230 [M+H]⁺。

Step 3: the synthesis of compound BB-46-4

Compound BB-46-3 (90.00mg) and BB-16-2 (48.91mg) are dissolved in methylene chloride (3.00mL), stirred 12 hours under conditions of 25 DEG C.The solvent of reaction solution is removed, is concentrated under reduced pressure with water pump, obtains target compound BB-46-4 (colorless oil, 120.00mg, crude product), is not purified again through a step.MS (ESI) m/z:313 [M+H]⁺。

Step 4: the synthesis of compound BB-46

Compound BB-46-4 (90.00mg) is dissolved in methylene chloride (1.00mL), then trifluoroacetic acid (308.00mg) is added in above-mentioned reaction solution under conditions of 0 DEG C, continues stirring 2 hours under conditions of 25 DEG C.Reaction solution is concentrated under reduced pressure with water pump, the hydrochloride (faint yellow solid, 60.00mg, crude product) of target compound BB-46 is obtained, does not purify further.MS (ESI) m/z:213 [M+H]⁺。

Reference example 47: segment BB-47

Synthetic route:

Using compound BB-2 and BB-47-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-47 is synthesized.MS (ESI) m/z:538 [M+H]⁺。

Reference example 48: segment BB-48

Synthetic route:

It is raw material with compound 0144, with reference to the synthesis step 2 of segment BB-29 in reference example 29, synthesizes segment BB-48.MS (ESI) m/z:524 [M+H]⁺。

Reference example 49: segment BB-49

Synthetic route:

Using compound BB-1 and BB-49-1 as raw material, with reference to the synthesis step 1 of segment BB-29 in reference example 29, segment BB-49 is synthesized.MS (ESI) m/z:493 [M+H]⁺。

Reference example 50: segment BB-50

Synthetic route:

Using compound BB-2 and BB-50-1 as raw material, with reference to the synthesis step 1-2 of segment BB-29 in reference example 29, segment BB-50 is synthesized.MS (ESI) m/z:526 [M+H]⁺。

Reference example 51: segment BB-51

Synthetic route:

Step 1: the synthesis of compound BB-51-2

Compound BB-51-1 (400.00mg) is dissolved in N, in dinethylformamide (8.00mL), then by diisopropylethylamine (884.00mg), compound BB-16 (539.76mg) and 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (1.04g) sequentially add in reaction system, react 5 hours at 25 DEG C.Reaction system is added in water (15mL), ethyl acetate (4 × 20mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains target compound BB-51-2 (yellow oil, 410.00mg, yield: 23.85%, purity: 47%), not purified directly to carry out next step reaction.MS (ESI) m/z:355 [M+H]⁺。

Step 2: the synthesis of compound BB-51

Compound BB-51-2 (400.00mg) is dissolved in methylene chloride (10.00mL), reaction system is added in hydrochloric acid/dioxane (1.00mL, 4mol/L) at 25 DEG C, is reacted 1 hour at 25 DEG C.Organic phase is spin-dried for, obtain target compound BB-51 hydrochloride (yellow solid, 280.00mg, yield: 68.17%, purity: 80%).MS (ESI) m/z:255 [M+H]⁺。

Reference example 52: segment BB-52

Synthetic route:

Step 1: the synthesis of compound BB-52-2

Compound BB-52-1 (1.00g) is dissolved in pyridine (8.00mL), compound BB-1-2 (1.86g) is added portionwise in reaction system at 25 DEG C, after adding, is reacted 2 hours at 25 DEG C.Reaction system is added in 3N hydrochloric acid (15mL), ethyl acetate (3 × 25mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains target compound BB-52-2 (yellow solid, 612.00mg, yield: 23.74%, purity: 96%), not purified directly to carry out next step reaction.MS (ESI) m/z:236 [M+H]⁺。

Step 2: the synthesis of compound BB-52-3

Compound BB-52-2 (300.00mg) is dissolved in N, in dinethylformamide (5.00mL), then system temperature is down to 0 DEG C, by sodium hydride (112.80mg, 60% purity) reaction system is added, stirring 0.5 hour, then reaction system is added in compound BB-3-4 (352.44mg) at 0 DEG C, it is reacted 5 hours at 25 DEG C, reaction system is added in water (10mL), ethyl acetate (20mL × 3) extraction, anhydrous sodium sulfate is dry, crude product is through column chromatography (petroleum ether: ethyl acetate=3:1) purifying, obtain target compound BB-52-3 (yellow oily, 90.00mg, yield: 22.19%, purity: 97%) MS (ESI) m/z:308 [M+ H]⁺。

Step 3: the synthesis of compound BB-52

Compound BB-52-3 (85.00mg) is dissolved in dioxane (1.80mL) and water (200.00 μ L), reaction system then is added in a hydronium(ion) lithia (58.03mg), is reacted 2 hours at 25 DEG C.With 6N hydrochloric acid tune pH value to 5-6, ethyl acetate (3 × 20mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains target compound BB-52 (yellow solid, 65.00mg, yield: 48.08%, purity: 60%), does not purify directly carry out next step reaction.MS (ESI) m/z:294 [M+H]⁺。

Reference example 53: segment BB-53

Synthetic route:

Using compound BB-53-1 and BB-2-1 as raw material, with reference to the synthesis step 1-3 of segment BB-10 in reference example 10, segment BB-53 is synthesized.MS (ESI) m/z:345 [M+H]⁺。

Reference example 54: segment BB-54

Synthetic route:

Step 1: the synthesis of compound BB-54-2

Compound BB-1-1 (300.00mg) is dissolved in tetrahydrofuran (3.00mL), then system temperature is down to -78 DEG C, by hmds lithium (1M, reaction system is added in tetrahydrofuran solution 2.30mL), at -78 DEG C, reaction system is added in compound BB-54-1 (258.12mg), stirring 1 hour, it is warming up to 25 DEG C and reacts 6 hours, reaction solution is added in water (10mL), is extracted with ethyl acetate (3 × 20mL), organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains yellow oil.Crude product through column chromatographic purifying (petroleum ether: ethyl acetate=4:1), obtain target compound BB-54-2 (light yellow oil, 162.00mg, yield: 11.80%, purity: 45%) MS (ESI) m/z:404 [M+H] ⁺

Step 2: the synthesis of compound BB-54-3

Compound BB-54-2 (120.00mg) is dissolved in dioxane (5.00mL) and water (2.00mL), reaction system is added in potassium hydroxide (133.39mg), reactant is heated to 100 DEG C and stirs 1 hour.With 6N hydrochloric acid tune pH value to 5-6, organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 15mL) extraction.Crude product obtains target compound BB-54-3 (yellow solid, 80.00mg, yield: 89.83%) MS (ESI) m/z:300 [M+H] through column chromatography (petroleum ether: ethyl acetate=3:1) purifying⁺

Step 3: the synthesis of compound BB-54-4

Compound BB-54-3 (65.00mg) is dissolved in N, in N-dimethylformamide (2.00mL), then reaction system is added in potassium carbonate (59.95mg) and compound BB-1-4 (72.44mg), system temperature is increased to 60 DEG C, 1 hour is reacted by water (10mL) and reaction system, ethyl acetate (3 × 15mL) extraction is added, organic phase is dry with anhydrous sodium sulfate, filtering, is spin-dried for, obtains yellow oil.Crude product through column chromatography (petroleum ether: ethyl acetate=4:1) purifying, obtain target compound BB-54-4 (light yellow oil, 45.00mg, yield: 49.43%, purity: 91.9%) MS (ESI) m/z:386 [M+H]⁺

Step 4: the synthesis of compound BB-54

Compound BB-54-4 (43.00mg) is dissolved in dioxane (1.00mL) and water (200.00 μ L), then reaction system is added in a hydronium(ion) lithia (28.06mg), it is stirred 2 hours at 25 DEG C, adding 6N hydrochloric acid tune pH value is 5-6, ethyl acetate (3 × 10mL) extraction, organic phase is dry with anhydrous sodium sulfate, filtering, it is spin-dried for, obtain target compound BB-54 (faint yellow solid, 36.00mg, yield: 90.29%), not purified directly to carry out next step reaction.MS (ESI) m/z:358 [M+H⁺]

Reference example 55: segment BB-55

Synthetic route:

Using compound BB-55-1 and BB-2-1 as raw material, with reference to the synthesis step 1-3 of segment BB-10 in reference example 10, segment BB-55 is synthesized.MS (ESI) m/z:397 [M+H]⁺。

Reference example 56: segment BB-56

Synthetic route:

Step 1: the synthesis of compound BB-56-2

Compound BB-56-1 (50.00mg) and compound BB-16-2 (17.42mg) are dissolved in methylene chloride (2.00mL), and reacted 1 hour at 30 DEG C.Reaction solution is spin-dried for, target compound BB-56-2 (white solid, 52.00mg, yield: 78.98%), not purified directly to carry out next step reaction are obtained.MS (ESI) m/z:346 [M+H]⁺。

Step 2: the synthesis of compound BB-56

Compound BB-56-2 (50.00mg) is dissolved in methanol (2.00mL); then by palladium dydroxide (101.64mg; 20% purity) reaction system is added; it is reacted 5 hours at the hydrogen shield of 15psi and 30 DEG C, reaction solution is filtered, is spin-dried for; obtain target compound BB-56 (white solid; 30.00mg, yield: 98.09%), not purified directly to carry out next step reaction.MS (ESI) m/z:212 [M+H]⁺。

Reference example 57: segment BB-57

Synthetic route:

It is raw material with compound BB-2, BB-49-1, with reference to segment BB-29 synthesis step 1 in reference example 29, synthesized reference example BB-57.MS (ESI) m/z:527 [M+H]⁺。

Embodiment 1: compound 0079

Synthetic route:

Step 1: the synthesis of compound 0079

Compound BB-1 (60.00mg) and compound 0079-1 (32.66mg) are dissolved in N, in dinethylformamide (1.00mL), then by N, N- diisopropylethylamine (59.08mg) and 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (86.91mg) are added in reaction solution.Reaction solution is stirred 16 hours at 25 DEG C.Reaction solution filtering.Filtrate is by preparation HPLC (0.05%HCl-ACN, 250 × 21.2mm × 4 μm Phenomenex Synergi C18) isolate and purify after, LCMS shows that product is impure, then again pass by preparation HPLC (0.05%ammonia-ACN, 150 × 25 5u of Gemini) it isolates and purifies, obtain target compound 0079 (14.30mg, yield: 14.86%, purity: 93.421%).MS (ESI) m/z:612 [M+Na]⁺。

¹HNMR (400MHz, CD₃OD): δ 8.00-7.90 (m, 1H), 7.70-7.45 (m, 7H), 4.70-4.50 (m, 2H), 4.20-4.12 (m, 1H), 3.84-3.70 (m, 1H), 3.15-2.45 (m, 5H), 1.85-1.55 (m, 3H), 1.41 (s, 9H), 1.30-1.15 (m, 1H)

Embodiment 2:0172

Synthetic route:

Step 1: the synthesis of compound 0172

Compound 0079 (280.00mg) is dissolved in methylene chloride (5.00mL), (4M) hydrochloric acid/dioxane (5.00mL) then is added, is stirred 1 hour at 25 DEG C.Reaction solution is directly spin-dried for, faint yellow crude product 260mg is obtained.Take crude product 25mg by HPLC (condition: 0.05%HCl-ACN；Pillar: 150 × 25 5u of Gemini) separation, obtain target compound 0172 (19mg, yield: 76%).MS (ESI) m/z:490 [M+H]⁺。¹HNMR (400MHz, MeOD): δ 8.05-8.01 (m, 1H), 7.79-7.55 (m, 7H), 4.75-4.52 (m, 2H), 4.31-3.75 (m, 2H), 3.02-2.89 (m, 4H), 1.99-1.82 (m, 3H), (1.62-1.36 m, 2H)

Embodiment 3:0245

Synthetic route:

It is raw material, 0172 synthesis step 1 in reference implementation example 2, synthesis 0245 with compound 0182.MS (ESI) m/z:538 [M+H]⁺。

¹HNMR (400MHz, MeOD): δ 8.09-8.12 (m, 1H), 7.71-7.66 (m, 4H), 7.64-7.56 (m, 2H), 4.52-4.64 (m, 2H), 3.47-3.36 (m, 3H), 3.08-2.92 (m, 5H), 1.99-1.97 (m, 2H), 1.85-1.82 (m, 2H), 1.45-1.35 (m, 2H)

Referring to the synthetic method of step 1 in embodiment 1 (compound 0079), each embodiment in following table is synthesized:

Embodiment 105:0147

Synthetic route:

Step 1: the synthesis of compound 0147

Compound 0172 (50.00mg) and n,N-diisopropylethylamine (36.83mg) are dissolved in methylene chloride (2.00mL), then compound BB-16-2 (10.26mg) is added in reaction solution.Reaction solution is stirred 3 hours at 20 DEG C.Reaction solution is spin-dried for, and is dissolved with acetonitrile (4mL), filtering.Filtrate by preparation HPLC (150 × 25 5u of 0.05%ammonia-ACN, Gemini) isolate and purify after obtain target compound 0147 (26.80mg, yield: 49.24%, purity: 100%).MS (ESI) m/z:573 [M+H]⁺。¹HNMR (400MHz, CDCl₃): 7.89 (s of δ, 1H), 7.72-7.68 (m, 2H), 7.64-7.61 (m, 1H), 7.52-7.48 (m, 4H), 5.55-5.54 (m, 0.5H), 5.27-5.26 (m, 0.5H), 4.80-4.79 (m, 0.5H), 4.68-4.67 (m, 0.5H), 4.52-4.50 (m, 1H), 4.14-4.13 (m, 0.5H), 3.89-3.88 (m, 0.5H), 3.50-3.42 (m, 3H), 3.25-3.23 (m, 0.5H), 2.83-2.80 (m, 0.5H), 2.80-2.75 (m, 0.5H), 2.52-2.50 (m, 0.5H), 2.43-2.39 (m, 0.5H), 1.85-1.80 (m, 2H), 1.73-1.72 (m, 0.5H), 1.55-1.45 (m, 2H), 1.29-1.23 (m, 0.5H), 0.80-0.73 (m, 2H), 0.59-0.54 (m, 1H)

Referring to the synthetic method of step 1 in embodiment 105 (compound 0147), each embodiment in following table is synthesized:

Embodiment 123:0333

Synthetic route:

Step 1: the synthesis of compound 0333

Compound 0172 (150.00mg) is dissolved in methylene chloride (4.00mL), and carbonyl dimidazoles (49.64mg) and triethylamine (30.98mg) are added, while hydroxylamine hydrochloride (21.28mg) being dissolved in methylene chloride (4.00mL) and triethylamine (30.98mg) is added.Two reaction solutions are stirred 2 hours at 20 DEG C respectively, are stirred 12 hours at 20 DEG C again after being then combined with.Reaction solution after merging is concentrated to remove solvent, residue is dissolved in 3mL acetonitrile.The acetonitrile solution of the crude product passes through preparation (150 × 30mm × 4 μm Phenomenex Synergi C18 HPLC, 0.05%HCl-ACN) isolate and purify, obtain 0333 (67.00mg of target compound, yield: 39.86%, purity: 100%) MS (ESI) m/z:571 [M+Na]⁺。¹HNMR (400MHz, MeOD): δ=7.89 (m, 1H), 7.63-7.72 (m, 3H), 7.28-7.56 (m, 4H), 6.39 (s, 1H), 4.52 (br.s., 2H), 3.67-4.25 (m, 3H), 6.65-3.28 (m, 5H), 1.27-1.89 (m, 5H)

Referring to the synthetic method of step 1 in embodiment 123 (compound 0333), each embodiment in following table is synthesized:

Embodiment 141:0183

Synthetic route:

Step 1: the synthesis of compound 0183

Compound 0245 (100.00mg) is dissolved in methylene chloride (2.00mL), compound 0183-1 (20.00mg) and triethylamine (52.81mg) is added, is stirred 3 hours at 15 DEG C.The reaction solution is concentrated to remove methylene chloride, residue is dissolved in 4mL acetonitrile.The acetonitrile solution of target product by preparation HPLC (Agela DuraShell 150mm_25mm_5 μm, 0.05%HCl-ACN) purifying obtain target compound 0183 (44.50mg, yield: 42.96%, purity: 100%).MS (ESI) m/z:595 [M+H]⁺。¹HNMR (400MHz, CDCl3): δ=7.92-7.83 (m, 1H), 7.64 (d, J=8.5Hz, 2H), 7.54 (s, 2H), 7.45 (d, J=8.5Hz, 2H), (4.79-4.29 m, 1H), 4.02-3.91 (m, 1H), 3.88-3.73 (m, 2H), (3.29-3.13 m, 2H), 3.02 (s, 2H), 2.89 (s, 1H), (2.86-2.75 m, 5H), 1.88-1.75 (m, 1H), 1.74-1.56 (m, 1H), (1.28 d, J=9.5Hz, 2H)

Referring to the synthetic method of step 1 in embodiment 141 (compound 0183), each embodiment in following table is synthesized:

Embodiment 144:0330

Synthetic route:

Step 1: the synthesis of compound 0330

Compound 0172 (150.00mg) and potassium cyanate (24.84mg) are dissolved in water (5.00mL) and are flowed back 5 hours.The reaction solution is poured into 30mL ethyl acetate, liquid separation, organic phase is washed with water (10mL × 2), is then concentrated, and crude product is obtained.The crude product passes through preparation HPLC (150 × 30 5u of Boston Green ODS, it 0.05%HCl-ACN) isolates and purifies to obtain target compound 0330 (46.00mg, yield: 28.19%) MS (ESI) m/z:533 [M+H]⁺。

¹HNMR (400MHz, MeOD): δ=8.02-7.90 (m, 1H), 7.72 (d, J=7.8Hz, 5H), 7.60-7.52 (m, 2H), 4.82-4.39 (m, 2H), 4.18 (d, J=11.5Hz, 1H), 3.93-3.76 (m, 1H), 3.25-2.97 (m, 3H), 2.90 (br.s., 1H), 2.74 (br.s., 1H), 1.92-1.63 (m, 3H), 1.60-1.25 (m, 2H)

Embodiment 145:0435

Synthetic route:

Step 1: the synthesis of compound 0435-2

Compound BB-1 (71.61mg) is dissolved in N, in dinethylformamide (3.00mL), then compound 0435-1 (200.00mg) is sequentially added, 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (231.75mg), with diisopropylethylamine (196.93mg), reaction solution turns yellow.The reaction solution stirs 2 hours at 25 DEG C.Reaction solution is filtered.Crude product through combiflash companion instrument separate (0-100% ethyl acetate is in petroleum ether), obtain target compound 0435-2 (colorless oil, 200.00mg, yield: 72.67%, purity: 93%).MS(ESI) M/z:504 [M+H]⁺。

Step 2: the synthesis of compound 0435

Compound 0435-2 (200.00mg) is dissolved in dioxane (3.00mL), compound BB-16-2 (36.28mg) then is added, which stirs 30 hours at 100 DEG C.Reaction solution is spin-dried for, crude product is by efficiently preparing chromatographic isolation (condition: water (0.1%TFA)-ACN, pillar: 150 × 30 5u of Boston Green ODS), obtain 0435 (12.00mg of target compound, yield: 5.15%, purity: 100%) MS (ESI) m/z:609 [M+Na]⁺。¹HNMR (400MHz, CD₃OD): δ 8.01-7.93 (m, 1H), 7.77-7.61 (m, 5H), 7.59-7.52 (m, 2H), 4.76-4.62 (m, 2H), 4.39-4.30 (m, 0.5H), 3.95-3.75 (m, 1.5H), 3.57-3.41 (m, 0.5H), 3.21-3.05 (m, 1H), 2.95-2.79 (m, 0.5H), 2.73-2.38 (m, 2H), 2.05-1.29 (m, 4H), 0.84-0.70 (m, 2H), 0.60-0.48 (m, 2H)

Embodiment 146:0444

Synthetic route:

Step 1: the synthesis of compound 0444-2

Compound BB-48 (200.00mg, hydrochloride) is dissolved in methylene chloride (4.00mL), diisopropylethylamine (138.26mg) and compound 0444-1 (79.07mg) is then added, reaction solution turns yellow.The reaction solution is stirred 16 hours at 25 DEG C.Reaction solution is spin-dried for, and obtains target compound 0444-2 (yellow oily, 250.00mg, crude product), is directly used in and is reacted in next step.MS (ESI) m/z:689 [M+H]⁺。

Step 2: the synthesis of compound 0444

Compound 0444-2 (50.00mg) is dissolved in methylene chloride (3.00mL), then diisopropylethylamine (28.12mg) is sequentially added, with compound 0444-3 (8.90mg, hydrochloride), which is stirred 16 hours at 40 DEG C.Reaction solution is spin-dried for, and obtains crude product.Crude product is by efficiently preparing chromatographic isolation (condition: water (10mM NH₄HCO₃)-ACN, pillar: 150 × 25 5u of Waters Xbridge), obtain target compound 0444 (8.50mg, yield: 18%, purity: 98.8%).MS (ESI) m/z:625 [M+H]⁺。¹HNMR (400MHz, CD₃OD): δ 8.05-7.97 (m, 1H), 7.72-7.63 (m, 4H), 7.61-7.55 (m, 2H), 4.62-4.44 (m, 3H), 4.22-4.06 (m, 1H), 3.85-3.68 (m, 1H), 3.22-2.59 (m, 5H), 1.88-1.22 (m, 6H), 0.95-0.85 (m, 1H)

Embodiment 147:0344

Synthetic route

Step 1: the synthesis of compound 0344

Compound 0172 (150.00mg) and dicyandiamide sodium (40.89mg) are dissolved in n-butyl alcohol (4.00mL), reaction solution is stirred 5 hours at 120 DEG C, filtering reacting liquid, filtrate passes through preparation (150 × 30mm × 4 μm Phenomenex Synergi C18 HPLC, 0.05%HCl-ACN) isolate and purify, obtain 0344 (68.00mg of target compound, yield: 39.88%, purity: 100%) MS (ESI) m/z:557 [M+H]⁺。¹HNMR (400MHz, MeOD): δ=7.92-7.96 (m, 1H), 7.55-7.71 (m, 7H), 4.64 (m, 2H), 4.84-4.50 (m, 2H), 4.1-4.13 (m, 1H), 3.79-3.81 (m, 2H), 3.04-3.31 (m, 4H), 1.27-1.83 (m, 5H)

Embodiment 148:0042

Synthetic route:

Step 1: the synthesis of compound 0042-2

Mixture 0042-1 (1.41g) is suspended in acetonitrile (28.00mL), is added hexamethyldisilazane (14.11g), reaction mixture is heated to reflux 48 hours, and reaction mixture becomes clarification, is in brown.Reaction solution is cooling, methanol 8mL (cooling with ice-water bath in advance) is added, water pump vacuum distillation, when obtained residue is extracted with chloroform (35mL), residue almost dissolves, it is directly filtered with funnel, water pump decompression boils off solvent, obtains target compound 0042-2 (brown solid, 850.00mg, crude product), and be directly used in and react in next step.¹HNMR (400MHz, DMSO): δ 3.23-3.18 (m, 1H), 3.12-3.06 (m, 2H), 2.24-2.21 (m, 1H), 1.65-1.59 (m, 1H)

Step 2: the synthesis of compound 0042-4

By compound 0042-2 (300.00mg), compound 0042-3 (116.14mg); (±) -2; bis- (diphenylphosphinos) -1 of 2'-; 1'- dinaphthalene (72.23mg) and cesium carbonate (453.54mg) are blended in toluene (10.00mL); after water pump decompression is taken a breath 3 times with nitrogen; three (dibenzalacetone) palladiums (53.11mg) are added; water pump decompression is taken a breath 3 times with nitrogen again, and final reaction solution stirs 16 hours in 100 DEG C under nitrogen protection.It is filtered with diatomite, water pump decompression boils off solvent, it is that the resulting crude product of 90mg merges that residue, which is obtained, with another batch of compound 0042-2 inventory, with acidity preparation HPLC separation (pillar: 250 × 21.2mm × 4 μm Phenomenex Synergi C18, condition: 0.05%HCl-ACN), water pump decompression boils off partial solvent, residue freeze-drying, obtain target compound 0042-4 (colorless oil, 90.00mg, yield: 21.42%)¹HNMR (400MHz, CDCl3): δ 7.694 (s, 1H), 7.61-7.54 (m, 2H), 4.17 (t, J=9.6Hz, 1H), 3.90-3.83 (m, 1Hz), 3.76 (t, J=9.2Hz, 1H), 2.82-2.75 (m, 1H), (2.52-2.44 m, 1H)

Step 3: the synthesis of compound 0042-5

Compound 0042-4 (90.00mg) is dissolved in pyridine (1.00mL), is added dropwise compound BB-1-2 (57.04mg), reaction solution stirs 2 hours at 15 DEG C.Ethyl acetate (10mL) is added in reaction solution, it is washed with water (10mL × 2), 2N aqueous hydrochloric acid solution (10mL × 2) washing, saturated sodium bicarbonate aqueous solution (10mL) washing, saturated salt solution (10mL) washing, organic layer is dried, filtered with anhydrous sodium sulfate, and water pump decompression boils off solvent, obtain target compound 0042-5 (white solid, 110.00mg, crude product), it is directly used in and reacts in next step.MS (ESI) m/z:419 [M+H]⁺。

Step 4: the synthesis of compound 0042

Compound 0042-5 (20.00mg) is dissolved in dry tetrahydrofuran (1.00mL), it is cooled to 0 DEG C, sodium hydride (4.78mg is added, purity 60%), reactant is after 0 DEG C is stirred 30 points, the hydrobromate (14.49mg) of compound 0042-6 is added, is then to slowly warm up to 15 DEG C, and continues stirring 16 hours.Then reaction mixture is heated to 50 DEG C, continues stirring 16 hours.Reaction mixture is quenched with saturated aqueous ammonium chloride (5mL), is extracted with ethyl acetate (10mL × 3), is merged organic layer, is dried, filtered with anhydrous sodium sulfate, and water pump decompression boils off solvent, is obtained The acid preparation HPLC separation (pillar: 150 × 25 5u of Gemini of the residue arrived；Condition: 0.05%HCl-ACN), obtain target compound 0042 hydrochloride (6.70mg, yield: 25.68%, purity: 100%) MS (ESI) m/z:510 [M+H]⁺。¹HNMR (400MHz, CD₃OD): δ 8.79 (d, J=6.4Hz, 2H), 8.33 (d, J=6.4Hz, 2H), 8.03-8.01 (m, 2H), 7.77-7.65 (m, 6H), 5.23 (t, J=9.8Hz, 1H), 4.79-4.70 (m, 2H), 3.81 (t, J=6.4Hz, 1H), 3.66 (t, J=9.2Hz, 1H), 2.42-2.34 (m, 1H), 2.14-2.03 (m, 1H)

Embodiment 149:0291

Synthetic route:

Step 1: the synthesis of compound 0291

Compound 0290 (200.00mg) and iodomethane (870mg) are dissolved in acetonitrile (2.00mL), silver oxide (176.44mg) then is added, and stir 16 hours at 60 DEG C.Reaction solution is filtered, filtrate is poured into 20mL ethyl acetate, then is washed with water (10mL), and organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains crude product.The crude product passes through preparation HPLC (150 × 30 5u of Boston Green ODS, 0.05%HCl-ACN) isolate and purify, obtain target compound 0291 (24.00mg, yield: 11.64%, purity: 99.6%) MS (ESI) m/z:539 [M+H]⁺。¹HNMR (400MHz, MeOD): δ=8.02-8.16 (m, 1H), 7.61-7.71 (m, 4H), 7.57-7.66 (m, 2H), 4.84-4.46 (m, 2H), 4.26 (m, 1H), 3.36-3.77 (m, 2H), 3.33 (br.s., 3H), 3.29-3.12 (m, 2H), 2.61 (m, 1H), 1.33-1.798 (m, 5H)

Embodiment 150:0328

Synthetic route:

Step 1: the synthesis of compound 0328-2

Compound BB-2 (200.00mg) is dissolved in N, in dinethylformamide (4.00mL), then 2- (7- azo benzotriazole)-N is added, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (266.39mg), and compound 0328-1 (101.02mg) is added dropwise, which stirs 3 hours at 20 DEG C.The reaction solution is poured into 50mL ethyl acetate, is then washed with water (10mL × 4).Organic phase is dried, filtered with anhydrous sodium sulfate, and concentration obtains faint yellow solid target product crude product.The crude product is isolated and purified with combiflash companion instrument (petroleum ether: ethyl acetate=3:1), obtain target compound 0328-2 (white solid, 150.00mg, yield: 50.24%, purity: 98%) MS (ESI) m/z:648 [M+Na]⁺。

Step 2: the synthesis of compound 0328

Compound 0328-2 (120.00mg) is dissolved in methylene chloride (2.00mL), and triethylamine (58.15mg) is added, then in 0 DEG C of addition mesyl chloride (43.88mg), which stirs 5 hours at 20 DEG C.The reaction solution is concentrated, crude product is obtained.Crude product is isolated and purified by combiflash companion instrument (petroleum ether: ethyl acetate=2:1), obtain 0328 (100.00mg of target compound, yield: 94.52%, purity: 100%) MS (ESI) m/z:574 [M+Na]⁺。¹HNMR (MeOD, 400Hz) δ ppm=7.75-7.89 (m, 1H), 7.47-7.65 (m, 6H), 4.43-4.71 (m, 4H), 3.80-4.01 (m, 4H), 3.11-3.22 (m, 2H), 2.50-2.67 (m, 1H)

Embodiment 151:0362

Synthetic route:

Step 1: the synthesis of compound 0361

Compound 0361 (20.00mg); cyclopropylboronic acid (3.95mg); palladium acetate (688.80 μ g); tricyclohexyl phosphine (1.29mg) and potassium phosphate (13.02mg) are dissolved in toluene (1.00mL) and water (200.00 μ L); then system temperature is risen to 70 DEG C, is reacted 5 hours under nitrogen protection.Reaction system is added in water (5mL), organic phase is dried, filtered with anhydrous sodium sulfate, is spin-dried for, obtains yellow oil by ethyl acetate (3 × 15mL) extraction.Yellow oil through performance liquid chromatographic column purify (Boston Green ODS 150 × 30 5u, water (0.1%TFA)-ACN), obtain target compound 0362 (3.21mg, yield: 17.07%, purity: 100%).MS (ESI) m/z:613 [M+H]⁺。¹HNMR (400MHz, CD₃OD): δ 7.93-7.84 (m, 1H), 7.74-7.62 (m, 2H), 7.59-7.52 (m, 2H), 7.28-7.18 (m, 2H), 4.72-4.45 (m, 1H), 4.25-3.98 (m, 1H), 3.92-3.66 (m, 1H), 3.27-3.04 (m, 2H), 2.99-2.63 (m, 2H), 2.54-2.40 (m, 1H), 2.08-1.97 (m, 1H), 1.91-1.48 (m, 4H), 1.45-1.21 (m, 2H), 1.16-1.06 (m, 2H), 0.84-0.78 (m, 2H), 0.76-0.68 (m , 2H), 0.49 (m, 2H)

Embodiment 152:0353

Synthetic route:

Step 1: the synthesis of compound 0353

Compound 0330 (65.00mg) and acetic anhydride (62.25mg) are uniformly mixed, reaction system is added in the concentrated sulfuric acid (598.09 μ g, 6.10 μm of ol), system temperature is increased to 50 DEG C, is reacted 0.5 hour.Reaction system plus water (5mL) are diluted, adding saturated sodium bicarbonate aqueous solution to pH value is 8-9, obtains weak yellow liquid.The aqueous solution of crude product through high performance liquid chromatography separation (150 × 30mm × 4 μm Phenomenex Synergi C18, 0.1%TFA-ACN), target compound 0353 (17.88mg, yield: 25.50%) MS (ESI) m/z:575 [M+H] are obtained⁺。¹HNMR (400MHz, CD₃OD): δ 7.90 (s, 1H), 7.78-7.60 (m, 5H), 7.60-7.52 (m, 2H), 4.79-4.47 (m, 2H), 4.27-4.05 (m, 1H), 3.94-3.72 (m, 1H), 3.28-2.86 (m, 3H), 2.83-2.52 (m, 1H), 1.91-1.66 (m, 3H), 1.64-1.37 (m, 1H), 1.34-1.21 (m, 1H)

Embodiment 153:0197

Synthetic route:

Step 1: the synthesis of compound 0197

Compound 0245 (100.00mg) is dissolved in methylene chloride (2.00mL), then 0197-1 (45.00mg) is added, copper acetate (67.00mg) and pyridine (98.00mg) react 24 hours at 25 DEG C.The water of 10mL is added, is extracted with methylene chloride (20mL × 2), organic phase is washed with saturated salt solution (10mL × 2), dried, filtered with anhydrous sodium sulfate, is spin-dried for, and brown oil is obtained.The grease passes through HPLC (pillar: 0.05%HCl-ACN；Condition: Agela DuraShell 150mm_25mm_5 μm) separation, obtain target compound 0197 hydrochloride (30.00mg, yield: 24.56%, purity: 99%).MS (ESI) m/z:614 [M+H]⁺。¹HNMR (400MHz, MeOD): δ 8.12 (m, 1H), 7.68-7.50 (m, 11H), 5.07-4.95 (m, 1H), 4.62-4.36 (m, 1H), 3.68-3.55 (m, 4H), 3.47-3.37 (m, 2H), 3.12-2.82 (m, 3H), 2.25-2.05 (m, 3H), 1.85-1.62 (m, 2H) ..

Embodiment 154:0186

Synthetic route:

Step 1: the synthesis of compound 0186

By 0245 (100.00mg of compound; its hydrochloride); compound 0186-1 (30.00mg) is dissolved in methanol (2.00mL); then sodium carbonate (55.00mg) and copper acetate (32.00mg) is added; under the protection of (15psi) oxygen, 65 DEG C are reacted 12 hours.Reaction solution is directly spin-dried for, green residue is obtained.It is extracted with ethyl acetate (20mL × 2), organic phase is washed with saturated salt solution (10mL × 2), and after anhydrous sodium sulfate drying, filtering is spin-dried for, obtains green residue.After the residue is dissolved with acetonitrile, by HPLC (condition: 0.1%TFA-ACN；Pillar: 150 × 30mm × 4 μm Phenomenex Synergi C18) separation, obtain target compound 0186 trifluoroacetate (21.00mg, yield: 20.87%, purity: 100%).MS (ESI) m/z:578 [M+H]⁺。¹HNMR (400MHz, MeOD): δ 8.08-8.05 (m, 1H), 7.70-7.64 (m, 4H), 7.58-7.56 (m, 2H), 4.50-4.73 (m, 2H), 3.86-3.63 (m, 1H), 3.51-3.39 (m, 1H), 3.22-2.92 (m, 3H), 2.12-1.30 (m, 6H), 1.05-0.98 (m, 4H)

Embodiment 155:0411

Synthetic route:

Step 1: the synthesis of compound 0411-1

Compound BB-48 (300.00mg) is dissolved in water (10.00mL), potassium cyanate (48.71mg) then is added, and reaction solution is flowed back 5 hours under conditions of 100 DEG C.200 milliliters of ethyl acetate is added into reaction solution, then washes 30mL × 3, organic phase anhydrous sodium sulfate Dry, filter, be concentrated under reduced pressure with water pump, obtain target compound 0411-1 (white solid, 300.00mg, yield: 85.95%, purity: 93%), which does not purify further.MS (ESI) m/z:567 [M+H]⁺。

Step 2: the synthesis of compound 0411

Compound 0411-1 (80.00mg) and compound 0411-2 (16.79mg) are dissolved in acetic anhydride (1.00mL), stirred 0.5 hour under conditions of 70 DEG C.Reaction solution plus water (2mL) are quenched, it is added methanol (2mL), then it filters, filtrate is through preparing HPLC (150 × 30 5u of Boston Green ODS, water (0.05%HCl)-ACN) purifying, target compound 0411 (36.00mg, yield: 39.60%, purity: 98.4%).MS (ESI) m/z:634 [M+H]⁺。¹HNMR (400MHz, Methanol-d₄): δ 7.99~8.01 (m, 1H), 7.69~7.73 (m, 4H), 7.57~7.67 (m, 2H), 4.58 (br, 1H), 4.17~4.20 (m, 1H), 3.75~3.87 (m, 3H), 3.15~3.26 (m, 3H), 2.50~2.95 (m, 2H), 1.72~2.09 (m, 3H), 1.32~1.44 (m, 2H)

Embodiment 156:0354

Synthetic route:

Step 1: the synthesis of compound 0354

Triethylamine (69.20mg) is added in 1- amylalcohol (2.00mL) solution of compound 0172 (120.00mg, hydrochloride), compound 0354-1 (52.22mg), which reacts 16 hours at 100 DEG C.The reaction solution is concentrated to remove solvent, crude product is obtained.The crude product passes through preparation (250 × 21.2mm × 4 μm Phenomenex Synergi C18 HPLC, 0.05%HCl-ACN) isolate and purify, obtain 0354 (53.50mg of target compound, yield: 40.49%, purity: 98%) MS (ESI) m/z:568 [M+H]⁺。¹HNMR (400MHz, MeOD): δ=8.86-8.41 (m, 2H), 8.13-7.91 (m, 1H), 7.77-7.47 (m, 7H), 7.08-6.99 (m, 1H), 4.81-4.34 (m, 2H), 4.32-3.70 (m, 2H), 3.58-3.39 (m, 2H), 3.30-2.62 (m, 2H), 2.23-1.75 (m, 3H), 1.67-1.28 (m, 2H)

Referring to the synthetic method of step 1 in embodiment 156 (compound 0354), each embodiment in following table is synthesized:

Embodiment 159:0195

Synthetic route:

Step 1: the synthesis of compound 0195

Compound 0245 (150.00mg) is dissolved in dichloroethanes (4.00mL), it is added triethylamine (26.40mg), it is stirred 0.5 hour at 15 DEG C, then the acetaldehyde (57.47mg) and acetic acid (15.67mg) that content is 40% is added, which stirs 0.5 hour at 15 DEG C.Then in 0 DEG C of addition sodium cyanoborohydride (24.60mg).The reaction solution reacts 12 hours at 15 DEG C.2mL water is added into reaction solution, is then extracted with methylene chloride (15mL × 3), organic phase is concentrated, obtains crude product.The crude product is dissolved in 4mL acetonitrile, and pass through preparation HPLC (Agela DuraShell 150mm_25mm_5 μm, 0.05%HCl-ACN) isolate and purify, obtain 0195 (19.00mg of target compound, yield: 12.08%, purity: 100%) MS (ESI) m/z:566 [M+H]⁺。

¹HNMR (400MHz, MeOD): δ=8.15-8.02 (m, 1H), 7.73-7.64 (m, 4H), 7.61-7.54 (m, 2H), 4.84-4.33 (m, 2H), 3.68-3.53 (m, 2H), 3.31-3.14 (m, 4H), 3.09 (s, 3H), 2.93 (s, 2H), 2.04-1.83 (m, 3H), 1.54-1.30 (m, 5H)

Referring to the synthetic method of step 1 in embodiment 159 (compound 0195), each embodiment in following table is synthesized:

Embodiment 163:0267

Synthetic route:

Step 1: the synthesis of compound 0267-1

Compound BB-41 (500.00mg) is dissolved in methylene chloride (20.00mL), then triethylamine (206.43mg) is added, reaction solution is stirred 1 hour under the conditions of 0 DEG C, then mesyl chloride (128.53mg) is slowly added into above-mentioned reaction solution, temperature is slowly increased to 25 DEG C and stirs 11 hours.Reaction solution is added to the water of 50mL, is extracted with methylene chloride (100mL × 3), organic phase merges, dry with anhydrous sodium sulfate, filtering, is concentrated under reduced pressure, obtains target compound 0267-1 (oily, 560.00mg, crude product), it is not further purified and is directly used in next step.MS (ESI) m/z:569 [M+H]⁺。

Step 2: the synthesis of compound 0267

The methanol solution (54.58mg, 30% purity) of compound 0267-1 (100.00mg) and methylamine is dissolved in tetrahydrofuran (2.00mL), is stirred 12 hours under conditions of 50 DEG C.Solvents tetrahydrofurane removes under reduced pressure.The residual crude product through preparation HPLC (Boston Green ODS150 × 30 5u, 0.05%HCl-ACN) purifying, obtain target compound 0267 hydrochloride (56.00mg, yield: 58.96%, purity: 100%).MS (ESI) m/z:504 [M+H]⁺。¹HNMR (400MHz, Methanol-d₄): δ 7.90~8.10 (m, 1H), 7.53~7.73 (m, 7H), 4.60 (br, 2H), 4.03~4.07 (m, 1H), 3.71 (br, 1H), 3.26~3.30 (m, 1H), 2.96~3.03 (m, 3H), 2.74~2.78 (m, 3H), 1.82~1.97 (m, 3H), 1.49~1.65 (m, 2H)

Referring to the synthetic method of step 1-2 in embodiment 163 (compound 0267), each embodiment in following table is synthesized:

Embodiment 175:0406

Synthetic route:

Step 1: the synthesis of compound 0406

Compound 0405 (230.00mg) is dissolved in methylene chloride (5.00mL), carbonyl dimidazoles (174.60mg) are added in above-mentioned reaction solution under conditions of 25 DEG C, and continues stirring 14 hours under conditions of 25 DEG C.Solvent is removed at reduced pressure with water pump, then obtains colourless oil liquid.By the crude product through preparation HPLC (Boston Green ODS 150 × 30 5u, water (0.05%HCl)-ACN) purifying, obtain target compound 0406 (44.00mg, yield: 18.06%, purity: 99%).MS (ESI) m/z:582 [M+Na]⁺。¹HNMR (400MHz, CDCl₃): δ 7.84 (s, 1H), 7.66~7.71 (m, 3H), 7.47~7.53 (m, 4H), 4.31~4.70 (m, 3H), 4.00~4.20 (m, 2H), 3.50~3.75 (m, 3H), 2.90~3.26 (m, 3H), 2.50~2.75 (m, 1H), 1.71~2.01 (m, 3H), 1.28~1.49 (m, 2H)

Embodiment 176:0380

Synthetic route:

Step 1: the synthesis of compound 0380

By compound BB-51 (49.37mg, its hydrochloride) it is dissolved in methylene chloride (2.00mL), then reaction system is added in triethylamine (100.00 μ L) at 25 DEG C, reaction system then is added in compound 0380-1 (40.00mg), and is reacted 2 hours at 25 DEG C.Reaction is spin-dried for, yellow oil is obtained.Crude product is dissolved in methanol, through high performance liquid chromatography separation (150 × 30 5u of Boston Green ODS, water (0.1%TFA)-ACN), obtain 0380 (3.12mg of target compound, yield: 3.98%, purity: 100%) MS (ESI) m/z:445 [M+H]⁺。¹HNMR (400MHz, CD₃OD): δ 8.77-8.67 (m, 1H), 8.27-8.22 (m, 1H), 8.19-8.12 (m, 1H), 8.06-7.99 (m, 1H), 7.75-7.54 (m, 3H), 4.09-3.86 (m, 1H), 3.84-3.73 (m, 2H), 3.65-3.43 (m, 1H), 3.14-2.92 (m, 2H), 2.85-2.51 (m, 2H), 2.49-2.37 (m, 1H), 1.82-1.44 (m, 3H), 1.41-1.11 (m, 2H), 0.77-0.66 (m, 2H), 0.46 (m., 2H)

Referring to the synthetic method of step 1 in embodiment 176 (compound 0380), each embodiment in following table is synthesized:

Embodiment 180:0398

Synthetic route:

Step 1: the synthesis of compound 0398-2

Compound BB-1 (400.00mg) is dissolved in N, in dinethylformamide (4.00mL), then compound 0398-1 (174.66mg) is sequentially added, diisopropylethylamine (395.47mg) and 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (465.40mg), reaction solution turn yellow.The reaction solution stirs 2 hours at 25 DEG C.Ethyl acetate (50mL) is added in reaction solution, then (20mL × 3) are washed with saturated common salt, it is dry with anhydrous sodium sulfate, filtering, filtrate concentration, obtains target compound 0398-2 (yellow oily, 550.00mg, yield: 76.69%, crude product) it is directly used in and reacts in next step.MS (ESI) m/z:569 [M+Na]⁺。

Step 2: the synthesis of compound 0398-3

Compound 0398-2 (550.00mg) is dissolved in tetrahydrofuran (4.00mL) and water (3.00mL), a hydronium(ion) lithia (127.14mg) is then added, reaction solution turns yellow.The reaction solution stirs 1 hour at 25 DEG C.Reaction solution 3N hydrochloric acid tune pH to 1, (50mL × 2) are extracted with ethyl acetate in mixed liquor, organic phase washes (25mL) with saturated common salt, and anhydrous sodium sulfate dries, filters, filtrate concentration, obtain target compound 0398-3 (yellow oily, 500.00mg, yield: 80.90%, crude product), it is directly used in and reacts in next step.MS (ESI) m/z:519 [M+H]⁺。

Step 3: the synthesis of compound 0398-5

Compound 0398-3 (200.00mg) is dissolved in N, in dinethylformamide (4.00mL), then compound 0398-4 (28.55mg) is sequentially added, diisopropylethylamine (149.43mg), with 2- (7- azo benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (175.85mg), reaction solution turn yellow.The reaction solution is stirred 16 hours at 25 DEG C.Ethyl acetate (50mL) is added in reaction solution, then (20mL × 3) are washed with saturated common salt, it is dry with anhydrous sodium sulfate, filtering, filtrate concentration, obtain target compound 0398-5 (yellow oily, 200.00mg, crude product) MS (ESI) m/z:575 [M+H]⁺。

Step 4: the synthesis of compound 0398

Compound 0398-5 (200.00mg) is dissolved in methylene chloride (3.00mL), paratoluensulfonyl chloride (99.47mg) and diisopropylethylamine (134.86mg) are then sequentially added, reaction solution turns yellow.The reaction solution stirs 24 hours at 25 DEG C.Reaction solution is spin-dried for obtaining crude product.Crude product is by efficiently preparing chromatographic isolation (condition: 0.05%HCl-ACN, pillar: 250 × 50mm × 10 μm Phenomenex Synergi Max-RP), obtain 0398 (53.00mg of target compound, yield: 27.24%, purity: 99.575%) MS (ESI) m/z:579 [M+Na]⁺。¹HNMR (400MHz, CD₃OD): δ 7.99-7.84 (m, 1H), 7.74-7.51 (m, 7H), (4.80-4.42 m, 2H), 4.23-3.75 (m, 2H), 3.24-3.01 (m, 1H), (2.97-2.60 m, 3H), 2.54 (d, J=7.3Hz, 3H), 2.21-1.70 (m, 3H), 1.65-1.26 (m, 2H)

Referring to the synthetic method of step 3-4 in embodiment 180 (compound 0398), each embodiment in following table is synthesized:

Part of compounds is subjected to SFC chiral resolution, obtains each embodiment in following table:

Experimental example 1: in-vitro evaluation

Experiment purpose:

By stable cccDNA detection platform, exploitation is able to suppress the newtype drug of HBV cccDNA formation.

Background introduction:

HepDES19 is derived from the cell line of human liver cancer cell HepG2, carries 1.1 times of body DNA of HBV gene group by Tetracycline regulation.

The characteristics of cell line is that cccDNA content is high.HepDES19 cell is widely used in HBV research and the test of Anti-HBV drugs.

In this experiment, test-compound is measured to the inhibitory activity of cccDNA forming process with the content of test-compound treated HepDES19 intracellular HBV cccDNA by Southern blot detection.

Experimental material:

Cell line: 19 cell of HepDES comes from Institute of Hepatitis and Virus Research, the U.S.

Cell culture fluid: DMEM/F12 (Invitrogen, Cat.#11330057) culture solution adds 10% fetal calf serum (FBS, Corning, Cat.#35-076-CV), 1% glutamine (Invitrogen, Cat.#25030081), 1%MEM NEAA (Invitrogen,) and 1% dual anti-(penicillin 5000IU/mL Cat.#11140076, streptomysin 10mg/mL, Hyclone, Cat.#SV30010).

Pancreatin (Invitrogen, Cat.#25300062).

DPBS(Hyclone,Cat.#SH30028.01B)。

Tetracycline hydrochloride (Sigma, Cat.#T7660).

Agarose (Biowest, Cat.#111860).

RNase A (Sigma, Cat.#R4642).

Phenol chloroform isoprene (raw work, Cat.#PD0419-1).

Glyco Blue Coprecipitant(Ambion,Cat.#9515)。

Southern denaturing liquid (0.5M NaOH, 1.5M NaCl).

Southern neutralizer (1M Tris.HCl, pH7.4and 1.5M NaCl).

Buffer 20×SSC(Shuiyuan Bio)。

DIG Easy Hyb(Roche,Cat.#11603558001)。

DIG Wash and Block Buffer Set(Roche,Cat.#11585762001)。

Anti-Digoxigenin-AP(Roche,Cat.#11093274910)。

CDP-Star(Roche,Cat.#11759051001)。

CO2 incubator, Thermo 240I.

Nanodrop 1000, Thermo.

Experimental procedure and method:

1. compound handles cell

By HepDES19 cell (buying from Institute of Hepatitis and Virus Research, the U.S.) the DMEM/F12 culture medium culture for containing 10% serum and 1ng/ml tetracycline.It when cell confluency degree in logarithmic growth phase reaches 80% or more, is digested with pancreatin, with containing 2% serum and removing the DMEM/F12 culture medium of tetracycline and being resuspended and cell and count, is added 2.5 × 10 to every hole in 12 porocyte culture plates⁵A HepDES19 cell, and at 37 DEG C, 5%CO₂It is incubated overnight.The certain density compound diluted with DMSO is added within 2nd day to handle the cell in 12 orifice plates, and sets the hole DMSO without compound as control.37 DEG C, 5%CO₂Culture 3 days to the 5th day, discard culture solution, the culture solution of replacement compound containing same concentrations continues culture 3 days to the 8th day, culture solution is discarded again, and the culture solution for replacing the compound containing same concentrations continues culture 3 days to the 11st day, culture solution is discarded, cell is collected, be stored in -20 DEG C or carries out Hirt DNA extraction immediately.

2.Hirt DNA is extracted

The cell that step 1 is collected is with 1 milliliter of lysate (containing 10 mM/ls of Triza, the SDS of 10 mM/ls of EDTA and 0.7%) at normal temperature crack 30 minutes after, 0.24 milliliter of concentration is added as the sodium chloride solution of 5 mol/Ls, is incubated overnight in 4 DEG C.After second day with DEG C centrifugation of 12,000 × g, 4 30 minutes, 900 microlitres of supernatants is taken to be transferred in new centrifuge tube, the RNase A solution that the concentration for being added 3 microlitres is 10mg/ml, 37 DEG C are incubated for 1 hour, then remove RNA.With the phenol of isometric (900 microlitres): chloroform: after isoprene (proportions 25:24:1) extracts 3 times, the isopropanol of 0.7 times of volume and 5 microlitres of glycoblue coprecipitator is added, 1 hour is placed at room temperature for after mixing well.With DEG C centrifugation of 12,000 × g, 4 30 minutes to precipitate DNA.Abandon supernatant, 1 milliliter of 70% ethanol washing is added twice, extra ethyl alcohol is discarded, obtained DNA precipitating is dissolved in 30 microlitres of TE (10mmol/L Tris-HCl (pH 8.0) and 1mmol/L EDTA (pH 8.0)) by drying at room temperature.

3.Southern blot detects cccDNA

The Ago-Gel for being 1.2% with 1 × TAE electrophoretic buffer compound concentration, the Hirt DNA electrophoresis Sample (loading after mixing with sample-loading buffer) extracted in 10 microlitres of step 2 is added in each gel pore, and the HBV segment mixed liquor that size is respectively 3.2kb, 2.0kb and 1.3kb is added and is compareed as molecular mass mark.Gel is placed under 80 volts of constant pressure 3 to 4 hours of electrophoresis to separate different size of DNA fragmentation.After electrophoresis, glue is immersed in 250 mM/ls of hydrochloric acid, shaking table is incubated for 7 minutes so that DNA depurination, it is denaturalized 30 minutes after distilling the water washing several seconds with denaturing liquid (sodium chloride of sodium hydroxide and 1.5 mol/Ls containing 0.5 mol/L), neutralizer (the sodium chloride of Tris hydrochloric acid and 1.5 mol/Ls containing 1 mol/L is used after distilling the water washing several seconds, pH value is 7.4) to neutralize 30 minutes, after distilling water washing, DNA on gel is transferred on the nylon membrane of solid phase by capillary siphoning blotting, after transfer, take out nylon membrane, 2 × SSC solution is immersed after UV crosslinking to wash several minutes, film is placed on filter paper dry.Then, film is put into hybridization bottle, is added 10 milliliters of hybridization solution, 60 DEG C discard hybridization solution after prehybridization 1 hour, and the hybridization solution hybridized overnight for containing the probe through digoxigenin labeled is added.Second day through 2 × SSC, 0.1%SDS room temperature washing 2 × 5 minutes, then through 0.1 × SSC, 0.1%SDS is washed 3 × 20 minutes in 60 DEG C, then by film with 1 × maleic acid Rapid Cleaning 2 × 5 minutes.Again after confining liquid is closed 50 minutes, it is incubated for 30 minutes with antibody diluent.After cleaning solution cleans 3 × 15 minutes, CDP-star is added, film is exposed to development in darkroom, controls the time for exposure, the film drying that will have been exposed analyzes DNA band after scanner scanning.

4. data processing and analysis

Film is judged into the inhibitory effect of formation of the compound to cccDNA by directly observing the power of cccDNA band in picture at picture format by scanner scanning

Biologically active data: three sections: 10 μm of A >, 10 μm >=B >=3 μm, 3 μm of C < have been divided by active size；Two sections: 50 μm of D >, E≤50 μm have been divided by the size of cytotoxicity.

Claims

Compound, its tautomer or pharmaceutically acceptable salt shown in general formula (I) and general formula (II),

Wherein,

R⁹Selected from hydrogen or methyl；

R¹Selected from hydrogen,

R²Selected from hydrogen or C₁-C₆Alkyl；

Structural unitIt is selected from

M is selected from 1,2,3,4 or 5；

Each R³Separately it is selected from hydrogen, halogen, C₁-C₆Alkoxy ,-NH (C₁-C₆Alkyl) ,-N (C₁-C₆Alkyl)₂, 3~6 yuan of naphthenic base or 3~6 membered heterocycloalkyls；

Structural unitIt is selected from

Each R⁵Independently selected from hydrogen or methyl；

Each R⁸Independently selected from hydrogen, halogen or C₁-C₆Alkyl；

Each W is independently selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or C₁-C₆Alkyl；

T^a、T^bAnd T^cSeparately it is selected from -CHR^hOr-C (R^h)₂, wherein each R^hSeparately it is selected from hydroxyl, C₁-C₆Alkyloxycarbonyl amino or C₁-C₆Alkyloxycarbonyl amino methyl；Or T^a、T^bAnd T^cSeparately it is selected from-C (R^h)₂, and two R^h4~6 membered heterocycloalkyls are formed together with the C being connected with them, 4~6 membered heterocycloalkyl is optionally independently selected by one or more from=O or C₁-C₆The group of alkyloxycarbonyl replaces；

Ring Z¹For 3~5 membered heterocycloalkyls；

Ring Z²For 3~6 membered heterocycloalkyls, 5~6 unit's heteroaryls or phenyl；

Each R^bSeparately it is selected from halogen ,=O, cyano, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls；

P is selected from 0,1,2,3 or 4；

Each R^cWith each R^dSeparately it is selected from hydrogen, halogen, C_1-6The C that alkyl or halogen replace_1-6Alkyl；

Each R^gIndependently selected from-C (O)-NH (C₁-C₆Alkyl), 6-10 member aryl or 5~10 unit's heteroaryls, wherein 6~10 yuan of aryl and 5~10 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；

Ring Z³For 3~5 membered heterocycloalkyls；

Each R^eSeparately it is selected from halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls；

Q is selected from 0,1,2,3 or 4；

Structural unitSelected from following radicals: 3~6 membered heterocycloalkyl methyl, 5~9 unit's heteroaryl methyl ,-CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, wherein 3~6 membered heterocycloalkyl methyl and 5~9 unit's heteroaryl methyl are respectively independent Ground is independently selected by one or more from halogen, hydroxyl, cyano, C_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；

R⁴Selected from hydrogen, cyano, hydroxyl, C_1-6Alkyl, C_2-6Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls, wherein C_1-6Alkyl and C_2-6The group that alkenyl is independently selected by one or more from halogen, hydroxyl, cyano ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls each independently optionally replaces, wherein 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl and 5~9 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；

L⁵Selected from-CH₂-；

R⁶Selected from C_1-6Alkyl or 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group to form 3~8 member rings；

R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, wherein the pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl and thiazolyl are independently selected by one or more from halogen ,-R each independently^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；

R^fSelected from C_1-6Alkyl, 3~6 yuan of naphthenic base, 5~10 unit's heteroaryls or 6~10 yuan of aryl, wherein the C_1-6The group that alkyl is independently selected by one or more from halogen, hydroxyl, amino, cyano, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；

Condition is: working as R¹Selected from hydrogen orOr structural unitIt is selected fromWhen, structural unitFor For-CH₂NHC (=O) NHR⁴, and R⁴It is not aryl or heteroaryl.
Compound as described in claim 1, compound shown in formula of (I) are general formula (I -1) compound, preferably general formula (I -2) compound represented,
Compound as claimed in claim 1 or 2, wherein R¹Selected from following radicals: hydrogen, Preferably More preferably
Compound as claimed in any one of claims 1-3, wherein structural unitSelected from following radicals: Preferably More preferably Still more preferably
Compound shown in compound as described in claim 1, formula of (I) and general formula (II) is respectively general formula (VII) and logical (VIII) compound represented:
Compound as claimed in claim 5, compound shown in formula of (VII) are respectively general formula (VII -1), general formula (VII -2), general formula (VII -3), general formula (VII -4), general formula (VII -5), general formula (VII -6), general formula (VII -7) or general formula (VII -8) compound represented:
Such as compound of any of claims 1-6, wherein R³Separately it is selected from hydrogen, halogen, C₁-C₆Alkoxy ,-N (C₁-C₆Alkyl)₂Or 3~6 yuan of naphthenic base, preferably hydrogen, halogen, C₁-C₄Alkoxy ,-N (C₁-C₄Alkyl)₂Or 3~6 yuan of naphthenic base, more preferably hydrogen, halogen, methoxyl group, dimethylamino or cyclopropyl, most preferably hydrogen, chlorine, bromine, methoxyl group, dimethylamino or cyclopropyl.
Such as compound of any of claims 1-7, wherein W is selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or C₁-C₄Alkyl；Preferably, W is selected from-O- ,-N (R^a)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or methyl；It is highly preferred that W is selected from-O- ,-N (CH₃)-or-C (R^a)₂, wherein each R^aSeparately it is selected from hydrogen, halogen or methyl；Most preferably, W is selected from-O- ,-N (CH₃)-、-CH₂-、-CH(CH₃)-or-CF₂-。
Compound according to any one of claims 1 to 5, wherein structural unitIt is selected from Preferably More preferably
Compound as claimed in any one of claims 1-9 wherein, wherein R^cAnd R^dSeparately it is selected from hydrogen or C_1-6Alkyl, preferably hydrogen or C_1-4Alkyl, more preferably hydrogen or methyl.
Such as compound of any of claims 1-10, wherein R⁸Selected from hydrogen, halogen or C₁-C₄Alkyl, preferably hydrogen, fluorine, chlorine or C₁-C₄Alkyl, more preferably hydrogen, fluorine or methyl.
Such as compound of any of claims 1-11, wherein T^a、T^bAnd T^cSeparately it is selected from -CH(R^h)-or-C (R^h)₂, wherein each R^hSeparately it is selected from hydroxyl, C₁-C₄Alkyloxycarbonyl amino or C₁-C₄Alkyloxycarbonyl amino methyl；Or T^a、T^bAnd T^cSeparately it is selected from-C (R^h)₂, and two R^h4~6 membered heterocycloalkyls are formed together with the C being connected with them, 4~6 membered heterocycloalkyl is optionally independently selected by one or more from=O or C₁-C₄The group of alkyloxycarbonyl replaces.
Such as the compound of any one of claim 1-12, middle ring Z¹For 5 membered heterocycloalkyls, preferably nitrogenous and oxygen atom 5 circle heterocyclic ring alkane Base, more preferably oxazolidinyl, most preferably
Such as compound of any of claims 1-13, middle ring Z²For 5~6 membered heterocycloalkyls, 6 unit's heteroaryls or phenyl, preferably phenyl, 6 nitrogenous unit's heteroaryls or 5~6 nitrogenous membered heterocycloalkyls, more preferably phenyl, pyridyl group, pyrrolidinyl or piperidyl, most preferably
Compound as described in any one of claim 1-14, wherein R^bSelected from halogen ,=O, cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-4Alkyloxycarbonyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, 6~10 yuan of aryl or 5~9 unit's heteroaryls, preferably=O or C_1-4Alkyloxycarbonyl, more preferably=O or tert-butoxycarbonyl.
Compound as described in any one of claim 1-15, middle ring Z³For 5 membered heterocycloalkyls, preferably 5 yuan of nitrogenous Heterocyclylalkyls, more preferably pyrrolidinyl, most preferably
Compound as described in any one of claim 1-16, wherein R^eSelected from C_1-6Alkyloxycarbonyl, preferably C_1-4Alkyloxycarbonyl, more preferably tertbutyloxycarbonyl.
Compound as described in any one of claim 1-17, wherein R^gSelected from-C (O)-NH (C₁-C₄Alkyl), phenyl or 5~6 unit's heteroaryls, wherein phenyl and 5~6 unit's heteroaryls are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls optionally replaces；Preferably, R^gSelected from-C (O)-NH (C₁-C₄Alkyl), phenyl or pyridyl group, wherein phenyl and pyridyl group are independently selected by one or more from halogen, hydroxyl, cyano, C each independently_1-6The C that alkyl, halogen replace_1-6The group of alkyl, cyclopropyl or 5~6 unit's heteroaryls optionally replaces；It is highly preferred that R^gSelected from-C (O)-NH (C₁-C₄Alkyl), phenyl,
Compound as described in any one of claim 1-18, wherein structural unitIt is selected from -CH₂NHR⁴、-CH₂OR⁴、-CH₂CH₂C (=O) NHR⁴,-C (=O) NHR⁴,-C (=O) NHC (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴、-CH₂OC (=O) NHR⁴、-CH₂CH₂NHC (=O) OR⁴、-CH₂NHC (=O) NHR⁴,-NHC (=O) NHR⁴,-NHC (=O) OR⁴、-CH(CH₃) NHC (=O) NHR⁴、-CH₂N(CH₃) C (=O) NHR⁴、-CH₂NHC (=O) N (CH₃)R⁴、-CH₂NHC(NH₂)=NR⁴Or-CH₂NHC (=O) NHC (=O) R⁴, whereinOptionally replaced by methyl or cyclopropyl, it is preferable that structural unitSelected from-CH₂NHR⁴、-CH₂OR⁴,-C (=O) NHR⁴、-CH₂NHC (=O) R⁴、-CH₂NHC (=O) OR⁴、-CH₂NHCH₂CH₂OR⁴Or-CH₂NHC (=O) NHR⁴。
Compound as described in any one of claim 1-19, wherein R⁴Selected from hydrogen, cyano, hydroxyl, C_1-4Alkyl, C_2-4Alkenyl, 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl or 5~9 unit's heteroaryls, wherein C_1-4Alkyl and C_2-4Alkenyl is optionally replaced by 1,2 or 3 group independently selected from halogen, hydroxyl, cyano ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls each independently, wherein 3~6 yuan of naphthenic base, 3~6 membered heterocycloalkyls, phenyl and 5~9 unit's heteroaryls are each independently by 1,2 or 3 independently selected from halogen, hydroxyl, cyano, C_1-6The C that alkyl, halogen replace_1-6Alkyl ,=O, 3~6 yuan of naphthenic base or 5~6 unit's heteroaryls group optionally replace；Preferably, R⁴Selected from hydrogen, cyano, hydroxyl, methyl, ethyl, tert-butyl, isopropyl, vinyl, cyclopropyl, phenyl, pyridyl group, pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, isothiazolyl or azetidinyl, wherein methyl, ethyl, tert-butyl, isopropyl and vinyl are each independently by 1, 2 or 3 independently selected from halogen, hydroxyl, cyano, the group of cyclopropyl or pyridyl group optionally replaces, wherein cyclopropyl, phenyl, pyridyl group, pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, isothiazolyl and azetidinyl are each independently by 1, 2 or 3 independently selected from halogen, hydroxyl, cyano, methyl, the methyl that halogen replaces,=O or the group of cyclopropyl optionally replace；It is highly preferred that R⁴Selected from hydrogen, cyano, hydroxyl, methyl, the methyl that pyridine replaces, cyano methyl, cyclopropyl methyl, ethyl, fluorine-substituted ethyl, tert-butyl, isopropyl, vinyl, cyclopropyl, fluorine-substituted cyclopropyl, the cyclopropyl that cyano replaces, methyl substituted cyclopropyl, the cyclopropyl that 1- methyl fluoride replaces, phenyl, p-fluorophenyl, rubigan, pyridyl group, fluorine-substituted pyridyl group, pyrimidine radicals, methyl substituted pyrimidine radicals, purine radicals, imidazole radicals, oxazolyl, isoxazolyl, tetrahydrofuran base, thiazolyl, azetidinyl, the azetidinyl that hydroxyl replaces, fluorine-substituted azetidinyl or methyl substituted azetidinyl；It is more preferred still that R⁴Selected from hydrogen, cyano, hydroxyl, methyl,Ethyl,Tert-butyl, isopropyl, vinyl, cyclopropyl, Phenyl, p-fluorophenyl, rubigan,
Compound as claimed in claim 1 or 5, wherein R⁶Selected from C_1-6Alkyl and 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group to form 5 member rings；Preferably, R⁶Selected from C_1-4Alkyl and 3~6 yuan of naphthenic base or R⁶With L⁵It is connected with each other or is commonly connected on same group, so that structural unitFor structural unitIt is highly preferred that R⁶Selected from methyl, ethyl, propyl, isopropyl and cyclopropyl or R⁶With L⁵It is commonly connected on same group, so that structural unit For structural unit
Compound as claimed in claim 1 or 5, wherein R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, the pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl and thiazolyl are each independently by 1,2,3,4 or 5 independently selected from halogen ,-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace；Preferably, above-mentioned R⁷Selected from pyrrolidinyl, piperidyl, pyridyl group, THP trtrahydropyranyl or thiazolyl, the pyrrolidinyl and piperidyl are each independently by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup optionally replace, the pyridyl group optionally by halogen (preferably chlorine) replace；It is highly preferred that above-mentioned R⁷Selected from piperidyl, the piperidyl is optionally by 1,2,3,4 or 5 independently selected from-R^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup replace；It is more preferred still that above-mentioned R⁷Selected from piperidyl, the piperidyl is optionally selected from-R by 1^f,-C (=O) R^f,-C (=O) OR^fOr-C (=O) NHR^fGroup replace.
Compound as claimed in claim 1 or 5, wherein R^fSelected from C_1-6Alkyl, 3~6 yuan of naphthenic base, 5~6 unit's heteroaryls or phenyl, the C_1-6Alkyl is optionally replaced by one or more cyano；Preferably, R^fMethyl, pyrimidine radicals or the phenyl replaced selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, imidazole radicals, oxazolyl, isoxazolyl, cyano；It is highly preferred that R^fSelected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, phenyl,
Compound as claimed in claim 1 or 5, wherein R⁷It is selected from:
Compound shown in compound as described in any one of claim 1-24, formula of (I) and general formula (II) is selected from

Or its tautomer or its pharmaceutically acceptable salt.
Pharmaceutical composition contains compound described in any one of claim 1-25, its tautomer or pharmaceutically acceptable salt as work Property ingredient and one or more pharmaceutically acceptable carriers, excipient or medium.
The method for treating the disease of mammal mediated by cccDNA, including to the mammal for needing the treatment, it is preferred that the mankind, pharmaceutical composition described in compound described in any one of claim 1-25 of therapeutically effective amount, its tautomer or its pharmaceutically acceptable salt or claim 26 is applied.
Purposes in the drug of disease of the pharmaceutical composition described in compound described in any one of claim 1-25, its tautomer or its pharmaceutically acceptable salt or claim 26 in preparation for preventing or treating cccDNA mediation.
The purposes in the disease that cccDNA is mediated is being prevented or treated to pharmaceutical composition described in compound described in any one of claim 1-25, its tautomer or its pharmaceutically acceptable salt or claim 26.
Pharmaceutical composition described in compound described in any one of claim 1-25 of disease for preventing or treating cccDNA mediation, its tautomer or its pharmaceutically acceptable salt or claim 26.
Compound or pharmaceutical composition described in purposes described in as claimed in claim 27 method, claim 28 or 29 and claim 30, wherein the disease is virus B hepatitis.